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Immunotherapy’s cardiac effects require early monitoring, management
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
WASHINGTON – Unquestionably, immunotherapy is revolutionizing the care of patients with various solid tumors and hematologic malignancies.
But it’s equally true that there’s no such thing as either a free lunch or a cancer therapy free of side effects, whether it’s increased risk for heart failure associated with anthracycline-based chemotherapy, or inflammatory conditions, arrhythmias, and thromboembolic events associated with immune checkpoint inhibitors, said R. Frank Cornell, MD, of Vanderbilt University Medical Center in Nashville, Tenn.
“Early awareness and intervention is critical for improved outcomes, and a multidisciplinary approach between oncology, cardiology, the clinic nurse, and other health care providers is critical in managing these patients with these complicated therapies,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Checkpoint inhibitors and the heart
Toxicities associated with immune checkpoint inhibitors such as the programmed death 1/ligand 1 (PD-1/PD-L1) inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the cytotoxic T-lymphocyte antigen 4 antibody ipilimumab (Yervoy) tend to mimic autoimmune conditions, Dr. Cornell said.
Cardiovascular events associated with these agents, while uncommon, include myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, vasculitis, and venous thromboembolism, he said, citing an American Society of Clinical Oncology (ASCO) clinical practice guideline (J Clin Oncol 2018;36[17]:1714-68).
Dr. Cornell described the case of a 63-year-old woman with disseminated metastatic melanoma who presented to the emergency department 10 days after starting on combination therapy with ipilimumab and nivolumab. She had developed shortness of breath, pleuritic chest pain, and a mild cough for 1 or 2 days.
Her cardiac laboratory markers had been normal at baseline, but were markedly elevated on presentation, and electrocardiograms showed complete heart block and subsequent ventricular tachycardia.
The patient was started on high-dose prednisone, but she died in hospital, and an autopsy showed that the cause of death was infiltration into the myocardium of CD3-positive and CD8-positive T lymphocytes.
“So how do we manage this? This is a good opportunity, I think, for further cardiology and oncology collaboration to develop more robust guidelines for what we can do to best prevent this,” Dr. Cornell said.
Patients started on the ipilimumab/nivolumab combination should be tested weekly for cardiac troponin, creatine kinase (CK) and CK-muscle/brain (CK-MB) weekly for the first 3-4 weeks of therapy. Therapy should be stopped if troponin levels continue to rise, and the patient should be started on high-dose steroids, he said.
The role of other anti-inflammatory agents such as infliximab (Remicade and biosimilars) is unclear and needs further study, he added.
Dr. Cornell cited a 2018 letter to The Lancet by Javid J. Moslehi, MD, and colleagues from Vanderbilt describing an increase in reports of fatal myocarditis among patients treated with checkpoint inhibitors.
“We highlight the high mortality rate with severe immune checkpoint inhibitor–related myocarditis, which is more frequent with combination PD-1 and CTLA-4 blockade, but can also occur with monotherapy. Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD1 and anti-PD-L1 drugs. Furthermore, this condition occurs early on during therapy and across cancer types,” they wrote.
Most of the patients had no preexisting cardiovascular disease, and most were not taking medications for hypertension, cardiovascular disease, or diabetes.
CAR-T cells and cardiac disease
The primary cardiac complications associated with CAR-T cell therapy are related to the cytokine release syndrome (CRS), a condition marked by progressive elevation in inflammatory cytokines that in turn leads to marked elevations in C-reactive protein (CRP), interferon gamma, tumor necrosis factor al, and release of pro-inflammatory cytokines including interleukin (IL) 6, IL-10, IL-12, and IL-1 beta.
In rare instances, CRS can lead to disseminated intravascular coagulation (DIC), capillary leak syndrome, and a hemophagocytic lymphohistiocytosis-like (HLH) syndrome, Dr. Cornell said.
Package inserts for the two Food and Drug Administration–approved CAR-T cell products, axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) show that each was associated in clinical trials with a high incidence of CRS.
Among patients treated with axicabtagene ciloleucel, 94% developed CRS, which was grade 3 or greater in severity in 13%. The median time to onset was 2 days, and the median duration was 7 days. Cardiovascular adverse events included grade 3 or greater tachycardia in 2%, arrhythmias in 7%, edema in 1%, dyspnea in 3%, pleural effusion in 2%, hypotension in 15%, hypertension in 6%, and thrombosis in 1%.
Among patients treated with tisagenlecleucel, 79% treated for B-cell acute lymphoblastic leukemia (B-ALL) and 74% treated for diffuse large B cell lymphoma (DLBCL) developed CRS, which was grade 3 or greater in 49% and 23% of patients, respectively. The median time to onset was 3 days, and the median duration of CRS was 8 days.
