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Polycythemia Vera and Essential Thrombocythemia
From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
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From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
From the Columbia University Medical Center, New York, NY (Dr. Falchi), and the University of Texas MD Anderson Cancer Center, Houston, TX (Dr. Verstovsek).
ABSTRACT
- Objective: To review the clinical aspects and current practices in the management of polycythemia vera (PV) and essential thrombocythemia (ET).
- Methods: Review of the literature.
- Results: PV and ET are rare chronic myeloid disorders. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/acute myeloid leukemia (AML) transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, interferons, or anagrelide (for patients with ET). Ruxolitinib was recently approved for PV after hydroxyurea failure. PV/ET transformation into myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment of leukemic transformation of myeloproliferative neoplasms (MPN LT) follows recommendations set forth for primary myelofibrosis and AML.
- Conclusion: With appropriate management, patients with PV and ET typically enjoy a long survival and near-normal quality of life. Transformation into myelofibrosis or AML cannot be prevented by current therapies, however. Treatment results with MPN LT are generally poor and novel strategies are needed to improve outcomes.
Key words: myeloproliferative neoplasms; myelofibrosis; leukemic transformation.
Polycythemia vera (PV) and essential thrombocythemia (ET), along with primary myelofibrosis (PMF), belong to the group of Philadelphia-negative myeloproliferative neoplasms (MPN). All these malignancies arise from the clonal proliferation of an aberrant hematopoietic stem cell, but are characterized by distinct clinical phenotypes [1,2]. Although the clinical course of PV and ET is indolent, it can be complicated by thrombohemorrhagic episodes and/or evolution into myelofibrosis and/or acute myeloid leukemia (AML) [3]. Since vascular events are the most frequent life-threatening complications of PV and ET, therapeutic strategies are aimed at reducing this risk. Treatment may also help control other symptoms associated with the disease [4]. No therapy has been shown to prevent evolution of PV or ET into myelofibrosis or AML. The discovery of the Janus kinase 2 (JAK2)/V617F mutation in most patients with PV and over half of those with ET (and PMF) [5,6] has opened new avenues of research and led to the development of targeted therapies, such as the JAK1/2 inhibitor ruxolitinib, for patients with MPN [7,8].
Epidemiology
PV and ET are typically diagnosed in the fifth to seventh decade of life [9]. Although these disorders are generally associated with a long clinical course, survival of patients with PV or ET may be shorter than that of the general population [10–13]. Estimating the incidence and prevalence of MPN is a challenge because most patients remain asymptomatic for long periods of time and do not seek medical attention [13]. The annual incidence rates of PV and ET are estimated at 0.01 to 2.61 and 0.21 to 2.53 per 100,000, respectively. PV occurs slightly more frequently in males, whereas ET has a predilection for females [14]. Given the long course and low mortality associated with these disorders, the prevalence rates of PV and ET are significantly higher than the respective incidence rates: up to 47 and 57 per 100,000, respectively [15–17].
Molecular Pathogenesis
In 2005 researchers discovered a gain-of-function mutation of the JAK2 gene in nearly all patients with PV and more than half of those with ET and PMF [5,6,18,19]. JAK2 is a non-receptor tyrosine kinase that plays a central role in normal hematopoiesis. Substitution of a valine for a phenylalanine at codon 617 (ie, V617F) leads to its constitutive activation and signaling through the JAK-STAT pathway [5,6,18,19]. More rarely (and exclusively in patients with PV), JAK2 mutations involve exon 12 [20–22]. The vast majority of JAK2-negative ET patients harbor mutations in either the myeloproliferative leukemia (MPL) gene, which encodes the thrombopoietin receptor [23–25], or the calreticulin (CALR) gene [26,27], which encodes for a chaperone protein that plays a role in cellular proliferation, differentiation, and apoptosis [28]. Both the MPL and CALR mutations ultimately result in the constitutive activation of the JAK-STAT pathway. Thus, JAK2, MPL, and CALR alterations are collectively referred to as driver mutations. Moreover, because these mutations affect the same oncogenic pathway (ie, JAK-STAT), they are almost always mutually exclusive in a given patient. Patients with ET (or myelofibrosis) who are wild-type for JAK2, MPL, and CALR are referred to as having “triple-negative” disease. Many recurrent non-driver mutations are also found in patients with MPN. These are not exclusive of each other (ie, patients may have many at the same time) and involve for example ten-eleven translocation-2 (TET2), additional sex combs like 1 (ASXL1), enhancer of zeste homolog 2 (EZH2), isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH1/2), and DNA methyltransferase 3A (DNMT3A) genes, among others [29]. The biologic and prognostic significance of these non-driver alterations remain to be fully defined in ET and PV.
Diagnostic Criteria
Diagnostic criteria for PV and ET according to the World Health Organization (WHO) classification [30] are summarized in Table 1. Criteria for the diagnosis of prefibrotic myelofibrosis are included as well since this entity was formally recognized as separate from ET and part of the PMF spectrum in the 2016 WHO classification of myeloid tumors [30]. Clinically, both PV and ET generally remain asymptomatic for a long time. PV tends to be more symptomatic than ET and can present with debilitating constitutional symptoms (fatigue, night sweats, and weight loss), microvascular symptoms (headache, lightheadedness, acral paresthesias, erythromelalgia, atypical chest pain, and pruritus) [31], or macrovascular accidents (larger vein thrombosis, stroke, or myocardial ischemia) [32]. ET is often diagnosed incidentally, but patients can suffer from similar general symptoms and vascular complications. Causes of secondary absolute erythrocytosis (altitude, chronic hypoxemia, heavy smoking, cardiomyopathy, use of corticosteroids, erythropoietin, or other anabolic hormones, familial or congenital forms) or thrombocytosis (iron deficiency, acute blood loss, trauma or injury, acute coronary syndrome, systemic autoimmune disorders, chronic kidney failure, other malignancies, splenectomy) should be considered and appropriately excluded. Once the diagnosis is made, symptom assessment tools such as the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) [33] or the abbreviated version, the MPN-SAF Total Symptom Score (MPN-SAF TSS) [34], are generally used to assess patients’ symptom burden and response to treatment in everyday practice.
Risk Stratification
Thrombohemorrhagic events, evolution into myelofibrosis, and leukemic transformation (LT) are the most serious complications in the course of PV or ET. Only thrombohemorrhagic events are, at least partially, preventable. Arterial or venous thrombotic complications are observed at rates of 1.8 to 10.9 per 100 patient-years in PV (arterial thrombosis being more common than venous) and 0.74 to 7.7 per 100 patient-years in ET, depending on the risk group [35] and the presence of other factors (see below).
The risk stratification of patients with PV is based on 2 factors: age ≥ 60 years and prior history of thrombosis. If either is present, the patient is assigned to the high-risk category, whereas if none is present the patient is considered at low risk [36]. In addition, high hematocrit [37] and high white blood cell (WBC) count [38], but not thrombocytosis, have been associated with the development of vascular complications. In one study, the risk of new arterial thrombosis was increased by the presence of leukoerythroblastosis, hypertension, and prior arterial thrombosis, while karyotypic abnormalities and prior venous thrombosis were predictors of new venous thrombosis [39]. Another emerging risk factor for thrombosis in patients with PV is high JAK2 allele burden (ie, the normal-to-mutated gene product ratio), although the evidence supporting this conclusion is equivocal [40].
