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Intravascular Lymphoma Presenting as Acute Abdomen With Intestinal Perforation
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
Background: We present a case of a 69-year-old male with a past medical history of RA, Afib, COPD, and DVT with pulmonary embolism. He presented to the emergency department with encephalopathy and severe abdominal pain. On exam the patient was septic with a diffusely tender abdominal exam with peritoneal signs. The CT scan showed pneumoperitoneum. The patient underwent emergent laparotomy which revealed fecal peritonitis from a cecal perforation. After washout, patient had bowel resection of the involved intestine with a primary anastomosis. Biopsy of his resected small bowel and cecum showed submucosal blood vessels with numerous lymphoid cells. Immunohistochemical staining showed aberrant expression for CD43 and CD30 with an increased proliferation index (Ki67 80-90%). Molecular studies of both the lymphoid aggregates
and the atypical intravascular cells were negative for Ig heavy chain, t(11:18) & t(14,19). A diagnosis of intravascular lymphoma was still made. Patient underwent four further abdominal washouts with reconstruction of anterior abdominal wall with Permacol™ biological mesh. The patient condition continued to deteriorate, and he was transitioned to palliative care. He died a month after. An autopsy was not performed.
Discussion: Intravascular lymphoma is a rare and very aggressive malignancy characterized by proliferation of atypical B cell confined mostly to the vascular lumen. Its presentation is protean depending on the organs involved. It has been referred to as “the oncologists great imitator.” In a series of 38 patients by Ferreri et al, the most common symptoms were fever, cutaneous symptoms, neurological symptoms followed by abdominal pain. Most patients present in an advanced state, one series of 96 patients by Murase et al, 91% of the patient presenting with clinical stage III or stage IV disease.
There remain no standard diagnostic criteria for intravascular lymphoma. First step is demonstration of lymphoma cells in small- and medium-sized blood vessels with characteristic sparing of surrounding tissue. B cell clones are most common, but T and NK cells have also been reported. Molecular, immune histochemical and flow cytometry techniques may aid in establishing diagnosis. Prognosis remains poor even with aggressive treatment, the largest series by Murase et al, with mean survival of just 13 months with treatment.
MRD data added to venetoclax label
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.
The U.S. Food and Drug Administration (FDA) has expanded the label for venetoclax tablets (Venclexta®) to include data on minimal residual disease (MRD).
The drug’s prescribing information now includes details on MRD negativity in previously treated patients with chronic lymphocytic leukemia (CLL) who received venetoclax in combination with rituximab in the phase 3 MURANO trial.
The combination of venetoclax and rituximab was FDA approved in June for the treatment of patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who received at least one prior therapy.
The MURANO trial (NCT02005471), which supported the FDA approval, included 389 patients with relapsed or refractory CLL.
The patients were randomized to receive:
- Venetoclax at 400 mg daily for 24 months (after a 5-week ramp-up period) plus rituximab at 375 mg/m2 on day 1 for the first cycle and at 500 mg/m2 on day 1 for cycles 2 to 6 (n=194)
- Bendamustine at 70 mg/m2 on days 1 and 2 for 6 cycles plus rituximab at the same schedule as the venetoclax arm (n=195).
Researchers evaluated MRD in patients who achieved a partial response or better. MRD was assessed using allele-specific oligonucleotide polymerase chain reaction, and the definition of MRD negativity was less than one CLL cell per 10,000 lymphocytes.
The researchers assessed MRD in the peripheral blood 3 months after the last dose of rituximab. At that time, 53% (103/194) of patients in the venetoclax-rituximab arm were MRD negative, as were 12% (23/195) of patients in the bendamustine-rituximab arm.
The researchers also assessed MRD in the peripheral blood of patients with a complete response (CR) or CR with incomplete marrow recovery (CRi). MRD negativity was achieved by 3% (6/194) of these patients in the venetoclax-rituximab arm and 2% (3/195) in the bendamustine-rituximab arm.
Three percent (3/106) of patients in the venetoclax arm who achieved CR/CRi were MRD negative in both the peripheral blood and the bone marrow.
“The rates of MRD negativity seen with Venclexta plus rituximab are very encouraging,” said MURANO investigator John Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
Additional results from the MURANO trial were published in The New England Journal of Medicine in March and are included in the prescribing information for venetoclax.
Venetoclax is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside the U.S.
