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Approved TKI could treat drug-resistant CML, ALL
Photo courtesy of CDC
New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).
The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.
“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.
“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”
Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.
The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.
In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.
The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.
The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.
“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.
“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”
The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.
“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded. 
Photo courtesy of CDC
New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).
The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.
“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.
“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”
Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.
The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.
In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.
The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.
The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.
“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.
“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”
The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.
“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.
Photo courtesy of CDC
New research indicates that a tyrosine kinase inhibitor (TKI) approved to treat advanced renal cell carcinoma could prove useful in treating patients with drug-resistant chronic myeloid leukemia (CML) or acute lymphoblastic leukemia (ALL).
The study showed that the TKI, axitinib, can inhibit BCR-ABL1 (T315I), a mutation known to confer drug resistance in CML and ALL.
“Since axitinib is already used to treat cancer, its safety is known,” said Kimmo Porkka, MD, PhD, of the University of Helsinki in Finland.
“[A] formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened.”
Dr Porkka and his colleagues described the newfound activity of axitinib in Nature.
The researchers used a drug sensitivity and resistance testing method developed at the University of Helsinki’s Institute for Molecular Medicine Finland (FIMM) to examine how patient-derived leukemia cells responded to a large panel of drugs.
In this way, the group identified axitinib as a promising drug candidate for CML and ALL. Axitinib effectively eliminated drug-resistant leukemia cells.
The TKI inhibited BCR-ABL1 (T315I) at biochemical and cellular levels by binding to the active form of ABL1 (T315I) in a mutation-selective binding mode.
The researchers said this suggests the T315I mutation shifts the conformational equilibrium of the kinase in favor of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib.
“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key,” said study author Brion Murray, PhD, of Pfizer Worldwide Research & Development in San Diego, California.
“In the case of axitinib, it acts as two distinct keys—one for renal cell carcinoma and one for leukemia.”
The researchers also treated a CML patient with axitinib and observed a “rapid reduction” of T315I-positive cells in the patient’s bone marrow.
“Further research will determine whether these findings have the potential to significantly improve the standard of care for this select group of CML patients and patients with other related leukemias,” Dr Murray concluded.
Gene variation explains drug toxicity in ALL
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
Fusion protein fights resistant ALL
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
In a preclinical study, a fusion protein targeted treatment-resistant leukemia, demonstrating superiority over both chemotherapy and radiation.
The protein, CD19L-sTRAIL, induced apoptosis in radiation-resistant cells from patients with B-precursor acute lymphoblastic leukemia (ALL) and in
mouse models of the disease.
Additionally, mice that received CD19L-sTRAIL had significantly longer event-free survival than mice that received chemotherapy.
An account of this study appears in The Journal of Clinical Investigation.
Study investigators knew that TNF-related apoptosis-inducing ligand (TRAIL) can cause apoptosis in cancer cells by binding to TRAIL-receptor 1 and TRAIL-receptor 2.
“TRAIL is a naturally occurring part of the body’s immune system that kills cancer cells without toxicity to normal cells,” said Faith Uckun, MD, PhD, of Children’s Hospital Los Angeles in California.
“However, earlier clinical trials using TRAIL as a potential anticancer medicine candidate have not been successful, largely because of its propensity to bind, not only to cancer cells, but also to ‘decoy’ receptors.”
But Dr Uckun and her colleagues had discovered CD19-ligand (CD19L), a natural ligand of human CD19 that is expressed by almost all ALL cells. And they hypothesized that fusing CD19L to the portion of TRAIL that can kill cancer cells (known as sTRAIL) would produce a powerful weapon against leukemia cells.
The resulting fusion protein, CD19L-sTRAIL, would seek out, bind, and destroy only leukemia cells carrying CD19 as the target docking site.
In experiments, the investigators showed that their engineering converted sTRAIL into a much more potent “membrane-anchored” form that is capable of triggering apoptosis, even in the most aggressive and therapy-resistant ALL cells.
“Due to its ability to anchor to the surface of cancer cells via CD19, CD19L-sTRAIL was 100,000-fold more potent than sTRAIL and consistently killed more than 99% of aggressive leukemia cells taken directly from children with ALL—not only in the test tube but also in mice,” Dr Uckun said.
At a 2.1 pM concentration, CD19L-sTRAIL caused 84.0±4.7% apoptosis in leukemia cells from patients with B-precursor ALL, whereas radiation with 2 Gy γ-rays caused 45.0±9.0% apoptosis (P<0.0001). Higher concentrations of CD19L-sTRAIL prompted an apoptosis rate of more than 90%.