Traditionally, in ET patients, the thrombotic risk was assessed using the same 2 factors (age ≥ 60 years and prior history of thrombosis), separating patients into low- and high-risk groups. However, the prognostication of ET patients has been refined recently with the identification of new relevant factors. In particular, the impact of JAK2 mutations on thrombotic risk has been thoroughly studied. Clinically, the presence of JAK2V617F is associated with older age, higher hemoglobin and hematocrit, lower platelet counts, more frequent need for cytoreductive treatment, and greater tendency to evolve into PV (a rare event) [41,42]. Many [41,43–46], but not all [47–51], studies suggested a correlation between JAK2 mutation and risk of both arterial and venous thrombosis. Although infrequent, a JAK2V617F homozygous state (ie, the mutation is present in both alleles) might confer an even higher thrombotic risk [52]. Moreover, the impact of the JAK2 mutation on vascular events persists over time [53], particularly in patients with high or unstable mutation burden [54]. Based on JAK2V617F’s influence on the thrombotic risk of ET patients, a new prognostic score was proposed, the International Prognostic Score for ET (IPSET)-thrombosis (Table 2). The revised version of this model is currently endorsed by the National Comprehensive Cancer Network and divides patients into 4 risk groups: high, intermediate, low, and very low. Treatment recommendations vary according to the risk group (as described below) [55].
Other thrombotic risk factors have been identified, but deemed not significant enough to be included in the model. Cardiovascular risk factors (hypercholesterolemia, hypertension, smoking, diabetes mellitus) can increase the risk of vascular events [56–59], as can splenomegaly [60] and baseline or persistent leukocytosis [61–63]. Thrombocytosis has been correlated with thrombotic risk in some studies [64–68], whereas others did not support this conclusion and/or suggested a lower rate of thrombosis and, in some cases, increased risk of bleeding in ET patients with platelet counts greater than 1000 × 103/μL (due to acquired von Willebrand syndrome) [51,61,63,68,69].
CALR mutations tend to occur in younger males with lower hemoglobin and WBC count, higher platelet count, and greater marrow megakaryocytic predominance, as compared to JAK2 mutations [26,27,70–72]. The associated incidence of thrombosis was less than 10% at 15 years in patients with CALR mutations, lower than the incidence reported for ET patients with JAK2V617F mutations [73]. The presence of the mutation per se does not appear to affect the thrombotic risk [74–76]. Information on the thrombotic risk associated with MPL mutations or a triple-negative state is scarce. In both instances, however, the risk appears to be lower than with the JAK2 mutation [73,77–79].
Venous thromboembolism (VTE) in patients with PV or ET may occur at unusual sites, such as the splanchnic or cerebral venous systems [80]. Risk factors for unusual VTE include younger age [81], female gender (especially with concomitant use of oral contraceptive pills) [82], and splenomegaly/splenectomy [83]. JAK2 mutation has also been associated with thrombosis at unusual sites. However, the prevalence of MPN or JAK2V617F in patients presenting with splanchnic VTE has varied [80]. In addition, MPN may be occult (ie, no clinical or laboratory abnormalities) in around 15% of patients [84]. Screening for JAK2V617F and underlying MPN is recommended in patients presenting with isolated unexplained splanchnic VTE. Treatment entails long-term anticoagulation therapy. JAK2V617F screening in patients with nonsplanchnic VTE is not recommended, as its prevalence in this group is low (< 3%) [85,86].
Risk-Adapted Therapy
Low-Risk PV
All patients with PV should receive counseling to mitigate cardiovascular risk factors, including smoking cessation, lifestyle modifications, and lipid-lowering therapy, as indicated. Furthermore, all PV patients should receive acetylsalicylic acid (ASA) to decrease their risk for thrombosis and control vasomotor symptoms [55,87]. Aspirin 81 to 100 mg daily is the preferred regimen because it provides adequate antithrombotic effect without the associated bleeding risk of higher-dose aspirin [88]. Low-risk PV patients should also receive periodic phlebotomies to reduce and maintain their hematocrit below 45%. This recommendation is based on the results of the Cytoreductive Therapy in Polycythemia Vera (CYTO PV) randomized controlled trial. In that study, patients receiving more intense therapy to maintain the hematocrit below 45% had a lower incidence of cardiovascular-related deaths or major thrombotic events than those with hematocrit goals of 45% to 50% (2.7% versus 9.8%) [89]. Cytoreduction is an option for low-risk patients who do not tolerate phlebotomy or require frequent phlebotomy, or who have disease-related bleeding, severe symptoms, symptomatic splenomegaly, or progressive leukocytosis [38].
High-Risk PV
Patients older than 60 years and/or with a history of thrombosis should be considered for cytoreductive therapy in addition to the above measures. Frontline cytoreductive therapies include hydroxyurea or interferon (IFN)-alfa [87]. Hydroxyurea is a potent ribonucleotide reductase inhibitor that interferes with DNA repair and is the treatment of choice for most high-risk patients with PV [90]. In a small trial, hydroxyurea reduced the risk of thrombosis compared with historical controls treated with phlebotomy alone [91]. Hydroxyurea is generally well tolerated; common side effects include cytopenias, nail changes, and mucosal and/or skin ulcers. Although never formally proven to be leukemogenic, this agent should be used with caution in younger patients [87]. Indeed, in the original study, the rates of transformation were 5.9% and 1.5% for patients receiving hydroxyurea and phlebotomy alone [92], respectively, although an independent role for hydroxyurea in LT was not supported in the much larger European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP) study [93]. Approximately 70% of patients will have a sustained response to hydroxyurea [94], while the remaining patients become resistant to or intolerant of the drug. Resistant individuals have a higher risk of progression to acute leukemia and death [95].
IFN-alfa is a pleiotropic antitumor agent that has found application in many types of malignancies [96] and is sometimes employed as treatment for patients with newly diagnosed high-risk PV. Early studies showed responses in up to 100% of cases [97,98], albeit at the expense of a high discontinuation rate due to adverse events, such as flu-like symptoms, fatigue, and neuropsychiatric manifestations [99]. A newer formulation of the drug obtained by adding a polyethylene glycol (PEG) moiety to the native IFN-alfa molecule (PEG-IFN alfa) was shown to have a longer half-life, greater stability, less immunogenicity, and, potentially, better tolerability [100]. Pilot phase 2 trials of PEG-IFN-alfa-2a demonstrated its remarkable activity, with symptomatic and hematologic responses seen in most patients (which, in some cases, persisted beyond discontinuation), and reasonable tolerability, with long-term discontinuation rates of 20% to 30% [101–103]. In some patients, JAK2V617F became undetectable over time [104]. Results of 2 ongoing trials, MDP-RC111 (single-arm study, PEG-IFN-alfa-2a in high-risk PV or ET [NCT01259817]) and MPD-RC112 (randomized controlled trial, PEG-IFN-alfa-2a versus hydroxyurea in the same population [NCT01258856]), will shed light on the role of PEG-IFN-alfa in the management of patients with high-risk PV or ET. In two phase 2 studies of PEG-IFN-alfa-2b, complete responses were seen in 70% to 100% of patients and discontinuation occurred in around a third of cases [105,106]. A new, longer-acting formulation of PEG-IFN-alfa-2a (peg-proline INF-alfa-2b, AOP2014) is also undergoing clinical development [107,108].
The approach to treatment of PV based on thrombotic risk level is illustrated in Figure 1.