TP53 mutation plus complex karyotype equals poor prognosis
The presence of both TP53 gene mutation and complex karyotype may signal a dismal prognosis in patients with mantle cell lymphoma (MCL), according to results of a study.
All patients who had TP53 mutations and complex karyotype died within 1.2 years of diagnosis, while almost all patients with neither predictor were still alive at 2 years, according to study data reported in the journal Clinical Lymphoma, Myeloma & Leukemia.
By combining the markers, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment regimen, reported the study’s corresponding author Vít Procházka, MD, PhD, of the department of hemato-oncology faculty of medicine and dentistry at Palacký University, Olomouc, Czech Republic, and his coauthors.
“Our findings support a need to perform both tests, molecular cytogenetics, and next-generation sequencing simultaneously before initiation of treatment for MCL,” Dr. Procházka and his coauthors wrote.
In current clinical practice, TP53 mutational status and molecular cytogenetics are not routinely assessed prior to treatment initiation, they noted in their report.
The study, believed to be the first to evaluate the combined prognostic role of TP53 mutation and complex karyotype in an MCL cohort, included 74 consecutive adult patients newly diagnosed with MCL during 2000-2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or complex karyotype, was under observation without therapy.
Complex karyotype was found in 13 patients for whom fixed cells were available to perform cytogenetic analysis, the authors reported, while TP53 mutations were seen in 15 patients who were evaluated for that marker.
Altogether, 48 patients (64.9%) had biological material available to perform both analyses. Of those, 4 patients were found to have both TP53 mutation and complex karyotype, 12 had one of those two markers, and 32 had neither.
While patients with both markers all died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker; those differences were significant between groups (P less than .001), according to investigators.
Progression-free survival analyses showed similar results, with significant differences between the three groups, investigators reported.
Multivariate analysis showed that both TP53 mutation and complex karyotype were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index (MIPI).
While larger studies are needed to confirm the results, investigators suggested that novel treatment approaches might be warranted for patients in the highest-risk subgroup.
“The patients harboring the negative prognostic markers [TP53 mutation] and [complex karyotype] might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” they said.
The study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.
SOURCE: Obr A et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 23. doi: 10.1016/j.clml.2018.07.282.
The presence of both TP53 gene mutation and complex karyotype may signal a dismal prognosis in patients with mantle cell lymphoma (MCL), according to results of a study.
All patients who had TP53 mutations and complex karyotype died within 1.2 years of diagnosis, while almost all patients with neither predictor were still alive at 2 years, according to study data reported in the journal Clinical Lymphoma, Myeloma & Leukemia.
By combining the markers, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment regimen, reported the study’s corresponding author Vít Procházka, MD, PhD, of the department of hemato-oncology faculty of medicine and dentistry at Palacký University, Olomouc, Czech Republic, and his coauthors.
“Our findings support a need to perform both tests, molecular cytogenetics, and next-generation sequencing simultaneously before initiation of treatment for MCL,” Dr. Procházka and his coauthors wrote.
In current clinical practice, TP53 mutational status and molecular cytogenetics are not routinely assessed prior to treatment initiation, they noted in their report.
The study, believed to be the first to evaluate the combined prognostic role of TP53 mutation and complex karyotype in an MCL cohort, included 74 consecutive adult patients newly diagnosed with MCL during 2000-2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or complex karyotype, was under observation without therapy.
Complex karyotype was found in 13 patients for whom fixed cells were available to perform cytogenetic analysis, the authors reported, while TP53 mutations were seen in 15 patients who were evaluated for that marker.
Altogether, 48 patients (64.9%) had biological material available to perform both analyses. Of those, 4 patients were found to have both TP53 mutation and complex karyotype, 12 had one of those two markers, and 32 had neither.
While patients with both markers all died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker; those differences were significant between groups (P less than .001), according to investigators.
Progression-free survival analyses showed similar results, with significant differences between the three groups, investigators reported.
Multivariate analysis showed that both TP53 mutation and complex karyotype were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index (MIPI).
While larger studies are needed to confirm the results, investigators suggested that novel treatment approaches might be warranted for patients in the highest-risk subgroup.
“The patients harboring the negative prognostic markers [TP53 mutation] and [complex karyotype] might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” they said.
The study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.
SOURCE: Obr A et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 23. doi: 10.1016/j.clml.2018.07.282.