Cardiovascular adverse events of grade 3 or greater among these patients included tachycardia in 4%, fluid overload in 7%, edema in 1%, dyspnea in 12%, pulmonary edema in 4%, hypotension in 22%, and hypertension in 6%.
Risk factors for CRS include high pre-infusion tumor burden, active infections, and concurrent inflammatory processes, Dr. Cornell said.
Prevention of cardiovascular complications of CAR-T cell therapy requires management of CRS. Patients with grade 2 or greater CRS should receive the anti-IL-6 agent tocilizumab (Actemra) 8 mg/kg intravenously over 1 hour to a maximum dose of 800 mg. Tocilizumab infusions can be repeated every 8 hours as needed if the patient is not responsive to intravenous fluids or increasing supplement oxygen, but should be limited to a maximum of three doses over 24 hours, and a maximum total of four doses.
Patients with grade 3 CRS should also receive intravenous methylprednisolone 1 mg/kg twice daily or the equivalent amount of dexamethasone, with corticosteroids continued until the severity of CRS is grade 1 or less, then tapered over 3 days,
Patients with grade 4 CRS should also receive IV methylprednisolone 1,000 mg per day for 3 days, and if symptoms improve, continue management as per grade 3, Dr. Cornell said.
Dr. Cornell reported having nothing to disclose.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Monitor for cardiac symptoms and treat or interrupt immunotherapy as needed.
Major finding: Immune checkpoint inhibitors and CAR T-cell therapies are associated with distinct cardiovascular adverse events.
Study details: Review of strategies for managing the cardiovascular consequences of cancer immunotherapies.
Disclosures: Dr. Cornell reported having nothing to disclose.
EC approves blinatumomab for MRD-positive BCP-ALL
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).
The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.
Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.
The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.
The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).
The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.
The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.
However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.
The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.
Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.
The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).
The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.
Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.
The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.
The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).
The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.
The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.
However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.
The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.
Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.
The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.
The European Commission (EC) has expanded the approved indication for blinatumomab (Blincyto).
The drug is now approved in Europe to treat adults with Philadelphia chromosome–negative (Ph–), CD19-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in first or second complete remission with minimal residual disease (MRD) of at least 0.1%.
Blinatumomab is already approved in Europe to treat adults with Ph–, CD19-positive relapsed/refractory BCP-ALL and children aged 1 year or older who have relapsed/refractory Ph–, CD19-positive BCP-ALL and have received at least two prior therapies or relapsed after allogeneic hematopoietic stem cell transplant.
The drug was approved in the United States in March 2018 for the treatment of adults and children with BCP-ALL in first or second complete remission with MRD of at least 0.1%.
The EC’s decision to approve blinatumomab in MRD-positive patients was supported by the phase 2 BLAST trial (Blood. 2018;131[14]:1522-31).
The EC’s approval is also based on a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
That opinion, issued in November 2018, was a reversal of the opinion the committee issued in July 2018. At that time, the CHMP said the available data did not support approval for blinatumomab to treat MRD-positive BCP-ALL.
The CHMP acknowledged that blinatumomab produced MRD negativity in many patients in the BLAST trial but said there was no strong evidence that this led to improved survival. As a result, the CHMP said the benefits of blinatumomab do not outweigh its risks in MRD-positive BCP-ALL patients.
However, Amgen requested a reexamination of the CHMP’s opinion. During the reexamination, the CHMP reviewed all the data and consulted a group of experts.
The experts echoed the CHMP’s prior sentiment that there was no strong evidence of improved survival in MRD-positive patients treated with blinatumomab. However, they also said the data indicate a good response to blinatumomab, with around 78% of patients becoming negative for MRD after treatment.
Noting that MRD-positive patients have a high risk of relapse and few treatment options, the CHMP concluded that the benefits of blinatumomab outweigh its risks in this patient population.
The CHMP recommended expanding the approved indication for blinatumomab but also requested that Amgen provide data from ongoing studies of the drug in MRD-positive patients.
MD Anderson–led alliance seeks to advance leukemia drug development
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
The primarily for leukemia.
The collaboration, led by Hagop Kantarjian, MD, chair of leukemia at MD Anderson, will use Ascentage’s proprietary Protein-Protein Interaction drug discovery technology platform to develop the company’s apoptosis-targeted and tyrosine kinase inhibitor drug candidates.
The drug candidates will be studied as single-agent therapies and in combinations with other approved or investigational therapeutics. The candidates, chosen for their potential to treat acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), myeloproliferative neoplasms, and myelofibrosis, include:
- HQP1351, a third-generation BCR-ABL inhibitor that has been shown to be safe and “highly active” in treating patients with chronic- or accelerated-phase CML, with or without the T3151 mutation. Preliminary results of the phase 1 study were presented at the 2018 annual meeting of the American Society of Hematology (Abstract 791).