In cells from mouse models of B-precursor ALL, 2.1 pM of CD19L-sTRAIL caused 91.4±5.4% apoptosis, compared to 16.0±4.6% with 2 Gy γ-rays (P<0.0001).
In addition, administering 2 or 3 doses of CD19L-sTRAIL significantly improved event-free survival in mice challenged with an otherwise fatal dose of leukemia cells.
The median event-free survival was 17 days in control mice; 20 days in mice treated with either vincristine, dexamethasone, and peg-asparaginase or vincristine, doxorubicin, and peg-asparaginase; and 58 days in mice that received 2- to 3-day treatment with CD19L-sTRAIL (P<0.0001 vs controls; P=0.0002 vs chemo).
The investigators said these results support the clinical potential of CD19L-sTRAIL as a new agent against B-precursor ALL.
“We are hopeful that the knowledge gained from this study will open a new range of effective treatment opportunities for children with recurrent leukemia,” Dr Uckun said.
EC supports continued use of ponatinib
Credit: Rhoda Baer
The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.
After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.
Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.
Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.
The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.
In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.
However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.
The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.
Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.
Credit: Rhoda Baer
The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.
After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.
Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.
Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.
The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.
In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.
However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.
The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.
Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.
Credit: Rhoda Baer
The European Commission (EC) has concluded that ponatinib (Iclusig) should continue to be prescribed in accordance with its already approved indications.
After trial results suggested the drug poses an increased risk of thrombotic events, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) conducted a review of available ponatinib data.
Results of that review suggested the benefits of ponatinib outweigh the risks. So the committee said the drug should be prescribed as indicated.
The EMA’s Committee for Medicinal Products for Human Use (CHMP) recently endorsed this recommendation, and, now, the EC has followed suit. The EC’s decision is legally binding.
Ponatinib is approved in the European Union to treat adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia who are resistant to dasatinib or nilotinib, who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
The drug is also approved to treat adults with Philadelphia-chromosome positive acute lymphoblastic leukemia who are resistant to dasatinib, who cannot tolerate dasatinib and subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.
In October 2013, extended follow-up data from the PACE trial revealed that ponatinib-treated patients had a higher incidence of arterial and venous thrombotic events than was observed when the drug first gained approval. So one ponatinib trial was discontinued, and the rest were placed on partial clinical hold.
Soon after, ponatinib was pulled from the US market. The drug ultimately returned to the marketplace with new recommendations designed to decrease the risk of thrombotic events.
The EMA also revised its recommendations for ponatinib—discouraging use of the drug in certain patients, providing advice for managing comorbidities, and suggesting patient monitoring—but kept the drug on the market.
In October 2014, the PRAC concluded its 11-month review of ponatinib data, confirming that the benefit-risk profile of the drug was favorable in its approved indications and recommending that the indications remain unchanged.
However, the PRAC also said the risk of vascular occlusive events with ponatinib is likely dose-related. So the committee recommended that healthcare professionals monitor ponatinib-treated patients and consider dose reductions or discontinuing the drug in certain patients.
The CHMP endorsed these recommendations, and, now, the EC has as well. This is a legally binding decision for ponatinib to continue to be prescribed in Europe in accordance with its already approved indications.
Ponatinib is being developed by ARIAD Pharmaceuticals, Inc.
CARs come in different makes and models
Credit: NIAID
SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.
Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.
These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.
Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.
Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.
And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.
The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.
Credit: NIAID
SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.
Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.
These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.
Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.
Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.
And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.
The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.
Credit: NIAID
SAN FRANCISCO—CTL019, a chimeric antigen receptor (CAR) T cell targeting CD19, is not the only CAR in the production line.
Investigators at the National Cancer Institute in Bethesda, Maryland, and Memorial Sloan Kettering Cancer Center (MSKCC) in New York City are also pursuing CAR T-cell therapy.
These groups are using a retroviral platform to transduce the T cells rather than a lentiviral one, as is the case with CTL019.
Investigators reported progress to date on these makes of CARs at the 2014 ASH Annual Meeting.
Daniel W. Lee III, MD, of the National Cancer Institute, reported on a phase 1 study of CD19 CAR T cells in children and young adults with CD19+ acute lymphoblastic leukemia or non-Hodgkin lymphoma.