The presence of both TP53 gene mutation and complex karyotype may signal a dismal prognosis in patients with mantle cell lymphoma (MCL), according to results of a study.
All patients who had TP53 mutations and complex karyotype died within 1.2 years of diagnosis, while almost all patients with neither predictor were still alive at 2 years, according to study data reported in the journal Clinical Lymphoma, Myeloma & Leukemia.
By combining the markers, patients could be stratified into three prognostic groups that had distinct outcomes, regardless of treatment regimen, reported the study’s corresponding author Vít Procházka, MD, PhD, of the department of hemato-oncology faculty of medicine and dentistry at Palacký University, Olomouc, Czech Republic, and his coauthors.
“Our findings support a need to perform both tests, molecular cytogenetics, and next-generation sequencing simultaneously before initiation of treatment for MCL,” Dr. Procházka and his coauthors wrote.
In current clinical practice, TP53 mutational status and molecular cytogenetics are not routinely assessed prior to treatment initiation, they noted in their report.
The study, believed to be the first to evaluate the combined prognostic role of TP53 mutation and complex karyotype in an MCL cohort, included 74 consecutive adult patients newly diagnosed with MCL during 2000-2014. Seventy-three patients were treated with a rituximab-containing regimen. One patient, who did not have TP53 mutation or complex karyotype, was under observation without therapy.
Complex karyotype was found in 13 patients for whom fixed cells were available to perform cytogenetic analysis, the authors reported, while TP53 mutations were seen in 15 patients who were evaluated for that marker.
Altogether, 48 patients (64.9%) had biological material available to perform both analyses. Of those, 4 patients were found to have both TP53 mutation and complex karyotype, 12 had one of those two markers, and 32 had neither.
While patients with both markers all died within 1.2 years, 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker; those differences were significant between groups (P less than .001), according to investigators.
Progression-free survival analyses showed similar results, with significant differences between the three groups, investigators reported.
Multivariate analysis showed that both TP53 mutation and complex karyotype were predictors of inferior progression-free survival and overall survival, independent of age and scores on the MCL International Prognostic Index (MIPI).
While larger studies are needed to confirm the results, investigators suggested that novel treatment approaches might be warranted for patients in the highest-risk subgroup.
“The patients harboring the negative prognostic markers [TP53 mutation] and [complex karyotype] might be indicated for a novel induction treatment strategy probably in combination with maintenance therapy different from rituximab,” they said.
The study was supported by grants from the Czech Ministry of Health and Palacký University. The researchers reported having no conflicts of interest.
SOURCE: Obr A et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 23. doi: 10.1016/j.clml.2018.07.282.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: Patients with both markers all died within 1.2 years, while 2-year overall survival was 50.0% for those with one marker and 93.8% for those with neither marker (P less than .001).
Study details: A study of 74 consecutive adult patients newly diagnosed with MCL during 2000-2014.
Disclosures: The study was supported by grants from the Czech Ministry of Health and Palacký University, Olomouc, Czech Republic. Study authors reported having no conflicts of interest.
Source: Obr A et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 23. doi: 10.1016/j.clml.2018.07.282.
New guidelines on antimicrobial prophylaxis
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
Experts have published updated guidelines on antimicrobial prophylaxis for adults with cancer-related immunosuppression.
The guidelines include antibacterial, antifungal, and antiviral prophylaxis recommendations, along with additional precautions, such as hand hygiene, that may reduce infection risk.
The guidelines were developed by the American Society of Clinical Oncology (ASCO) with the Infectious Diseases Society of America (IDSA) and published in the Journal of Clinical Oncology.
For the most part, the expert panel that created these guidelines endorsed the previous ASCO recommendations, published in 2013.
However, the panel considered six new studies and six new or updated meta-analyses to make modifications and add some new recommendations.
Recommendations
The ASCO/IDSA guidelines say health care providers should systematically assess the risk of febrile neutropenia, taking into account patient-, cancer-, and treatment-related factors.
Fluoroquinolone prophylaxis is recommended for patients at high risk of febrile neutropenia or profound, protracted neutropenia. This includes most patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) and patients undergoing hematopoietic stem cell transplant (HSCT) who are treated with myeloablative conditioning regimens.
Antifungal prophylaxis with an oral triazole or parenteral echinocandin is recommended for patients at risk of profound, protracted neutropenia, which includes HSCT recipients and most patients with AML/MDS.