Very Low- and Low-Risk ET
Individuals with ET should undergo rigorous cardiovascular risk management and generally receive ASA to decrease their thrombotic risk and improve symptom control. Antiplatelet therapy may not be warranted in patients with documented acquired von Willebrand syndrome, with or without extreme thrombocytosis, or in those in the very low-risk category according to the IPSET-thrombosis model [55,87]. The risk/benefit ratio of antiplatelet agents in patients with ET at different thrombotic risk levels was assessed in poor-quality studies and thus remains highly uncertain. Platelet-lowering agents are sometimes recommended in patients with low-risk disease who have platelet counts ≥ 1500 × 103/μL, due to the potential risk of acquired von Willebrand syndrome and a risk of bleeding (this would require stopping ASA) [109]. Cytoreduction may also be used in low-risk patients with progressive symptoms despite ASA, symptomatic or progressive splenomegaly, and progressive leukocytosis.
Intermediate-Risk ET
This category includes patients older than 60 years, but without thrombosis or JAK2 mutations. These individuals would have been considered high risk (and thus candidates for cytoreductive therapy) according to the traditional risk stratification. Guidelines currently recommend ASA as the sole therapy for these patients, while reserving cytoreduction for those who experience thrombosis (ie, become high-risk) or have uncontrolled vasomotor or general symptoms, symptomatic splenomegaly, symptomatic thrombocytosis, or progressive leukocytosis.
High-Risk ET
For patients with ET in need of cytoreductive therapy (ie, those with prior thrombosis or older than 60 years with a JAK2V617F mutation), first-line options include hydroxyurea, IFN, and anagrelide. Hydroxyurea remains the treatment of choice in most patients [110]. In a seminal study, 114 patients with ET were randomly assigned to either observation or hydroxyurea treatment with the goal of maintaining the platelet count below 600 × 103/μL. At a median follow-up of 27 months, patients in the hydroxyurea group had a lower thrombosis rate (3.6% versus 24%, P = 0.003) and longer thrombosis-free survival, regardless of the use of antiplatelet drugs [64].
Anagrelide, a selective inhibitor of megakaryocytic differentiation and proliferation, was compared with hydroxyurea in patients with ET in 2 randomized trials. In the first (n = 809), the group receiving anagrelide had a higher risk of arterial thrombosis, major bleeding, and fibrotic evolution, but lower incidence of venous thrombosis. Hydroxyurea was better tolerated, mainly due to anagrelide-related cardiovascular adverse events [111]. As a result of this study, hydroxyurea is often preferred to anagrelide as frontline therapy for patients with newly diagnosed high-risk ET. In the second, more recent study (n = 259), however, the 2 agents proved equivalent in terms of major or minor arterial or venous thrombosis, as well as discontinuation rate [112]. The discrepancy between the 2 trials may be partly explained by the different ET diagnostic criteria used, with the latter only enrolling patients with WHO-defined true ET and the former utilizing Polycythemia Vera Study Group-ET diagnostic criteria that included patients with increases in other blood counts or varying degrees of marrow fibrosis.
Interferons were studied in ET in parallel with PV. PEG-IFN-alfa-2a proved effective in patients with ET, with responses observed in 80% of patients [103]. PEG-IFN- alfa-2b produced similar results, with responses in 70% to 90% of patients in small studies and discontinuation observed in 20% to 38% of cases [105,106,113]. Because the very long-term leukemogenic potential of hydroxyurea has remained somewhat uncertain, anagrelide or IFN might be preferable choices in younger patients.
The approach to treatment of ET based on thrombotic risk level is illustrated in Figure 2.
Assessing Response to Therapy
For both patients with PV and ET the endpoint of treatment set forth for clinical trials has been the achievement of a clinicohematologic response. However, studies have failed to show a correlation between response and reduction of the thrombohemorrhagic risk [114]. Therefore, proposed clinical trial response criteria were revised to include absence of hemorrhagic or thrombotic events as part of the definition of response (Table 3) [94].
Approach to Patients Refractory to or Intolerant of First-line Therapy
According to the European LeukemiaNet recommendations, an inadequate response to hydroxyurea in patients with PV (or myelofibrosis) is defined as a need for phlebotomy to maintain the hematocrit below < 45%, the platelet count > 400 × 103/μL, and a WBC count > 10,000/μL, or failure to reduce splenomegaly > 10 cm by > 50% at a dose of ≥ 2 g/day or maximum tolerated dose. Historically, treatment options for patients with PV or ET who failed first-line therapy (most commonly hydroxyurea) have included alkylating agents, such as busulfan, chlorambucil, pipobroman, and phosphorus (P)-32. However, the use of these drugs is limited by the associated risk of LT [93,115,116]. IFN (or anagrelide for ET) is often considered in patients previously treated with hydroxyurea, and vice versa.
Ruxolitinib is a JAK1 and JAK2 inhibitor currently approved for the treatment of PV patients refractory to or intolerant of hydroxyurea [7]. Following promising results of a phase 2 trial [117], ruxolitinib 10 mg twice daily was compared with best available therapy in the pivotal RESPONSE trial (n = 222). Ruxolitinib proved superior in achieving hematocrit control, reduction of spleen volume, and improvement of symptoms. Grade 3-4 hematologic toxicity was infrequent and similar in the 2 arms [118]. In addition, longer follow-up of that study suggested a lower rate of thrombotic events in patients receiving ruxolitinib (1.8 versus 8.2 per 100 patient-years) [119]. In a similarly designed randomized phase 3 study in PV patients without splenomegaly (RESPONSE-2), more patients in the ruxolitinib arm had hematocrit reduction without an increase in toxicity. Based on the results of these studies, ruxolitinib can be considered a standard of care for second-line therapy in this post-hydroxyurea patient population [120]. Ruxolitinib is also being tested in patients with high-risk ET who have become resistant to, or were intolerant of hydroxyurea, but currently has no approved indication in this setting [121,122]. Common side effects of ruxolitinib include cytopenias (especially anemia), increased risk of infections, hyperlipidemia, and increased risk of non-melanoma skin cancer.
Novel agents that have been studied in patients with PV and ET are histone deacetylase inhibitors, murine double minute 2 (MDM2, or HDM2 for their human counterpart) inhibitors (which restore the function of p53), Bcl-2 homology domain 3 mimetics such as navitoclax and venetoclax, and, for patients with ET, the telomerase inhibitor imetelstat [123].
Disease Evolution
Post-PV/Post-ET Myelofibrosis
Diagnostic criteria for post-PV and post-ET myelofibrosis are outlined in Table 4. Fibrotic transformation represents a natural evolution of the clinical course of PV or ET. It occurs in up to 15% and 9% of patients with PV and ET, respectively, in western countries [124]. The true percentage of ET patients who develop myelofibrosis is confounded by the inclusion of prefibrotic myelofibrosis cases in earlier series. The survival of patients who develop myelofibrosis is shortened compared to those who do not. In patients with PV, risk factors for myelofibrosis evolution include advanced age, leukocytosis, JAK2V617F homozygosity or higher allele burden, and hydroxyurea therapy. Once post-PV myelofibrosis has occurred, hemoglobin < 10 g/dL, platelet count < 100 × 103/μL, and WBC count > 30,000/μL are associated with worse outcomes [125]. In patients with ET, risk factors for myelofibrosis transformation include age, anemia, bone marrow hypercellularity and increased reticulin, increased lactate dehydrogenase, leukocytosis, and male gender. The management of post-PV/post-ET myelofibrosis recapitulates that of PMF.
Leukemic Transformation
The presence of more than 20% blasts in peripheral blood or bone marrow in a patient with MPN defines LT. This occurs in up to 5% to 10% of patients and may or may not be preceded by a myelofibrosis phase [126]. In cases of extramedullary transformation, a lower percentage of blasts can be seen in the bone marrow compared to the peripheral blood. The pathogenesis of LT has remained elusive, but it is believed to be associated with genetic instability, which facilitates the acquisition of additional mutations, including those of TET2, ASXL1, EZH2 DNMT3, IDH1/2, and TP53 [127].