- APG-1252, a highly potent Bcl-2 family inhibitor, has high binding affinities to Bcl-2, Bcl-xL and Bcl-w. It has achieved tumor regression in small cell lung cancer, colon, breast, and ALL xenografts. A phase 1, dose-escalating study is currently being conducted (NCT03387332).
- APG-2575, a selective Bcl-2 inhibitor, is being studied in a phase 1, multicenter, single-agent trial in patients with B-cell hematologic malignancies, including multiple myeloma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, non-Hodgkin lymphomas, and AML (NCT03537482).
- APG-1387, an inhibitor of apoptosis protein, is being studied in solid tumors and hematologic malignancies (NCT03386526). Investigators asserted that combining it with an anti–programmed death 1 antibody would be “a very attractive approach” for cancer therapy. In advanced solid tumors it has been well tolerated with manageable adverse events, according to a study presented at the 2018 annual meeting of the American Society of Clinical Oncology (Abstract 2593).
- APG-115 is an MDM2-p53 inhibitor that, when combined with radiotherapy, has been shown to enhance the antitumor effect in gastric adenocarcinoma, according to a paper published in the Journal of Experimental & Clinical Cancer Research.
“We will be investigating this pipeline of candidate therapies, and we are interested in the novel mechanism of their actions,” Dr. Kantarjian said in a statement.
FDA approves new ALL treatment for children, young adults
The in pediatric and young adult patients aged 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses, compared with other available pegaspargase products. The recommended dosage of calaspargase pegol-mknl is 2,500 units/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years.
Study participants received calaspargase pegol-mknl at 2,500 U/m2 (n = 118) or pegaspargase at 2,500 U/m2 (n = 119) as part of a Dana-Farber Cancer Institute ALL Consortium backbone therapy. The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase. Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events in the calaspargase pegol-mknl and pegaspargase arms included elevated transaminase (52% and 66%, respectively), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%). There was one fatal adverse event among patients on calaspargase pegol-mknl – multiorgan failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL. The patients received calaspargase pegol-mknl at 2,500 U/m2 (n = 43) or 2,100 U/m2 (n = 68) or pegaspargase at 2,500 U/m2 (n = 52) as a component of an augmented Berlin-Frankfurt-Münster regimen. The patients’ median age was 11 years. The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase. There were 3 induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information. Calaspargase pegol-mknl is a product of Servier.
The in pediatric and young adult patients aged 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses, compared with other available pegaspargase products. The recommended dosage of calaspargase pegol-mknl is 2,500 units/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years.
Study participants received calaspargase pegol-mknl at 2,500 U/m2 (n = 118) or pegaspargase at 2,500 U/m2 (n = 119) as part of a Dana-Farber Cancer Institute ALL Consortium backbone therapy. The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase. Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events in the calaspargase pegol-mknl and pegaspargase arms included elevated transaminase (52% and 66%, respectively), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%). There was one fatal adverse event among patients on calaspargase pegol-mknl – multiorgan failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL. The patients received calaspargase pegol-mknl at 2,500 U/m2 (n = 43) or 2,100 U/m2 (n = 68) or pegaspargase at 2,500 U/m2 (n = 52) as a component of an augmented Berlin-Frankfurt-Münster regimen. The patients’ median age was 11 years. The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase. There were 3 induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information. Calaspargase pegol-mknl is a product of Servier.
The in pediatric and young adult patients aged 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses, compared with other available pegaspargase products. The recommended dosage of calaspargase pegol-mknl is 2,500 units/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years.
Study participants received calaspargase pegol-mknl at 2,500 U/m2 (n = 118) or pegaspargase at 2,500 U/m2 (n = 119) as part of a Dana-Farber Cancer Institute ALL Consortium backbone therapy. The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase. Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events in the calaspargase pegol-mknl and pegaspargase arms included elevated transaminase (52% and 66%, respectively), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%). There was one fatal adverse event among patients on calaspargase pegol-mknl – multiorgan failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL. The patients received calaspargase pegol-mknl at 2,500 U/m2 (n = 43) or 2,100 U/m2 (n = 68) or pegaspargase at 2,500 U/m2 (n = 52) as a component of an augmented Berlin-Frankfurt-Münster regimen. The patients’ median age was 11 years. The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase. There were 3 induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information. Calaspargase pegol-mknl is a product of Servier.
ALL chemotherapy looks effective in mixed phenotype leukemia
SAN DIEGO – The majority of pediatric patients with mixed phenotype acute leukemia (MPAL) who were treated with acute lymphoblastic leukemia (ALL)–directed chemotherapy achieved a minimum residual disease (MRD)–negative complete response by the end of consolidation, according to findings from a multicenter retrospective cohort study.