However, neither antifungal nor antibiotic prophylaxis are routinely recommended for patients with solid tumors.
Prophylaxis with a nucleoside analog, such as acyclovir, is recommended in patients who are herpes simplex virus–seropositive and are undergoing allogeneic HSCT or leukemia induction.
Pneumocystis jirovecii prophylaxis, such as trimethoprim-sulfamethoxazole, is recommended for patients receiving chemotherapy regimens associated with a greater than 3.5% risk for pneumonia from P jirovecii.
Treatment with a nucleoside reverse transcription inhibitor, such as entecavir or tenofovir, is recommended for patients at high risk of hepatitis B virus reactivation.
Yearly influenza vaccination with an inactivated quadrivalent vaccine is recommended for all patients undergoing chemotherapy for malignancy as well as their family members, household contacts, and health care providers.
Health care workers should follow hand hygiene and respiratory hygiene/cough etiquette to reduce the risk of pathogen transmission, according to the guidelines.
The guidelines also note that outpatients who develop neutropenia following cancer therapy should avoid prolonged contact with environments that have high concentrations of airborne fungal spores.
The guidelines do not recommend interventions such as neutropenic diet, footwear exchange, nutritional supplements, and surgical masks. “Evidence of clinical benefit is lacking” for those interventions, the expert panel said.
Members of the expert panel disclosed potential conflicts of interest related to Merck, Chimerix, GlyPharma Therapeutic, Pfizer, Cidara Therapeutics, Celgene, Astellas Pharma, Gilead Sciences, and Allergan, among other entities.
First CAR T-cell therapy approved in Canada
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Health Canada has authorized use of tisagenlecleucel (Kymriah™), making it the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.
Tisagenlecleucel (formerly CTL019) is approved to treat patients ages 3 to 25 with B-cell acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.
Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.
Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers, and Novartis is enhancing manufacturing capacity to meet patient needs.
Tisagenlecleucel has been studied in a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
JULIET enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The overall response rate was 52%, and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.
The 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
These results were presented at the 23rd Annual Congress of the European Hematology Association in June (abstract S799).
ELIANA trial
ELIANA included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi. All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
Ninety-five percent of patients had AEs thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
These results were published in The New England Journal of Medicine in February.
Regimens produce similar results in FL
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in the treatment of follicular lymphoma (FL) in a phase 3 trial.
Patients with previously untreated FL had similar complete response (CR) rates and progression-free survival (PFS) rates whether they received rituximab-based chemotherapy or rituximab plus lenalidomide.
These results were published in The New England Journal of Medicine.
The trial, RELEVANCE, included 1,030 patients with previously untreated FL. They were randomized to receive rituximab plus chemotherapy (n=517) or rituximab plus lenalidomide (n=513) for 18 cycles.
Patients in the chemotherapy arm received one of three regimens—R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), rituximab and bendamustine, or R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone).
Patients in both treatment arms went on to receive rituximab maintenance every 8 weeks for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years.
The coprimary endpoints were CR (confirmed or unconfirmed) and PFS. After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the treatment arms.
CR was observed in 48% of the rituximab-lenalidomide arm and 53% of the rituximab-chemotherapy arm (P=0.13).
The interim 3-year PFS rate was 77% in the rituximab-lenalidomide arm and 78% in the rituximab-chemotherapy arm. The hazard ratio for progression or death from any cause was 1.10 (P=0.48).
The efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose disease was Ann Arbor stage I or II, whereas the efficacy of rituximab-lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some adverse events (AEs) being more common in one arm than the other.
AEs that were more common with rituximab-lenalidomide include cutaneous reactions (43% vs 24%), diarrhea (37% vs 19%), rash (29% vs 8%), abdominal pain (15% vs 9%), peripheral edema (14% vs 9%), muscle spasms (13% vs 4%), myalgia (14% vs 6%), and tumor flare reaction (6% vs <1%).
AEs that were more common with rituximab-chemotherapy were anemia (89% vs 66%), fatigue (29% vs 23%), nausea (42% vs 20%), vomiting (19% vs 7%), febrile neutropenia (7% vs 2%), leukopenia (10% vs 4%), and peripheral neuropathy (16% vs 7%).
Grade 3/4 cutaneous reactions were more common with rituximab-lenalidomide (7% vs 1%), and grade 3/4 neutropenia was more common with rituximab-chemotherapy (50% vs 32%).