Clinical risk factors for LT include advanced age, karyotypic abnormalities, prior therapy with alkylating agents or P-32, splenectomy, increased peripheral blood or bone marrow blasts, leukocytosis, anemia, thrombocytopenia, and cytogenetic abnormalities. Hydroxyurea, IFN, and ruxolitinib have not been shown to have leukemogenic potential thus far. Prognosis of LT is uniformly poor and patient survival rarely exceeds 6 months.
There is no standard of care for MPN LT. Treatment options range from low-intensity regimens to more aggressive AML-type induction chemotherapy. No strategy appears clearly superior to others [128]. Hematopoietic stem cell transplantation is the only therapy that provides clinically meaningful benefit to patients [129], but it is applicable only to a minority of patients with chemosensitive disease and good performance status [130]. Notable experimental approaches to MPN LT include hypomethylating agents, such as decitabine [131] or azacytidine [132], with or without ruxolitinib [133–135].
Conclusion
PV and ET are rare, chronic myeloid disorders. Patients typically experience a long clinical course and enjoy near-normal quality of life if properly managed. The 2 most important life-limiting complications of PV and ET are thrombohemorrhagic events and myelofibrosis/AML transformation. Vascular events are at least in part preventable with counseling on risk factors, phlebotomy (for patients with PV), antiplatelet therapy, and cytoreduction with hydroxyurea, IFNs, or anagrelide (for patients with ET). In addition, ruxolitinib was recently approved for PV patients after hydroxyurea failure. PV/ET transformation in myelofibrosis or AML is part of the natural history of the disease and no therapy has been shown to prevent it. Treatment follows recommendations set forth for PMF and AML, but results are generally poorer and novel strategies are needed to improve outcomes.
Corresponding author: Lorenzo Falchi, MD, Columbia University Medical Center, New York, NY.
Financial disclosures: None.
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110. Cortelazzo S, Finazzi G, Ruggeri M, et al. Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. N Engl J Med 1995;332:1132–7.
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112. Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood 2013;121:1720–8.
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117. Verstovsek S, Passamonti F, Rambaldi A, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014;120: 513–20.
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127. Rampal R, Mascarenhas J. Pathogenesis and management of acute myeloid leukemia that has evolved from a myeloproliferative neoplasm. Curr Opin Hematol 2014;21:65–71.
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132. Thepot S, Itzykson R, Seegers V, et al. Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM). Blood 2010;116:3735–42.
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134. Rampal RK, Mascarenhas JO, Kosiorek HE, et al. Safety and efficacy of combined ruxolitinib and decitabine in patients with blast-phase MPN and post-MPN AML: results of a phase I study (Myeloproliferative Disorders Research Consortium 109 trial) [abstract]. Blood 2016;128. Abstract 1124.
135. Bose P, Verstovsek S, Gasior Y, et al. Phase I/II study of ruxolitinib (RUX) with decitabine (DAC) in patients with post-myeloproliferative neoplasm acute myeloid leukemia (post-MPN AML): phase I results [abstract]. Blood 2016;128. Abstract 4262.
Bacteremic sepsis in ALL linked to later cognitive issues
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
Bacteremic sepsis during acute lymphoblastic leukemia (ALL) treatment may contribute to neurocognitive dysfunction later in life, results of a cohort study suggest.
Pediatric ALL survivors who had sepsis while on treatment performed worse on measures of intelligence, attention, executive function, and processing speed than survivors with no sepsis history, according to study results.
Links between sepsis and impaired neurocognitive function found in this study have “practice-changing implications” for cancer survivors, investigators reported in JAMA Pediatrics.
“Prevention of infection, early recognition and appropriate management of sepsis, and preemptive neurocognitive interventions should be prioritized, because these might prevent or ameliorate neurologic damage,” said Joshua Wolf, MBBS, of St. Jude Children’s Research Hospital, Memphis, and the coauthors of the report.
The study included 212 children who, at a median age of 5 years, had received risk-adapted chemotherapy for ALL with no hematopoietic cell transplant or cranial irradiation.
Sixteen of the patients (7.5%) had a history of bacteremic sepsis during ALL therapy, according to retrospectively obtained data.
As a part of the study, all participants participated in neurocognitive testing, which was done at a median of 7.7 years after diagnosis.
Patients with a history of bacteremic sepsis performed poorly on multiple measures of neurocognitive function, as compared with all other participants, according to results of analyses that were adjusted for multiple potentially confounding factors, such as age, race, and leukemia risk category.
Although not all neurocognitive measures were significantly different between groups, survivors with a sepsis history performed worse on evaluations of spatial planning (difference, 0.78; 95% confidence interval, 0.57-1.00), verbal fluency (0.38; 95% CI, 0.14-0.62), and attention (0.63; 95% CI, 0.30-0.95), among other measures, investigators said.
This is believed to be the first published study looking at potential links between sepsis during ALL treatment and long-term neurocognitive dysfunction, investigators said. However, similar observations have been made in other patient populations, they added.
Exactly how sepsis might lead to neurocognitive deficits remains unclear. “In the population of children with cancer, these mechanisms might be augmented by increased blood-brain barrier permeability to neurotoxic chemotherapy drugs,” they said in their report.
Further study is needed to look at potential brain injury mechanisms, and to validate the current findings in other ALL patient cohorts, they concluded.
The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
SOURCE: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
FROM JAMA PEDIATRICS
Key clinical point:
Major finding: ALL survivors with a sepsis history performed worse than did those with no sepsis history on evaluations of spatial planning (difference, 0.78), verbal fluency (0.38), and attention (0.63).
Study details: Prospective cohort study of 212 ALL survivors who underwent neurocognitive testing at a median of nearly 8 years after diagnosis.
Disclosures: The study was supported by the National Institute of Mental Health, the National Cancer Institute, and the American Lebanese Syrian Associated Charities. The researchers reported having no conflicts of interest.
Source: Cheung YT et al. JAMA Pediatr. 2018 Sep 24. doi:10.1001/jamapediatrics.2018.2500.
Adjuvant Pembrolizumab Improves Progression-Free Survival in Stage III Melanoma
Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.
Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
Study Overview
Objective. To evaluate pembrolizumab as adjuvant therapy for patients with resected, high-risk stage III melanoma.
Design. International randomized phase 3 trial.
Setting and participants. This multicenter international trial enrolled patients who had histologically confirmed cutaneous melanoma with regional lymph node metastasis (stage IIIA, IIIB or IIIC with no in-transit metastases). Patients had to have undergone a complete regional lymphadenectomy within 13 weeks before the start of treatment. Exclusion criteria were: ECOG performance status score > 1, autoimmune disease, current steroid use, and prior systemic therapy for melanoma. All tumor samples from melanoma-positive lymph nodes were required to be sent to the central lab for evaluation of programmed death ligand 1 (PD-L1) expression; PD-L1 positivity was defined as a tumor proportion score (TPS) ≥ 1%.
Intervention. Patients were randomized in a 1:1 fashion and stratified according to stage and geographic region. Local pharmacies were aware of trial-group assignments. Patients received either an intravenous infusion of pembrolizumab 200 mg or placebo every 3 weeks for a total of 18 doses or until disease recurrence or unacceptable toxicity occurred. If recurrence was detected, patients were able to cross over.
Main outcome measures. The primary outcome was recurrence-free survival (RFS) in the intention-to-treat population and in the subgroup of PD-L1–positive patients. Secondary endpoints included distant metastasis–free survival, overall survival (OS), safety, and quality of life.