And Jae H. Park, MD, of MSKCC, presented data from a trial of JCAR015—autologous T cells genetically modified to express a 19-28z CAR targeting CD19—in patients with B-cell acute lymphoblastic leukemia.
The study is sponsored by MSKCC, but JCAR015 is a product of Juno Therapeutics.
CAR is feasible in majority of ALL patients, team says
Credit: Bill Branson
SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.
Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).
Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.
Dose levels were 1 x 106 CAR+ T cells/kg, 3 x 106 CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.
Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.
All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.
The investigators determined that the maximally tolerated dose was 1 x 106 CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.
Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.
Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.
The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.
“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”
Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).
At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.
The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.
The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.
*Information in the abstract differs from that presented at the meeting.
Credit: Bill Branson
SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.
Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).
Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.
Dose levels were 1 x 106 CAR+ T cells/kg, 3 x 106 CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.
Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.
All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.
The investigators determined that the maximally tolerated dose was 1 x 106 CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.
Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.
Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.
The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.
“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”
Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).
At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.
The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.
The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.
*Information in the abstract differs from that presented at the meeting.
Credit: Bill Branson
SAN FRANCISCO—A chimeric antigen receptor (CAR) T-cell therapy is feasible in 90% of heavily pretreated or transplanted patients with acute lymphoblastic leukemia (ALL) and can serve as a bridge to transplant, according to investigators.
Daniel W. Lee III, MD, of the National Cancer Institute in Bethesda, Maryland, reported on a phase 1 study of this CD19 CAR T-cell therapy in children and young adults with CD19+ ALL or non-Hodgkin lymphoma at the 2014 ASH Annual Meeting (abstract 381*).
Twenty-one patients were enrolled on the trial. They had a preparative regimen of fludarabine and cyclophosphamide and were infused with CAR T cells 11 days after the peripheral blood mononuclear cells were collected.
Dose levels were 1 x 106 CAR+ T cells/kg, 3 x 106 CAR+ T cells/kg, or the maximum number of cells generated if below either one of these levels. Two patients received less than the dose assigned and were not evaluated for toxicity.
Patients were a median age of 13 years (range, 5 to 27). Fourteen were male, 20 had ALL, and 1 had diffuse large B-cell lymphoma.
All had detectable disease, and 2 were CNS2 at the time of T-cell infusion. Six had primary refractory disease, 8 had at least 1 prior stem cell transplant, and 4 had prior immunotherapy.
The investigators determined that the maximally tolerated dose was 1 x 106 CAR+ T cells/kg. The dose-limiting toxicities were related to cytokine release syndrome (CRS), which was reversible if managed appropriately with tocilizumab, with or without steroids.
Grade 3 adverse events possibly related to therapy included fever (47%), febrile neutropenia (37%), electrolyte disturbance (29%), CRS (16%), hypotension (11%), transaminitis (16%), and 5% each for hypertension, prolonged QTc, dysphasia, LV systolic dysfunction, multiorgan failure, hypoxia, and pulmonary edema.
Grade 4 events possibly related to treatment included electrolyte disturbance (5%), CRS (16%), hypotension (11%), cardiac arrest (5%), and hypoxia (5%). There was no evidence of graft-vs-host disease.
The complete response (CR) rate was 67% in the intent-to-treat population and 70% in patients with ALL.
“Those patients who responded tended to have some degree of cytokine release syndrome, whereas those patients who did not respond or had stable disease did not have any CRS,” Dr Lee said. “But, also, it’s important to note that you don’t have to have severe grade 3 or grade 4 CRS in order to have significant response.”
Dr Lee also pointed out that in vivo CAR T-cell expansion significantly correlated with response (P=0.0028). And CRS severity correlated with IL-6 (P=0.0002), INF-γ (P=0.0002), C-reactive protein (P=0.0015), and CAR (P=0.0011).
At a median follow-up of 10 months, minimal residual disease-negative patients had a 79% leukemia-free survival. Overall survival was 52% for all patients enrolled. Two patients had CD19-negative relapses.
The investigators also found that CAR T cells can eliminate CNS leukemia, with 11 of 17 patients (65%) having CAR T cells detectable in their cerebrospinal fluid.
The team concluded that this therapy is feasible in 90% of heavily pretreated or transplanted ALL patients and can serve as a bridge to transplant.
*Information in the abstract differs from that presented at the meeting.
CAR produces durable responses in B-cell ALL
Credit: Charles Haymond
SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.
JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
JCAR015 was tested at a dose of 1 - 3 x 106 CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.
Twenty-one patients were male, and the median age was 55 (range, 23 to 74).
Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).
Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.
Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.
The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).
The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.
Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.
At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.
Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.
The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.
For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.
Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.
The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.
Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.
The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.
Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.
He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.
*Information in the abstract differs from that presented at the meeting.
Credit: Charles Haymond
SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.
JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
JCAR015 was tested at a dose of 1 - 3 x 106 CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.
Twenty-one patients were male, and the median age was 55 (range, 23 to 74).
Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).
Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.
Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.
The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).
The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.
Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.
At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.
Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.
The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.
For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.
Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.
The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.
Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.
The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.
Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.
He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.
*Information in the abstract differs from that presented at the meeting.
Credit: Charles Haymond
SAN FRANCISCO—JCAR015, a chimeric antigen receptor (CAR) T-cell therapy, can produce durable responses in patients with B-cell acute lymphoblastic leukemia (ALL) who do not undergo subsequent hematopoietic stem cell transplant (HSCT), new research suggests.
JCAR015 consists of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19.
Jae H. Park, MD, of Memorial Sloan Kettering Cancer Center in New York, presented data on JCAR015 at the 2014 ASH Annual Meeting (abstract 382).* The study is sponsored by Memorial Sloan Kettering, but funding has also been provided by Juno Therapeutics, the company developing JCAR015.
JCAR015 was tested at a dose of 1 - 3 x 106 CAR cells/kg in 33 adults with relapsed/refractory B-cell ALL. Twenty-eight patients were evaluable for toxicity, 27 for response, and 5 patients were too early in their treatment to evaluate at the time of data cutoff.
Twenty-one patients were male, and the median age was 55 (range, 23 to 74).
Thirteen patients (46%) had minimal disease (<5% blasts) immediately prior to T-cell infusion, and 15 patients (54%) had morphologic disease of 5% to 100% blasts (median 63%).
Eighteen patients (64%) had received 2 prior lines of therapy, and 5 (18%) each had 3 or more prior lines.
Eight patients (29%) underwent prior allogeneic HSCT, 9 patients (32%) were Philadelphia chromosome positive (Ph+), and 3 (11%) had the T315I mutation.
The overall complete response (CR) rate was 89%, and the minimal residual disease-negative CR rate was 88%. The median time to CR was 22.5 days (range, 9 to 33).
The investigators performed a subgroup analysis and found that 100% of the 13 patients with minimal disease before therapy achieved a CR, compared to 79% of patients with morphologic disease.
Eighty-six percent (6/7) of patients who had a prior HSCT and 90% (18/20) without a prior HSCT achieved a CR. Eighty-nine percent (8/9) of Ph+ patients achieved a CR, and 89% (16/18) of Philadelphia-negative patients (89%) achieved a CR.
At a median follow-up of 6 months (range, 1 to 38 months), 12 patients remained disease-free, including 7 patients who had more than a year of follow-up. Seven patients are disease-free without a subsequent HSCT.
Nine patients relapsed during a follow-up of 3 to 8 months, and 10 patients proceeded to HSCT. Two relapses occurred after HSCT, one in a patient who had CD19-negative blasts, and 7 relapses occurred without HSCT.
The overall survival rate at 6 months was 57%, and the median survival was 8.5 months.
For those patients who had a transplant after CAR therapy, the median survival was 10.8 months, and the survival rate at 6 months was 68%.
Dr Park pointed out that maximum T-cell expansion occurred between days 7 and 14 and correlated with the occurrence of cytokine release syndrome (CRS). The T cells persisted for 1 to 3 months following infusion.
The main adverse events were those associated with CRS and neurologic changes. Severe CRS requiring vasopressors or mechanical ventilation occurred in 5 patients (18%) overall and in 5 patients (33%) with morphologic disease before therapy. Severe CRS did not occur in any patient with minimal disease before therapy.
Grade 3 or 4 neurotoxicity occurred in 7 patients (25%) overall, in 6 patients (40%) with morphologic disease, and in 1 with minimal disease (8%) before therapy.
The investigators observed no graft-vs-host disease exacerbation, and CRS was managed with an IL-6R inhibitor, steroids, or both.
Dr Park noted that the neurologic symptoms are reversible and can occur independently of CRS.
He also pointed out that CR rates were similar regardless of different disease risk factors, and that durable responses have been achieved in patients who did not have a subsequent HSCT.
*Information in the abstract differs from that presented at the meeting.