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
Ibrutinib maintains efficacy over time
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
Extended follow-up of the RESONATE-2 trial showed that first-line ibrutinib sustained efficacy in elderly patients with chronic lymphocytic leukemia (CLL).
Patients who received ibrutinib had a long-term progression-free survival benefit over those who received chlorambucil.
The depth of response to ibrutinib improved over time, which meant there was a substantial increase in the proportion of patients achieving complete response.
Additionally, rates of some serious adverse events associated with ibrutinib decreased over time.
Paul M. Barr, MD, of the University of Rochester in New York, and his colleagues reported these findings in Haematologica.
Previously reported results of the RESONATE-2 trial, which showed an 84% reduction in the risk of death for ibrutinib versus chlorambucil, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized to receive ibrutinib (n=136) or chlorambucil (n=133).
At a median follow-up of 29 months, 79% (107/136) of patients remained on ibrutinib.
There was an 88% reduction in the risk of progression or death for patients randomized to ibrutinib (P<0.0001).
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months to 15% at 24 months and 18% at 36 months (maximum follow-up).
The overall response rate (ORR) with ibrutinib was 92%, with comparable findings in high-risk subgroups. The ORR was 100% in patients with del(11q) and 95% in those with unmutated IGHV.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42%, compared to 7% of patients who received chlorambucil.
Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients and 52% in chlorambucil recipients, with complete resolution in 56% and 22%, respectively.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time.
The rate of grade 3 or higher neutropenia decreased from 8.1% in the first 12 months of treatment to 0% in the third year. The rate of grade 3 or higher anemia decreased from 5.9% to 1%. And the rate of grade 3 or higher thrombocytopenia decreased from 2.2% to 0%.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up. However, investigators said ibrutinib dose reductions and discontinuations because of this adverse event were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
RESONATE-2 update: First-line ibrutinib has sustained efficacy in older CLL patients
In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.
The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.
Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.
“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.
Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.
Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.
The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.
The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.
In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.
The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.
Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.
“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.
Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.
Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.
The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.
The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.
In older patients with chronic lymphocytic leukemia (CLL), first-line treatment with ibrutinib resulted in a long-term progression-free survival benefit versus chemotherapy, according to extended follow-up results of a phase 3 trial.
The quality of response to ibrutinib continued to improve over time in the study, including a substantial increase in the proportion of patients achieving complete response, the updated results of the RESONATE-2 trial show.
Rates of serious adverse events decreased over time in the study, while common reasons for initiating treatment, such as marrow failure and disease symptoms, all improved to a greater extent than with chlorambucil, reported Paul M. Barr, MD, of the University of Rochester (N.Y.) and colleagues.
“These data support the use of ibrutinib in the first-line treatment of CLL as a chemotherapy-free option that can be taken continuously, achieving long-term disease control for the majority of patients, including those with high-risk features,” Dr. Barr and coauthors said in the journal Haematologica.
Previously reported primary results of the RESONATE-2 trial, which showed an 84% reduction in risk of death for ibrutinib versus chlorambucil with a median follow-up of 18 months, led to the approval of ibrutinib for first-line CLL treatment, the authors said.
The study included 269 patients with untreated CLL or small lymphocytic lymphoma who had active disease and were at least 65 years of age. They were randomized 1:1 to ibrutinib or chlorambucil.
Out of 136 ibrutinib-treated patients, 107 (79%) remained on therapy at this extended analysis, which had a median follow-up of 29 months.
The extended analysis also showed an 88% reduction in risk of progression or death for those patients randomized to ibrutinib (P less than .0001), with significant improvements in subgroups evaluated, which include groups typically considered high risk, according to Dr. Barr and colleagues.
The rate of complete response improved over time in ibrutinib-treated patients, from 7% at 12 months, to 15% at 24 months, and to 18% with a maximum of 36 months’ follow-up, they said.
The overall response rate for ibrutinib was 92% in this extended analysis, with comparable findings in high-risk subgroups, including those with del(11q) at 100% and unmutated IGHV at 95%, according to the report.
Lymphadenopathy improved in most ibrutinib-treated patients, with complete resolution in 42% versus 7% with chlorambucil. Splenomegaly improved by at least 50% in 95% of ibrutinib-treated patients versus 52% for chlorambucil, with complete resolution in 56% of ibrutinib-treated patients and 22% of chlorambucil-treated patients.