Results. A total of 1019 patients were recruited from 123 centers in 23 countries: 514 were assigned to the pembrolizumab group and 505 were assigned to the placebo group. In the pembrolizumab group, 70 patients (13.8%) discontinued treatment because of an adverse event; in 66 patients of these patients the event was deemed drug-related. In the placebo group, 11 (2.2%) patients discontinued treatment due to an adverse event. Discontinuation due to disease recurrence was seen in 109 (21%) patients in the pembrolizumab group and 179 (35.7%) patients in the placebo group. The median duration of follow up was 15 months. In the overall intention-to-treat population, the 12-month RFS rate was 75.4% in the pembrolizumab group versus 61% in the placebo group (P < 0.001). At 18 months the RFS rates were 71.4% and 53.2%, respectively. The 18-month incidence of distant metastasis at recurrence was lower in the pembrolizumab group (16.7% vs. 29.7%, hazard ratio [HR] 0.53; 95% confidence interval 0.37 to 0.76). In those who were PD-L1–positive (n = 853), the 12-month RFS rate was 77.1% in the pembrolizumab group versus 62.6% in the placebo group. PD-L1 status had no impact on pembrolizumab efficacy. The benefit of pembrolizumab was noted across all subgroups, and no difference was seen in patients with stage IIIA, IIIB or IIIC disease. The benefit of pembrolizumab was similar in those with macroscopic or microscopic nodal metastasis. BRAF status did not influence RFS between the pembrolizumab and placebo groups.
Adverse events of grade 3 or higher were seen in 14.7% and 3.4% of the pembrolizumab and placebo groups, respectively. Immune-related adverse events of any grade were noted in 37% of patients in the pembrolizumab group. There was 1 pembrolizumab-related death secondary to myositis. Grades 3 or 4 immune-related events in the pembrolizumab group occurred at a low rate, including colitis (2% and 0.2%), hypophysitis (0.6% and 0%), and type 1 diabetes mellitus (1% and 0%).
Conclusion. Adjuvant pembrolizumab for patients with high-risk stage III melanoma significantly improved RFS compared with placebo and should be considered as an option for adjuvant therapy in this patient population.
Commentary
Prior to the development of immune checkpoint inhibitors, high-dose interferon alfa was the sole option for adjuvant therapy in high-risk melanoma. Although adjuvant interferon alfa is associated with improvements in disease-free survival [1], it is also associated with significant toxicity, including myelosuppression, neurologic adverse effects, and hepatotoxicity. The development of checkpoint inhibition represents an important advancement in the management of patients with melanoma. In the previously reported EORTC 18071 trial, Eggermont and colleagues demonstrated that adjuvant therapy with the CTLA-4 antibody ipilimumab improved both RFS (41% vs. 30%) and OS (65% vs. 54%) at 5 years in patients with stage III melanoma [2]. In 2017, Weber and colleagues demonstrated superior RFS (70% vs. 60%) and a lower rate of grade 3 or 4 adverse events with adjuvant nivolumab compared to ipilimumab in the CheckMate-238 trial [3].
In the current article, Eggermont and colleagues present the results of the EORTC 1325/KEYNOTE-054 study comparing the use of the PD-1 antibody pembrolizumab to placebo in the adjuvant setting for stage III melanoma. This study demonstrated a 43% reduced risk of recurrence or death favoring the pembrolizumab group (HR 0.57; P < 0.001). The 12-month RFS was 75.4% in the pembrolizumab arm versus 61% in the placebo arm. Treatment-related adverse events of grade 3 or higher occurred more commonly in the pembrolizumab arm (14.7% vs. 3.4%), with approximately 7% of these patients experiencing a grade 3 or higher immune-related adverse event. The results of this study corroborate prior data on the efficacy of PD-1 inhibitors in melanoma. Also, the investigators assessed RFS based on patient’s PD-L1 status (positivity defined as TPS ≥ 1% ) as a co-primary endpoint, and found consistent efficacy regardless of PD-L1 expression, with a hazard ratio of 0.47 in the 116 patients who had no PD-L1 expression.
Although the results of this study demonstrate a significant increase in RFS associated with adjuvant pembrolizumab therapy, an OS benefit has not yet been demonstrated. As noted, the only adjuvant checkpoint inhibitor trial to demonstrate an OS advantage thus far is the EORTC 18071 study of ipilimumab. However, the toxicity profile of adjuvant ipilimumab makes it an unattractive option compared to the PD-1 inhibitors. Which of the PD-1 inhibitors should be the treatment of choice for adjuvant therapy remains unclear, although it is worth noting that only nivolumab was compared to the best alternate therapy, ipilimumab [3]. It is also important to note that EORTC 1325/KEYNOTE-054 included patients with stage IIIA disease (N1a disease with at least 1 micrometastasis > 1 mm) or stage IIIB or IIIC without in-transit metastases, while CheckMate-238 did not include stage IIIA patients. Thus, for stage IIIA patients pembrolizumab remains the only PD-1 inhibitor with randomized data demonstrating a benefit.
Applications for Clinical Practice
The results from the EORTC 1325/KEYNOTE-054 study demonstrate a 43% reduction in the risk of progression or death with the use of adjuvant pembrolizumab in patients with stage III melanoma. As of now, the only checkpoint inhibitor to demonstrate an improvement in OS is ipilimumab, and whether the RFS benefit of both pembrolizumab and nivolumab will translate into an OS benefit is yet to be demonstrated.
—Daniel Isaac, DO, MS
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.
1. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 1996;14:7–17.
2. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med 2016;375:1845–55.
3. Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med 2017;377:1824–35.
Rivaroxaban bonus: Early unmasking of occult GI cancers
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
MUNICH – The increased risk of major GI bleeding documented with dual-antiplatelet therapy using rivaroxaban and aspirin when compared with aspirin alone for vascular protection in the previously reported massive COMPASS trial may turn out to be a blessing in disguise.
“Among COMPASS patients with vascular disease receiving long-term antithrombotic therapy, more than 1 in 5 new diagnoses of cancer are preceded by bleeding. GI and GU bleeding are powerful and relatively specific predictors of new GI and GU cancer diagnoses, respectively, and more than 75% of these cancers diagnosed after bleeding are diagnosed within 6 months of the bleed,” John W. Eikelboom, MD, reported at the annual congress of the European Society of Cardiology.
These findings strongly suggest that rivaroxaban (Xarelto), a direct-acting oral anticoagulant (DOAC), may be unmasking occult GI and GU cancers earlier than the malignancies would otherwise have declared themselves.
“Although overall cancer rates were similar in the three treatment groups [rivaroxaban at 2.5 mg twice daily plus aspirin at 100 mg/day, rivaroxaban monotherapy at 5 mg twice daily, or aspirin alone at 100 mg/day], the early increase in GI bleeding with rivaroxaban-based therapy resulted in earlier diagnosis of GI cancer in these patients. By reducing major cardiovascular events and mortality, the combination of rivaroxaban and aspirin already produces a clear net benefit, and by unmasking GI cancers at an earlier stage, the combination could potentially lead to the added benefit of improved GI cancer outcomes,” commented Dr. Eikelboom, a hematologist at McMaster University in Hamilton, Ont., and lead investigator of the previously published COMPASS trial (N Engl J Med. 2017 Oct 5;377[14]:1319-30).
This possibility that unmasking of occult GI cancer might result in improved survival deserves to be a high research priority in light of the enormous death toll caused by colorectal cancer. Planned longer-term follow-up of the COMPASS participants should be helpful in this regard, he added.