The cohort included 94 patients aged 1-21 years who met strict World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions. Most had B/myeloid phenotype (89%), and 87 patients were treated with an ALL regimen, Etan Orgel, MD, reported at the annual meeting of the American Society of Hematology.
Of those 87 patients, 81 (93%) experienced an end-of-induction (EOI) complete response. One patient died during induction and six had induction failures, defined as either disease progression before EOI (two patients) or EOI MRD of 5% or greater (three patients), said Dr. Orgel of the University of Southern California, Los Angeles, and Children’s Hospital Los Angeles.
The MRD-negative rates, defined as MRD less than 0.01%, were 70% at EOI and 86% at EOI or end of consolidation (EOC); 12 of 14 patients who were MRD positive at EOI and continued on ALL therapy achieved an EOC MRD-negative complete response, including 8 of 8 with EOI MRD of 0.01%-0.09% and 4 of 6 with EOI MRD of 1% or greater.
Event-free survival at 5 years in the 78 patients without hematopoietic stem cell transplant at first remission was 75%, and 5-year overall survival was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said. “This is very different from the approach used at many adult centers and many of the adult recommendations.”
Overall 5-year EOI event-free survival was 80% in the 59 patients who were MRD negative at EOI, and 13% in 25 patients who were MRD-positive at EOI. The corresponding overall survival rates were 91% and 84%.
Overall 5-year EOC event-free survival was 77% in 74 patients who were MRD negative at EOC and was unavailable in 3 patients who were MRD positive at EOC, although all three were salvaged. The corresponding EOC overall survival rates were 89% and “not available,” Dr. Orgel reported.
Multivariable analysis confirmed the predictive value of MRD at EOI (hazard ratio for event-free survival and overall survival, 3.77 and 3.54, respectively).
Of note, there was a possible trend toward earlier failure and a trend toward worse overall survival (HR, 4.49, P = .074) for T-lineage–containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” he said.
MRD in pediatric MPAL is rare. Recent studies of MPAL biology show areas of similarity with ALL and AML, and while this could eventually help further subcategorize or classify the disease and lead to biology-driven therapies, it is important to know how to treat the disease today, Dr. Orgel said.
The evolving consensus is that ALL therapy is adequate for most MPAL, but there is no established threshold for MRD to enable a risk-stratified MPAL approach, he added.
The current findings suggest that ALL therapy – without hematopoietic stem cell transplant – may be sufficient to treat most patients with pediatric MPAL, Dr. Orgen reported, noting that clinical trials are necessary to prospectively validate MRD thresholds at EOI and EOC and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” he said.
Dr. Orgel reported having no financial disclosures.
SOURCE: Oberley M et al. ASH 2018, Abstract 558.
SAN DIEGO – The majority of pediatric patients with mixed phenotype acute leukemia (MPAL) who were treated with acute lymphoblastic leukemia (ALL)–directed chemotherapy achieved a minimum residual disease (MRD)–negative complete response by the end of consolidation, according to findings from a multicenter retrospective cohort study.
The cohort included 94 patients aged 1-21 years who met strict World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions. Most had B/myeloid phenotype (89%), and 87 patients were treated with an ALL regimen, Etan Orgel, MD, reported at the annual meeting of the American Society of Hematology.
Of those 87 patients, 81 (93%) experienced an end-of-induction (EOI) complete response. One patient died during induction and six had induction failures, defined as either disease progression before EOI (two patients) or EOI MRD of 5% or greater (three patients), said Dr. Orgel of the University of Southern California, Los Angeles, and Children’s Hospital Los Angeles.
The MRD-negative rates, defined as MRD less than 0.01%, were 70% at EOI and 86% at EOI or end of consolidation (EOC); 12 of 14 patients who were MRD positive at EOI and continued on ALL therapy achieved an EOC MRD-negative complete response, including 8 of 8 with EOI MRD of 0.01%-0.09% and 4 of 6 with EOI MRD of 1% or greater.
Event-free survival at 5 years in the 78 patients without hematopoietic stem cell transplant at first remission was 75%, and 5-year overall survival was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said. “This is very different from the approach used at many adult centers and many of the adult recommendations.”
Overall 5-year EOI event-free survival was 80% in the 59 patients who were MRD negative at EOI, and 13% in 25 patients who were MRD-positive at EOI. The corresponding overall survival rates were 91% and 84%.
Overall 5-year EOC event-free survival was 77% in 74 patients who were MRD negative at EOC and was unavailable in 3 patients who were MRD positive at EOC, although all three were salvaged. The corresponding EOC overall survival rates were 89% and “not available,” Dr. Orgel reported.
Multivariable analysis confirmed the predictive value of MRD at EOI (hazard ratio for event-free survival and overall survival, 3.77 and 3.54, respectively).