Adverse events of grade 3 or greater were generally seen more often in the first year of ibrutinib therapy and decreased over time. Rates of grade 3 or greater neutropenia, anemia, and thrombocytopenia were 8.1%, 5.9%, and 2.2%, respectively, in the first 12 months of treatment; those decreased to 0%, 1%, and 0% in the third year.
The rate of atrial fibrillation increased from 6% in the primary analysis to 10% in extended follow-up; however, investigators said ibrutinib dose reductions and discontinuations because of this adverse effect were uncommon and less frequent with extended treatment.
“Atrial fibrillation therefore appears manageable and does not frequently necessitate ibrutinib discontinuation,” they concluded.
The study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data. Several study authors reported funding from various companies, including Pharmacyclics.
SOURCE: Barr PM, et al. Haematologica. 2018;103(9):1502-10.
FROM HAEMATOLOGICA
Key clinical point:
Major finding: There was an 88% reduction in risk of progression-free survival events for those patients randomized to ibrutinib (P less than .0001).
Study details: Extended phase 3 results from the RESONATE-2 trial, including 269 older patients with untreated CLL or small lymphocytic lymphoma.
Disclosures: This study was supported by Pharmacyclics, an AbbVie company, and by grants from the National Institutes of Health and the MD Anderson Moon Shot Program in CLL. Pharmacyclics designed the study and performed analysis of the data.
Source: Barr PM et al. Haematologica. 2018;103(9):1502-10.
Rituximab/lenalidomide similar to rituximab/chemotherapy for follicular lymphoma
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
Rituximab plus lenalidomide had efficacy similar to that of rituximab plus chemotherapy in treatment of follicular lymphoma, according to results from a phase 3 trial.
RELEVANCE (NCT01476787) was a multicenter, international, randomized, open-label trial designed to determine the superiority of rituximab/lenalidomide over rituximab/chemotherapy.
This trial randomized 1,030 patients with previously untreated follicular lymphoma to receive either rituximab plus lenalidomide (n = 513) or rituximab plus chemotherapy (n = 517) for 18 cycles; both groups then went on to receive rituximab maintenance therapy for 12 cycles. The total duration of treatment was 120 weeks. The median age of the combined groups was 59 years. The study was published in the New England Journal of Medicine.
One of the coprimary endpoints was complete response (confirmed or unconfirmed) by the end of the treatment period; the other was progression-free survival, which was planned to be assessed through three analyses, including two interim analyses, the first of which was reported in this study.
After a median follow-up of 37.9 months, the rates of coprimary endpoints were similar between the two groups. Complete response (confirmed or unconfirmed) was seen in 48% of the rituximab/lenalidomide group (95% confidence interval [CI], 44-53) and in 53% of the rituximab/chemotherapy group (95% CI, 49-57; P = .13). The hazard ratio for progression or death from any cause was 1.10 (95% CI, 0.85-1.43; P = .48).
In the subgroup analyses, the efficacy of rituximab plus chemotherapy was greater in low-risk patients (based on Follicular Lymphoma International Prognostic Index scores) and in patients whose follicular lymphoma was Ann Arbor stage I or II, whereas efficacy of rituximab/lenalidomide was independent of prognostic factors.
Safety was the biggest area of difference, with some events being more common in one group than in the other. For example, cutaneous reactions, diarrhea, rash, and myalgia were more common with rituximab/lenalidomide treatment, whereas anemia, fatigue, nausea, and febrile neutropenia were more common with rituximab/chemotherapy treatment. Among grade 3 or 4 events, cutaneous reactions were more common with rituximab/lenalidomide, and grade 3 or 4 neutropenia was more common with rituximab/chemotherapy.
“Overall, both treatment groups showed good outcomes, and a median has not yet been reached for either progression-free survival or overall survival,” the study authors wrote.
The RELEVANCE trial was sponsored by Celgene and the Lymphoma Academic Research Organisation. The study authors reported various disclosures, including financial ties to Celgene.
SOURCE: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: Complete responses were seen in 48% of rituximab/lenalidomide patients versus 53% in the rituximab/chemotherapy patients (P = .13).
Study details: A phase 3 superiority trial of 1,030 patients with previously untreated follicular lymphoma.