This new COMPASS finding effectively makes a silk purse out of a sow’s ear. When the primary outcomes of COMPASS were announced, many physicians reasoned that if the other commercially available DOACs also outperform warfarin but don’t pose a significantly increased threat of serious bleeding events, why not preferentially turn to them rather than rivaroxaban in patients with high HAS-BLED scores? But now rivaroxaban’s increased GI bleeding risk has begun to look like a potentially important advantage.
As previously reported, COMPASS participants on rivaroxaban plus aspirin had a 3.1% major bleeding rate as defined according to modified International Society on Thrombosis and Hemostasis criteria, for a statistically significant 70% increase in risk, compared with the 1.9% rate in patients on aspirin alone. Rivaroxaban monotherapy also was associated with increased bleeding risk. Of note, most of the excess in bleeding involved GI bleeding, and it was front-loaded during the first year of the trial. Also, reassuringly, there was no increased incidence of intracranial or fatal bleeding in patients on rivaroxaban.
A total of 1,082 patients were diagnosed with a new cancer during 23 months of follow-up. Nearly a quarter (23%) of the new GI cancers and 45% of the new GU cancers were diagnosed after bleeding from those sites.
The incidence of GI cancer diagnosed after GI bleeding was 7.8%, whereas patients with no prior GI bleeding had a mere 0.9% rate of newly diagnosed GI cancer during the study period. Thus, roughly 1 out of every 12 cases of GI bleeding was associated with diagnosis of a new GI cancer, and GI bleeding was associated with a 13-fold increased risk of subsequent GI cancer diagnosis. Put another way, the number of cases of GI bleeding occurring in patients on rivaroxaban that needed to be investigated in order to find one new GI cancer was 12.
Similarly, 13% of COMPASS participants who developed GU bleeding were subsequently diagnosed with a new GU cancer, compared with just 0.3% of subjects without GU bleeding. That translates into an 83.4-fold increased risk of GU cancer in patients with GU bleeding.
In contrast, the incidence of non-GI cancer following a GI bleed was 1.5%, while the rate was 1.0% in patients with no prior GI bleeding.
“That relationship was much weaker, with an odds ratio of 1.77, indicating that the relationship between GI bleeding and GI cancer is not only very strong but it’s rather specific,” according to Dr. Eikelboom.
Of GI cancers associated with a prior major GI bleed, 77% were diagnosed within 6 months following the bleed, as were nearly 89% of GU cancers. Another 9%-10% were diagnosed 6-12 months after the bleeding event.
“The implication for clinical practice is certainly that in patients who have GI or GU bleeding while receiving antithrombotic therapy, we should conduct a vigorous search for underlying cancer in the same organ system,” he concluded.
Discussant Lars C. Wallentin, MD, concurred. He called it a wake-up call for cardiologists to broaden their horizons and recognize that their elderly patients with vascular disease also are at substantial competing risk for major noncardiovascular diseases – and that his colleagues may have an important role to play in earlier cancer diagnoses.
He and his coinvestigators in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) study made a similar point in their investigation of 18,113 patients with atrial fibrillation on oral anticoagulation for stroke protection. In that randomized trial of dabigatran (Pradaxa) versus warfarin, roughly 1 in 12 major GI bleeding events was found to be related to an occult colorectal or gastric cancer (Clin Gastroenterol Hepatol. 2017 May;15[5]:682-90).
“The data are very consistent. The message to cardiologists is that no bleeding should be disregarded in patients on oral anticoagulation,” declared Dr. Wallentin, professor of cardiology at Uppsala (Sweden) University.
COMPASS was sponsored by Bayer. Dr. Eikelboom reported receiving research grants from that company and more than half a dozen others.
REPORTING FROM THE ESC CONGRESS 2018
Key clinical point:
Major finding: Among patients on rivaroxaban, 1 in 12 GI bleeding events was associated with an occult GI cancer.
Study details: This was a secondary analysis looking at cancers in COMPASS, a randomized trial of more than 27,000 patients on rivaroxaban and/or aspirin for vascular prevention.
Disclosures: The presenter reported receiving research grants from Bayer, which sponsored the COMPASS trial.
Researchers propose new acute leukemia subtypes
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
An extensive analysis of mixed phenotype acute leukemia (MPAL) has led to new insights that may have implications for disease classification and treatment.
Researchers believe they have identified new subtypes of MPAL that should be included in the World Health Organization classification for acute leukemia.
Each of these subtypes share genomic characteristics with other acute leukemias, which suggests they might respond to treatments that are already in use.
This research also has shed light on how MPAL evolves and appears to provide an explanation for why MPAL displays characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
“ALL and AML have very different treatments, but MPAL has features of both, so the question of how best to treat patients with MPAL has been challenging the leukemia community worldwide, and long-term survival of patients has been poor,” said study author Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital in Memphis, Tenn.
In the current study, published in Nature, Dr. Mullighan and his colleagues used whole-genome, whole-exome, and RNA sequencing to analyze 115 samples from pediatric patients with MPAL.
The analysis revealed mutations that define the two most common subtypes of MPAL – B/myeloid and T/myeloid – and suggested these subtypes share similarities with other leukemia subtypes.
The researchers found that 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL. In fact, the team said the gene expression profiles of ZNF384r B-ALL and ZNF384r MPAL were indistinguishable.
“That is biologically and clinically important,” Dr. Mullighan said. “The findings suggest the ZNF384 rearrangement defines a distinct leukemia subtype, and the alteration should be used to guide treatment.”
The researchers noted that patients with ZNF384r exhibited higher FLT3 expression than that of patients with other types of B/myeloid or T/myeloid MPAL, so patients with ZNF384r MPAL might respond well to treatment with a FLT3 inhibitor.
This study also showed that cases of B/myeloid MPAL without ZNF384r shared genomic features with other B-ALL subtypes, such as Ph-like B-ALL.
In addition, the analysis showed that T/myeloid MPAL and early T-cell precursor ALL have similar gene expression profiles.
The team identified several genes that were mutated at similar frequencies in T/myeloid MPAL and early T-cell precursor ALL, including WT1, ETV6, EZH2, and FLT3.
WT1 was the most frequently mutated transcription factor gene in T/myeloid MPAL.
Based on these findings, the researchers said the WHO classification of acute leukemia should be updated to include: ZNF384r acute leukemia (either B-ALL or MPAL), WT1-mutant T/myeloid MPAL, and Ph-like B/myeloid MPAL.
This research was supported by the National Cancer Institute, the National Institutes of Health, Cookies for Kids’ Cancer, and other organizations. The researchers reported having no competing interests.
SOURCE: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
FROM NATURE
Key clinical point:
Major finding: In total, 48% of B/myeloid MPAL cases carried rearrangements in ZNF384, a characteristic that is also found in cases of B-cell ALL.
Study details: Whole-genome, -exome, and RNA sequencing of 115 samples from pediatric patients with MPAL.
Disclosures: This research was supported by the National Cancer Institute and other organizations. The researchers reported having no competing interests.
Source: Alexander TB et al. Nature. 2018 Sep 12. doi: 10.1038/s41586-018-0436-0.
ASCO addresses financial barriers to cancer clinical trials
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
The American Society of Clinical Oncology (ASCO) has released a policy statement addressing financial barriers that may prevent cancer patients from participating in clinical trials.
The four main recommendations in ASCO’s policy statement are:
- Payers should create clear, consistent, streamlined, and transparent policies regarding clinical trial coverage.
- Patients should receive easy-to-understand information about potential out-of-pocket costs.