Of note, there was a possible trend toward earlier failure and a trend toward worse overall survival (HR, 4.49, P = .074) for T-lineage–containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” he said.
MRD in pediatric MPAL is rare. Recent studies of MPAL biology show areas of similarity with ALL and AML, and while this could eventually help further subcategorize or classify the disease and lead to biology-driven therapies, it is important to know how to treat the disease today, Dr. Orgel said.
The evolving consensus is that ALL therapy is adequate for most MPAL, but there is no established threshold for MRD to enable a risk-stratified MPAL approach, he added.
The current findings suggest that ALL therapy – without hematopoietic stem cell transplant – may be sufficient to treat most patients with pediatric MPAL, Dr. Orgen reported, noting that clinical trials are necessary to prospectively validate MRD thresholds at EOI and EOC and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” he said.
Dr. Orgel reported having no financial disclosures.
SOURCE: Oberley M et al. ASH 2018, Abstract 558.
SAN DIEGO – The majority of pediatric patients with mixed phenotype acute leukemia (MPAL) who were treated with acute lymphoblastic leukemia (ALL)–directed chemotherapy achieved a minimum residual disease (MRD)–negative complete response by the end of consolidation, according to findings from a multicenter retrospective cohort study.
The cohort included 94 patients aged 1-21 years who met strict World Health Organization MPAL criteria and were treated between 2008 and 2016 at one of six U.S. institutions. Most had B/myeloid phenotype (89%), and 87 patients were treated with an ALL regimen, Etan Orgel, MD, reported at the annual meeting of the American Society of Hematology.
Of those 87 patients, 81 (93%) experienced an end-of-induction (EOI) complete response. One patient died during induction and six had induction failures, defined as either disease progression before EOI (two patients) or EOI MRD of 5% or greater (three patients), said Dr. Orgel of the University of Southern California, Los Angeles, and Children’s Hospital Los Angeles.
The MRD-negative rates, defined as MRD less than 0.01%, were 70% at EOI and 86% at EOI or end of consolidation (EOC); 12 of 14 patients who were MRD positive at EOI and continued on ALL therapy achieved an EOC MRD-negative complete response, including 8 of 8 with EOI MRD of 0.01%-0.09% and 4 of 6 with EOI MRD of 1% or greater.
Event-free survival at 5 years in the 78 patients without hematopoietic stem cell transplant at first remission was 75%, and 5-year overall survival was 89%, “thus demonstrating that, for a majority of patients, transplant in first remission may not be necessary,” Dr. Orgel said. “This is very different from the approach used at many adult centers and many of the adult recommendations.”
Overall 5-year EOI event-free survival was 80% in the 59 patients who were MRD negative at EOI, and 13% in 25 patients who were MRD-positive at EOI. The corresponding overall survival rates were 91% and 84%.
Overall 5-year EOC event-free survival was 77% in 74 patients who were MRD negative at EOC and was unavailable in 3 patients who were MRD positive at EOC, although all three were salvaged. The corresponding EOC overall survival rates were 89% and “not available,” Dr. Orgel reported.
Multivariable analysis confirmed the predictive value of MRD at EOI (hazard ratio for event-free survival and overall survival, 3.77 and 3.54, respectively).
Of note, there was a possible trend toward earlier failure and a trend toward worse overall survival (HR, 4.49, P = .074) for T-lineage–containing MPAL.
“That indicates that this might be a group that needs careful scrutiny of which form of ALL therapy they receive,” he said.
MRD in pediatric MPAL is rare. Recent studies of MPAL biology show areas of similarity with ALL and AML, and while this could eventually help further subcategorize or classify the disease and lead to biology-driven therapies, it is important to know how to treat the disease today, Dr. Orgel said.
The evolving consensus is that ALL therapy is adequate for most MPAL, but there is no established threshold for MRD to enable a risk-stratified MPAL approach, he added.
The current findings suggest that ALL therapy – without hematopoietic stem cell transplant – may be sufficient to treat most patients with pediatric MPAL, Dr. Orgen reported, noting that clinical trials are necessary to prospectively validate MRD thresholds at EOI and EOC and to establish the threshold for favorable survival.
“Future research should explore either intensification of therapy or different therapies for patients with persistent MRD,” he said.
Dr. Orgel reported having no financial disclosures.
SOURCE: Oberley M et al. ASH 2018, Abstract 558.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: MRD-negative rates were 70% at end of induction and 86% at end of induction or consolidation.
Study details: A retrospective cohort study of 87 pediatric MPAL patients.
Disclosures: Dr. Orgel reported having no financial disclosures.
Source: Oberley M et al. ASH 2018, Abstract 558.