Disclosures: Celgene and the Lymphoma Academic Research Organization funded the study. The authors reported various disclosures, including financial ties to Celgene.
Source: Morschhauser F et al. N Engl J Med. 2018;379:934-47.
Escalating methotrexate may improve survival in T-cell ALL
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
An escalating methotrexate strategy provided superior survival outcomes compared with high-dose methotrexate in a chemotherapy regimen for children and young adults with T-cell acute lymphoblastic leukemia (T-ALL), results of a large, randomized trial show.
There were also fewer relapses reported for escalating versus high-dose methotrexate in the study, which evaluated the effects of these two intensification strategies in patients receiving an augmented Berlin-Frankfurt-Muenster (ABFM) chemotherapy regimen.
These findings come from a report in the Journal of Clinical Oncology on the Children’s Oncology Group (COG) AALL0434 trial, which to the knowledge of the investigators is the largest T-ALL study ever conducted.
The improved survival outcomes in AALL0434 are the “opposite effect” of what was observed in a parallel trial, AALL0232, showing that high-dose methotrexate was superior to the escalating strategy in B-cell acute lymphoblastic leukemia (B-ALL), the authors reported.
The parallel trial design was in fact used because of the known differences between T-ALL and B-ALL in sensitivity to methotrexate and pegaspargase, according to investigator Stuart S. Winter, MD, of Children’s Minnesota Cancer and Blood Disorders Program, Minneapolis, and his coauthors.
“Although treatment intensification has improved survival for children with ALL, the best timing and sequence of key therapeutic interventions, such as asparaginase and methotrexate, which seem to be particularly important for T-ALL, remain unclear,” Dr. Winter and his colleagues said.
In the AALL0434 study, a total of 1,031 T-ALL patients between 1 and 31 years of age without CNS3 disease or testicular leukemia were randomized to postinduction therapy that included either the so-called Capizzi-style escalating intravenous methotrexate or high-dose methotrexate.
The escalating intravenous regimen was superior to high-dose methotrexate, according to investigators. Respectively, the 5-year rate of disease-free survival was 91.5% versus 85.3% (P = .005) and the 5-year rate of overall survival was 93.7% versus 89.4% (P = .036).
Relapses were observed in 32 patients receiving the escalating regimen, versus 59 for patients receiving high-dose methotrexate.
By contrast, the parallel AALL0232 study of B-ALL patients showed that high-dose methotrexate had superior 5-year event-free survival and overall survival, leading Dr. Winter and his colleagues to speculate on how the findings could be reconciled.
Neither trial was a strict comparison of two different methotrexate schedules, due to differences in doses of pegaspargase, 6-MP, and vincristine between arms, as well as differences in the timing of cranial radiation therapy.
Of note, patients randomized to escalated methotrexate had two additional doses of pegaspargase. As a result, enhanced asparagine depletion in that arm may have also prevented relapse events, the investigators said.
Differences in adherence could also have played a role, as the cost and time burden of the escalated approach are “substantially less” than the high-dose approach, they added.
The AALL0434 trial also included a second randomization to an addition of five, 6-day cycles of nelarabine versus no nelarabine. Results of that randomization, reported earlier this year, showed that nelarabine improved disease-free survival, including a 91% 4-year disease-free survival rate for patients receiving both nelarabine and escalating-dose methotrexate.
The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. Dr. Winter reported relationships with Amgen and Jazz Pharmaceuticals. Study coauthors reported relationships with Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
SOURCE: Winter SS et al. J Clin Oncol. 2018 Aug 23: doi: 10.1200/JCO.2018.77.7250.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: An (T-ALL).
Major finding: The 5-year disease-free survival rate was 91.5% versus 85.3% (P = .005) and overall survival was 93.7% versus 89.4% (P = .036), respectively, for the escalating and high-dose approaches.
Study details: Results after methotrexate randomization in 1,031 T-ALL patients without CNS3 disease or testicular leukemia in the Children’s Oncology Group (COG) AALL0434 trial.
Disclosures: The study was supported by grants from the National Institutes of Health and by St. Baldrick’s Foundation. The authors reported disclosures related to Amgen, Jazz Pharmaceuticals, Novo Nordisk, Tandem, Pfizer, Novartis, and TypeZero Technologies, among others.
Source: Winter SS et al. J Clin Oncol. 2018 Aug 23. doi: 10.1200/JCO.2018.77.7250.