- “Ethically appropriate” financial compensation for out-of-pocket costs should be allowed.
- Researchers should be incentivized to investigate and “better characterize” costs incurred by cancer patients in clinical trials as well as identify ways to “mitigate the risk of trial-associated financial hardship.”
ASCO’s full policy statement, “Addressing Financial Barriers to Patient Participation in Clinical Trials,” is available on the Journal of Clinical Oncology website.
SOURCE: Winkfield KM et al. J Clin Oncol. 2018 Sep 13:JCO1801132. doi: 10.1200/JCO.18.01132.
FROM JOURNAL OF CLINICAL ONCOLOGY
Standardization of the Discharge Process for Inpatient Hematology and Oncology
Purpose/Rationale: To standardize the discharge process for the hematology/oncology inpatient service at Hines VA Hospital to improve the transition of care
Background: The landmark 1999 report from the Institute of Medicine, To Err is Human, identified the impact of medical error on mortality and morbidity. Medical errors tend to occur during transitions of care. At Hines VA Hospital, a multidisciplinary team delivers specialized care to veterans on the hematology/oncology service. However, resident physicians staffing the inpatient hematology/oncology service may be unfamiliar with the unique needs of the service and population. Currently there is no standardized discharge process in place. Prior studies have demonstrated improved outcomes following standardization of the discharge process for hematology patients. The authors aim to develop and implement a standardized discharge process to minimize risk for medical error.
Method/Approach: A multidisciplinary team of hematology and oncology staff was formed, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, and patient care coordinators, and several interviews were conducted. A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology/oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, ambulatory hematology/oncology follow up within 1-2 weeks, primary care followup, communication with ambulatory hematology/oncology physician, written discharge instructions, and bedside teaching when appropriate. The standardized process will be taught to rotating resident physicians in the form of both online orientation and an in-person orientation. Outcome measures were identified including key components of medication reconciliation, time to hematology & oncology clinic visit, time to primary care visit, communication of discharge with outpatient hematology/oncology physician, and 30-day readmission rate.
Conclusions: All patients discharged during the twomonth period prior to and all patients discharged after the implementation of the standardized process will be reviewed; the above-mentioned variables will be recorded. Outcomes will be compared. Interim multidisciplinary team focus group meetings will be held every quarter to review and refine the process.
Purpose/Rationale: To standardize the discharge process for the hematology/oncology inpatient service at Hines VA Hospital to improve the transition of care
Background: The landmark 1999 report from the Institute of Medicine, To Err is Human, identified the impact of medical error on mortality and morbidity. Medical errors tend to occur during transitions of care. At Hines VA Hospital, a multidisciplinary team delivers specialized care to veterans on the hematology/oncology service. However, resident physicians staffing the inpatient hematology/oncology service may be unfamiliar with the unique needs of the service and population. Currently there is no standardized discharge process in place. Prior studies have demonstrated improved outcomes following standardization of the discharge process for hematology patients. The authors aim to develop and implement a standardized discharge process to minimize risk for medical error.
Method/Approach: A multidisciplinary team of hematology and oncology staff was formed, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, and patient care coordinators, and several interviews were conducted. A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology/oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, ambulatory hematology/oncology follow up within 1-2 weeks, primary care followup, communication with ambulatory hematology/oncology physician, written discharge instructions, and bedside teaching when appropriate. The standardized process will be taught to rotating resident physicians in the form of both online orientation and an in-person orientation. Outcome measures were identified including key components of medication reconciliation, time to hematology & oncology clinic visit, time to primary care visit, communication of discharge with outpatient hematology/oncology physician, and 30-day readmission rate.
Conclusions: All patients discharged during the twomonth period prior to and all patients discharged after the implementation of the standardized process will be reviewed; the above-mentioned variables will be recorded. Outcomes will be compared. Interim multidisciplinary team focus group meetings will be held every quarter to review and refine the process.
Purpose/Rationale: To standardize the discharge process for the hematology/oncology inpatient service at Hines VA Hospital to improve the transition of care
Background: The landmark 1999 report from the Institute of Medicine, To Err is Human, identified the impact of medical error on mortality and morbidity. Medical errors tend to occur during transitions of care. At Hines VA Hospital, a multidisciplinary team delivers specialized care to veterans on the hematology/oncology service. However, resident physicians staffing the inpatient hematology/oncology service may be unfamiliar with the unique needs of the service and population. Currently there is no standardized discharge process in place. Prior studies have demonstrated improved outcomes following standardization of the discharge process for hematology patients. The authors aim to develop and implement a standardized discharge process to minimize risk for medical error.
Method/Approach: A multidisciplinary team of hematology and oncology staff was formed, including attending physicians, fellows, residents, advanced practice nurses, registered nurses, clinical pharmacists, and patient care coordinators, and several interviews were conducted. A standardized discharge process was developed in the form of guidelines and expectations. These include an explanation of unique features of the hematology/oncology service and expectations of medication reconciliation with emphasis placed on antiemetics, antimicrobial prophylaxis, and bowel regimen when appropriate, ambulatory hematology/oncology follow up within 1-2 weeks, primary care followup, communication with ambulatory hematology/oncology physician, written discharge instructions, and bedside teaching when appropriate. The standardized process will be taught to rotating resident physicians in the form of both online orientation and an in-person orientation. Outcome measures were identified including key components of medication reconciliation, time to hematology & oncology clinic visit, time to primary care visit, communication of discharge with outpatient hematology/oncology physician, and 30-day readmission rate.
Conclusions: All patients discharged during the twomonth period prior to and all patients discharged after the implementation of the standardized process will be reviewed; the above-mentioned variables will be recorded. Outcomes will be compared. Interim multidisciplinary team focus group meetings will be held every quarter to review and refine the process.
Children with BCP-ALL show inflammatory marker differences at birth
Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.
Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.
“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”
She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.
For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.
Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.
Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.
On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.
The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.
“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”
The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.
Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.
However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.
“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”
The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.
SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.
Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.
Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.
“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”
She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.
For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.
Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.
Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.
On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.
The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.
“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”
The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.
Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.
However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.
“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”
The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.
SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.
Patients who develop B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in childhood may have dysregulated immune function at birth, according to a study published in Cancer Research.
Investigators evaluated neonatal concentrations of inflammatory markers and found significant differences between children who were later diagnosed with BCP-ALL and leukemia-free control subjects.
“Our findings suggest that children who develop ALL are immunologically disparate already at birth,” said study author Signe Holst Søegaard, PhD, of Statens Serum Institut in Copenhagen. “This may link to other observations suggesting that children who develop ALL respond differently to infections in early childhood, potentially promoting subsequent genetic events required for transformation to ALL, or speculations that they are unable to eliminate preleukemic cells.”
She noted that the study could not determine if the associations shown are causal or consequential so further studies will be needed both to confirm the findings and identify the underlying mechanisms.
For this study, Dr. Søegaard and her colleagues measured concentrations of 10 inflammatory markers on neonatal dried blood spots from 178 patients with BCP-ALL and 178 matched controls. The patients were diagnosed with BCP-ALL at ages 1-9 years.
Compared with controls, children who later developed BCP-ALL had significantly different neonatal concentrations of eight inflammatory markers.
Concentrations of interleukin (IL)–8, soluble receptor sIL-6R alpha, transforming growth factor (TGF)–beta 1, monocyte chemotactic protein (MCP)–1, and C-reactive protein (CRP) were significantly lower among the BCP-ALL patients.
On the other hand, concentrations of IL-6, IL-17, and IL-18 were significantly higher among BCP-ALL patients than controls.