FDA expands dasatinib indication to children with Ph+ ALL
The .
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients aged 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is already approved for use in children aged 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is approved to treat newly diagnosed, Ph+, chronic phase CML; chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL with resistance or intolerance to prior therapy. The approval in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol in patients (aged 1-17 years) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months.
The most common adverse events (AEs) in these patients were mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, and constipation.
Eight patients (10%) had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
The .
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients aged 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is already approved for use in children aged 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is approved to treat newly diagnosed, Ph+, chronic phase CML; chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL with resistance or intolerance to prior therapy. The approval in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol in patients (aged 1-17 years) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months.
The most common adverse events (AEs) in these patients were mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, and constipation.
Eight patients (10%) had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
The .
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients aged 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is already approved for use in children aged 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is approved to treat newly diagnosed, Ph+, chronic phase CML; chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib; and Ph+ ALL with resistance or intolerance to prior therapy. The approval in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 multi-agent chemotherapy protocol in patients (aged 1-17 years) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months.
The most common adverse events (AEs) in these patients were mucositis, febrile neutropenia, pyrexia, diarrhea, nausea, vomiting, musculoskeletal pain, abdominal pain, cough, headache, rash, fatigue, and constipation.
Eight patients (10%) had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
FDA approves dasatinib for kids with Ph+ ALL
The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is FDA-approved to treat:
- Newly diagnosed, Ph+, chronic phase CML
- Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
- Ph+ ALL with resistance or intolerance to prior therapy.
Trial results
The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).
The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).
Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is FDA-approved to treat:
- Newly diagnosed, Ph+, chronic phase CML
- Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
- Ph+ ALL with resistance or intolerance to prior therapy.
Trial results
The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).
The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).
Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
The U.S. Food and Drug Administration (FDA) has approved a second pediatric indication for dasatinib (Sprycel®).
The tyrosine kinase inhibitor is now approved for use in combination with chemotherapy to treat pediatric patients age 1 year and older who have newly diagnosed, Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
Dasatinib is also FDA-approved for use in children age 1 year and older who have chronic phase, Ph+ chronic myeloid leukemia (CML).
In adults, dasatinib is FDA-approved to treat:
- Newly diagnosed, Ph+, chronic phase CML
- Chronic, accelerated, or myeloid/lymphoid blast phase, Ph+ CML with resistance or intolerance to prior therapy including imatinib
- Ph+ ALL with resistance or intolerance to prior therapy.
Trial results
The FDA’s approval of dasatinib in children with Ph+ ALL is based on data from a phase 2 study (CA180-372, NCT01460160).
In this trial, researchers evaluated dasatinib in combination with the AIEOP-BFM ALL 2000 chemotherapy protocol in patients (ages 1 to 17) with newly diagnosed, B-cell precursor, Ph+ ALL.
There were 78 patients evaluated for efficacy in cohort 1. They had a median age of 10.4 years (range, 2.6 to 17.9 years). They received dasatinib at a daily dose of 60 mg/m2 for up to 24 months.
Patients with central nervous system 3 disease received cranial irradiation, and patients were assigned to stem cell transplant based on minimal residual disease if they were thought to have a high risk of relapse.
The 3-year event-free survival rate in the 78 patients was 64.1%.
There were 81 patients evaluable for safety who received dasatinib continuously in combination with chemotherapy. Their median duration of treatment was 24 months (range, 2 to 27 months).
The most common adverse events (AEs) in these patients were mucositis (93%), febrile neutropenia (86%), pyrexia (85%), diarrhea (84%), nausea (84%), vomiting (83%), musculoskeletal pain (83%), abdominal pain (78%), cough (78%), headache (77%), rash (68%), fatigue (59%), and constipation (57%).
Eight (10%) patients had AEs leading to treatment discontinuation. These included fungal sepsis, hepatotoxicity in the setting of graft-versus-host disease, thrombocytopenia, cytomegalovirus infection, pneumonia, nausea, enteritis, and drug hypersensitivity.
Three patients (4%) had fatal AEs, all infections.
This trial was sponsored by Bristol-Myers Squibb. Additional data are available in the prescribing information for dasatinib.
Group proposes new grading systems for CRS, neurotoxicity
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
A group of experts has proposed new consensus definitions and grading systems for cytokine release syndrome (CRS) and neurotoxicity related to immune effector cell therapies.
The group hopes their recommendations will be widely accepted and used in both trials and the clinical setting.
The recommendations were devised by 49 experts at a meeting supported by the American Society for Blood and Marrow Transplantation (ASBMT), compiled by a writing group, and reviewed by stakeholders.
Daniel W. Lee, MD, of the University of Virginia School of Medicine in Charlottesville, and his colleagues described the ASBMT consensus definitions and grading systems in Biology of Blood and Marrow Transplantation.
CRS
The ASBMT consensus definition for CRS is “a supraphysiologic response following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
To be diagnosed with CRS, a patient must have a fever and may have the following symptoms:
- Hypotension
- Capillary leak (hypoxia)
- End organ dysfunction.
The ASBMT consensus for grading CRS is as follows:
- Grade 1—Patient has a fever, defined as a temperature of 38.0°C or higher
- Grade 2—Patient has a fever, hypotension that doesn’t require vasopressors, and/or hypoxia that requires oxygen delivered by low-flow nasal cannula (≤6 L/min) or blow-by
- Grade 3—Patient has a fever, hypotension requiring one vasopressor (with or without vasopressin), and/or hypoxia (not attributable to any other cause) that requires high-flow nasal cannula (>6 L/min), facemask, non-rebreather mask, or venturi mask
- Grade 4—Patient has a fever, hypotension requiring multiple vasopressors (excluding vasopressin), and/or hypoxia (not attributable to any other cause) requiring positive-pressure ventilation
- Grade 5—Death due to CRS when there is no other “principle factor” leading to death.
Typically, severe CRS can be considered resolved if “fever, oxygen, and pressor requirements have resolved,” Dr. Lee and his coauthors said.
The authors also stressed that neurotoxicity that occurs with or after CRS “does not inform the grade of CRS but is instead captured separately in the neurotoxicity scale.”
Neurotoxicity
Dr. Lee and his coauthors said neurotoxicity in this setting is called “immune effector cell-associated neurotoxicity syndrome (ICANS).”
The ASBMT consensus definition for ICANs is “a disorder characterized by a pathologic process involving the central nervous system following any immune therapy that results in the activation or engagement of endogenous or infused T cells and/or other immune effector cells.”
Symptoms of ICANS may include:
- Aphasia
- Altered level of consciousness
- Impairment of cognitive skills
- Motor weakness
- Seizures
- Cerebral edema.
The ASBMT consensus for grading ICANS in adults and children age 12 and older is as follows:
- Grade 1—Patient has a score of 7-9 on the 10-point immune effector cell-associated encephalopathy (ICE) assessment and awakens spontaneously
- Grade 2—Patient has a score of 3-6 on the ICE assessment and will awaken to the sound of a voice
- Grade 3—Patient has a score of 0-2 on the ICE assessment, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform the ICE assessment, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors noted that the ICE assessment is not suitable for children younger than 12. For these patients (and older patients with baseline developmental delays), ICANS can be assessed using the Cornell Assessment of Pediatric Delirium (CAPD).
The ASBMT consensus for grading ICANS in children younger than 12 (or older patients with developmental delays) is as follows:
- Grade 1—Patient has a CAPD score lower than 9 and awakens spontaneously
- Grade 2—Patient has a CAPD score lower than 9 and will awaken to the sound of a voice
- Grade 3—Patient has a CAPD score of 9 or higher, awakens only to tactile stimulus, has any clinical seizure that resolves rapidly or non-convulsive seizures that resolve with intervention, and/or has focal/local edema on neuroimaging
- Grade 4—Patient is unable to perform CAPD, is unarousable or requires “vigorous stimuli” to be aroused, has life-threatening seizure (lasting more than 5 minutes) or repetitive clinical or electrical seizures without return to baseline in between, has deep focal motor weakness, and/or has decerebrate or decorticate posturing, cranial nerve VI palsy, papilledema, Cushing’s triad, or signs of diffuse cerebral edema on neuroimaging
- Grade 5—Death due to ICANS when there is no other “principle factor” leading to death.
Dr. Lee and his coauthors reported relationships with a range of companies.
FDA approves calaspargase pegol-mknl for ALL
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
The U.S. Food and Drug Administration (FDA) has approved calaspargase pegol-mknl (Asparlas) as a component of a multi-agent chemotherapeutic regimen to treat acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years.
Calaspargase pegol-mknl is an asparagine-specific enzyme intended to provide a longer interval between doses compared to other available pegaspargase products.
The recommended dosage of calaspargase pegol-mknl is 2,500 U/m2 given no more frequently than every 21 days.
The FDA said it approved calaspargase pegol-mknl because the drug maintained nadir serum asparaginase activity above the level of 0.1 U/mL when given at 2,500 U/m2 every 3 weeks.
Calaspargase pegol-mknl was evaluated in Study DFCI 11-001, a trial of 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma. The patients’ median age was 5 years (range, 1 to 20 years).
They received calaspargase pegol-mknl at 2,500 U/m2 (n=118) or pegaspargase at 2,500 U/m2 (n=119) as part of a Dana-Farber Cancer Institute (DFCI) ALL Consortium backbone therapy.