The investigators noted that IL-10 concentrations were too low for accurate measurement in all patients and controls. Additionally, a “large proportion” of patients and controls had IL-6 and IL-17 concentrations that were below the limit of detection.
“We also demonstrated that several previously shown ALL risk factors – namely, birth order, gestational age, and sex – were associated with the neonatal concentrations of inflammatory markers,” Dr. Søegaard said. “These findings raise the interesting possibility that the effects of some known ALL risk factors partly act through prenatal programming of immune function.”
The investigators found that increasing birth order was associated with significantly higher IL-18 and lower CRP concentrations.
Increasing gestational age was associated with significantly lower sIL-6R alpha and TGF-beta 1 concentrations and higher CRP concentrations. And boys had significantly lower sIL-6R alpha and IL-8 concentrations and higher CRP concentrations than girls.
However, none of the following factors were significantly associated with concentrations of inflammatory biomarkers: maternal age at delivery, maternal hospital contact attributable to infection during pregnancy, maternal prescription for antimicrobials during pregnancy, birth weight, and mode of delivery.
“Our findings underline the role the child’s baseline immune characteristics may play in the development of ALL,” Dr. Søegaard said. “However, we cannot yet use our research results to predict who will develop childhood ALL.”
The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.
SOURCE: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.
FROM CANCER RESEARCH
Key clinical point:
Major finding: Neonatal concentrations of some inflammatory markers were significantly different between BCP-ALL patients and controls.
Study details: Ten markers were measured in 178 patients with BCP-ALL and 178 matched controls.
Disclosures: The study was sponsored by the Dagmar Marshall Foundation, the A.P. Møller Foundation, the Danish Childhood Cancer Foundation, the Arvid Nilsson Foundation, and the Danish Cancer Research Foundation. The investigators reported having no conflicts of interest.
Source: Søegaard SH et al. Cancer Res. 2018;78(18);5458-63.
STORM trial shows response in penta-refractory myeloma
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
Treatment with selinexor and low-dose dexamethasone can provide a “meaningful clinical benefit” in patients with penta-refractory multiple myeloma, according to the principal investigator of the STORM trial.
Updated results from this phase 2 trial showed that selinexor and low-dose dexamethasone produced an overall response rate of 26.2% and a clinical benefit rate of 39.3%. The median progression-free survival was 3.7 months and the median overall survival was 8.6 months.
The trial’s principal investigator, Sundar Jagannath, MBBS, of the Icahn School of Medicine at Mount Sinai, New York, presented these results at the annual meeting of the Society of Hematologic Oncology.
“The additional phase 2b clinical results… are very encouraging for the patients suffering from penta-refractory multiple myeloma and their families,” Dr. Jagannath said in a statement. “Of particular significance, for the nearly 40% of patients who had a minimal response or better, the median survival was 15.6 months, which provided the opportunity for a meaningful clinical benefit for patients on the STORM [Selinexor Treatment of Refractory Myeloma] study.”
STORM (NCT02336815) included 122 patients with penta-refractory multiple myeloma. They had previously received bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, alkylating agents, and glucocorticoids. Their disease was refractory to glucocorticoids, at least one proteasome inhibitor, at least one immunomodulatory drug, daratumumab, and their most recent therapy.
The patients had received a median of seven prior treatment regimens. Their median age was 65 years, a little more than half were men, and more than half had high-risk cytogenetics. Patients received oral selinexor at 80 mg twice weekly plus dexamethasone at 20 mg twice weekly until disease progression.Two patients (1.6%) achieved stringent complete responses. They also had minimal residual disease negativity, one at the level of 1 x 10–6 and one at 1 x 10–4.
Very good partial responses were seen in 4.9% of patients, 19.7% had partial responses, 13.1% had minimal responses (MRs), and 39.3% had stable disease. Progressive disease occurred in 13.1% of patients; 8.2% were not evaluable for response.
The overall response rate (partial response or better) was 26.2%, the clinical benefit rate (MR or better) was 39.3%, and the disease control rate (stable disease or better) was 78.7%.
The median duration of response was 4.4 months. The median progression-free survival was 3.7 months overall, 4.6 months in patients with an MR or better, and 1.1 months in patients who had progressive disease or were not evaluable.
The median overall survival was 8.6 months for the entire cohort. Overall survival was 15.6 months in patients with an MR or better and 1.7 months in patients who had progressive disease or were not evaluable (P less than .0001).
The “most important” grade 3/4 adverse events, according to Dr. Jagannath, were thrombocytopenia (53.7%), anemia (29.3%), fatigue (22.8%), hyponatremia (16.3%), nausea (9.8%), diarrhea (6.5%), anorexia (3.3%), and emesis (3.3%). A total of 23 patients (19.5%) discontinued treatment because of a related adverse.
This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
SOURCE: Jagannath S et al. SOHO 2018, Abstract MM-255
FROM SOHO 2018
Key clinical point:
Major finding: The overall response rate was 26.2% and the clinical benefit rate was 39.3%.
Study details: A phase 2 trial of 122 patients with penta-refractory multiple myeloma.
Disclosures: This study was sponsored by Karyopharm Therapeutics. Dr. Jagannath reported relationships with Karyopharm, Janssen, Celgene, Amgen, and GlaxoSmithKline.
Source: Jagannath S et al. SOHO 2018, Abstract MM-255.
Impact of an Educational Seminar Series for VA Providers in Personalized Cancer Care Across Hematologic and Solid Tumors
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.
Purpose/Rationale: To address educational needs of hematology/oncology providers in VA and other federal settings, we conducted a national series of accredited 6-hour seminars. Through surveys, we assessed baseline barriers and educational outcomes.
Background: Recent landmark advances in cancer therapies engender pressing needs for education among VA providers.
Methods: The educational seminars were held in 9 US cities with large VA facilities between November 2017 and March 2018. The agenda, covering hematologic malignancies (3 hours) and solid tumors (3 hours), emphasized evidenced-based and guideline-directed uses of new cancer therapies. Before and after the seminars, participants completed surveys designed to assess self-reported barriers, confidence, and competence regarding personalized medicine approaches to implementing the therapies.
Results: Survey respondents (n = 639) were physicians (29%), pharmacists (23%), nurses (21%), physician assistants (18%), and nurse practitioners (9%) who practice in VA clinics and other federal settings; providers reported seeing an average of 103 oncology patients per month. On the pre-seminar survey, gaps were indicated by relatively small proportions of respondents who reported that their decision-making involving new cancer therapies is guided by genetic/prognostic testing (21%) and assessing patientspecific characteristics including comorbidities (38%); 42% reported having inadequate staff training for personalized hematology/oncology care.
Across the pre- to post-seminar surveys, there were significant increases (P < .0001 for all comparisons) in the proportions of respondents who reported: (1) high confidence in using immunotherapies (17% to 38%), targeted therapies (19% to 37%), and hormonal therapies (20% to 36%); and (2) high competence in performing various clinical skills, including identifying genetic tests for patients with acute myeloid leukemia (8% to 42%), interpreting genetic tests to support personalized treatment decision-making for patients with chronic lymphocytic leukemia (7% to 42%), recognizing and managing adverse events associated with targeted therapies (15% to 48%), and applying precision medicine principles in managing patients with highgrade gliomas (17% to 44%).
Conclusions/Implications: These findings indicate the positive impact of intensive education on self-reported confidence and competence among VA providers in applying personalized medicine approaches to implementing new cancer therapies. We will present additional baseline barriers and educational outcomes, as well as the seminar participants’ gap-targeted action plans for improvement.