The median duration of exposure was 8 months for both calaspargase pegol-mknl and pegaspargase.
Among the patients with B-cell lineage ALL, the complete remission rate was 98% in the calaspargase pegol-mknl arm and 99% in the pegaspargase arm. Estimated overall survival rates were comparable between the arms.
Common grade 3 or higher adverse events (in the calaspargase pegol-mknl and pegaspargase arms, respectively) included elevated transaminase (52% and 66%), bilirubin increase (20% and 25%), pancreatitis (18% and 24%), and abnormal clotting studies (14% and 21%).
There was one fatal adverse event among patients on calaspargase pegol-mknl—multi-organ failure in the setting of chronic pancreatitis associated with a pancreatic pseudocyst.
The safety of calaspargase pegol-mknl was also evaluated in Study AALL07P4, a trial of patients with newly diagnosed, high-risk B-precursor ALL.
The patients received calaspargase pegol-mknl at 2,500 U/m2 (n=43) or 2,100 U/m2 (n=68) or pegaspargase at 2,500 U/m2 (n=52) as a component of an augmented Berlin-Frankfurt-Münster regimen.
The patients’ median age was 11 years (range, 1 to 26 years). The median duration of exposure was 7 months for both calaspargase pegol-mknl and pegaspargase.
There were three induction deaths among the 111 patients who received calaspargase pegol-mknl (2.8%) but no induction deaths among the 52 patients treated with pegaspargase.
Additional details on these studies and calaspargase pegol-mknl can be found in the drug’s prescribing information.
Calaspargase pegol-mknl is a product of Servier Pharmaceuticals LLC.
FDA approves Elzonris for blastic plasmacytoid dendritic cell neoplasm
The Food and Drug Administration has approved tagraxofusp-erzs (Elzonris) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients, 2 years of age and older.
Approval was based on efficacy in two cohorts of patients in a single-arm clinical trial. Seven patients (54%) out of 13 with untreated BPDCN achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc) in the first cohort. In the second cohort of 15 patients, one patient achieved CR and one patient achieved CRc.
Common side effects for patients receiving tagraxofusp-erzs infusion were capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills, and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin, and calcium, and increases in glucose and liver enzymes (ALT and AST), the FDA said in a press statement.
The FDA placed a Boxed Warning on the drug to alert health care professionals and patients about the increased risk of capillary leak syndrome and recommends that health care providers monitor liver enzyme levels for signs of intolerance to the infusion.
BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia, the FDA said.
“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.
The Food and Drug Administration has approved tagraxofusp-erzs (Elzonris) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients, 2 years of age and older.
Approval was based on efficacy in two cohorts of patients in a single-arm clinical trial. Seven patients (54%) out of 13 with untreated BPDCN achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc) in the first cohort. In the second cohort of 15 patients, one patient achieved CR and one patient achieved CRc.
Common side effects for patients receiving tagraxofusp-erzs infusion were capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills, and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin, and calcium, and increases in glucose and liver enzymes (ALT and AST), the FDA said in a press statement.
The FDA placed a Boxed Warning on the drug to alert health care professionals and patients about the increased risk of capillary leak syndrome and recommends that health care providers monitor liver enzyme levels for signs of intolerance to the infusion.
BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia, the FDA said.
“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.
The Food and Drug Administration has approved tagraxofusp-erzs (Elzonris) infusion for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in adults and pediatric patients, 2 years of age and older.
Approval was based on efficacy in two cohorts of patients in a single-arm clinical trial. Seven patients (54%) out of 13 with untreated BPDCN achieved complete remission (CR) or CR with a skin abnormality not indicative of active disease (CRc) in the first cohort. In the second cohort of 15 patients, one patient achieved CR and one patient achieved CRc.
Common side effects for patients receiving tagraxofusp-erzs infusion were capillary leak syndrome, nausea, fatigue, peripheral edema, pyrexia, chills, and weight increase. Most common laboratory abnormalities were decreases in lymphocytes, albumin, platelets, hemoglobin, and calcium, and increases in glucose and liver enzymes (ALT and AST), the FDA said in a press statement.
The FDA placed a Boxed Warning on the drug to alert health care professionals and patients about the increased risk of capillary leak syndrome and recommends that health care providers monitor liver enzyme levels for signs of intolerance to the infusion.
BPDCN is an aggressive and rare disease of the bone marrow and blood that can affect multiple organs, including the lymph nodes and the skin. It often presents as leukemia or evolves into acute leukemia, the FDA said.
“Prior to today’s approval, there had been no FDA approved therapies for BPDCN. The standard of care has been intensive chemotherapy followed by bone marrow transplantation. Many patients with BPDCN are unable to tolerate this intensive therapy, so there is an urgent need for alternative treatment options,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in the statement.