CAR-T cell therapy rolls on in pediatric ALL
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
SAN FRANCISCO – CAR-T cell therapy drove relapsed, refractory acute lymphoblastic leukemia into complete remission in 92% or all but three of 39 children in a phase I/IIa study.
Complete responses were seen within 28 days of receiving a chimeric antigen receptor (CAR)-T cell infusion and have persisted in 15 patients for a year or more, Dr. Stephan A. Grupp reported at the annual meeting of the American Society of Hematology.
Ten relapses have occurred during follow-up of up to 31 months (median 6 months). Half were due to disappearance of the T cells, resulting in CD19-positive relapse, and half were related to antigen escape, resulting in CD19-negative relapse.
Five of the relapsed patients died. No events have been seen in patients who remain in remission after 12 months.
Importantly, CAR-T cell therapy was not used as a bridge to transplant, with only three patients subsequently going on to stem cell transplantation, Dr. Grupp, a pediatric oncologist at the Children’s Hospital of Philadelphia (CHOP) and professor of pediatrics at the University of Pennsylvania, said during a press briefing.
When asked whether CAR-T therapy could be a replacement for transplantation in the future, Dr. Grupp responded, “That would be my fondest hope. We’re not quite there yet, but we’re a lot closer than we used to be.”
The novel immunotherapy first hit the front pages in 2011 after researchers at CHOP and the University of Pennsylvania reported breakthrough results in a handful of children treated with CTL019 cells. T cells are collected from the patient and then genetically reengineered with a CAR directed against tumor B cells expressing the CD19 surface antigen.
More than 130 patients have now been treated by the Pennsylvania team with the CTL019 approach, which received breakthrough therapy status from the Food and Drug Administration in July 2014.
The updated results presented by Dr. Grupp build on those reported earlier this year (N. Engl. J. Med. 2014;371:1507-17) and involve 39 children and young adults. This includes the first 30 pediatric patients with relapsed, refractory ALL treated in the pilot trial. Their median age was 10 years and most were refractory to multiple prior therapies.
At 6 months, the duration of response was 76% and event-free survival was 70%.
The ability of patients to retain their T cells for 6 months or longer was observed in about two-thirds of patients and “is a key point in maintaining remission in these patients,” Dr. Grupp said.
Response rates were independent of disease burden at the time of infusion: 82% response in patients with more than 50% leukemia blast cells, 88% in those with more than 5% blasts, and 100% in those with 0.01%-5% blasts or less than 0.01% blasts.
Patients with higher baseline disease burden (more than 50% blasts), however, were significantly more likely to experience severe cytokine release syndrome (CRS), compared with those with lower disease burden (P < .002).
CRS has been seen across CAR-T cell studies, but there are insufficient data to determine whether this toxicity differs between adult and pediatric patients.
“The key to the cytokine release syndrome, and I believe this carries across platforms and actually may also apply to blinatumomab, is the amplification of the macrophage system through interleukin-6,” Dr. Grupp explained. “This is a classical feedback loop that is actually druggable” using the IL-6 receptor blocker tocilizumab (Actemra).
This strategy produced “remarkable control” of the CRS toxicity, with many of the severe CRS cases experiencing resolution within hours and all cases resolving within 2-3 days, he said.
B-cell aplasia was observed in all responding patients to date and was managed with intravenous immunoglobulin replacement therapy.
The two key questions for the future of CTL019 therapy are toxicity and the logistics of collecting a cell sample and sending it to a centralized manufacturing facility, Dr. Grupp said. This process has already been done on a small scale at CHOP because their cells are made at the University of Pennsylvania. Novartis, which licensed the technology, has built a cell-manufacturing facility and an ongoing phase II study is evaluating whether the technology can be safely rolled out to eight or nine pediatric centers across the country. An adult study will follow, he said.
AT ASH 2014
Key clinical point: CAR-T cell therapy continues to provide durable responses in early studies of children with refractory ALL.
Major finding: Complete remission occurred in 36 of 39 patients (92%) treated with CAR-T cell therapy.
Data source: Phase I/IIa a study in 39 children and young adults with relapsed, refractory acute lymphoblastic leukemia.
Disclosures: The authors reported financial ties with Novartis, the study sponsor.
Blinatumomab confirmed as treatment option in MRD+ ALL
SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.
In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.
This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.
Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.
“The question,” she said, “is how to treat these patients.”
She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).
The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10-3.
Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.
Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10-2 to < 10-1, and 45% were ≥ 10-3 to < 10-2.
Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.
The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.
Patients received 15 μg/m2 of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.
Results
In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10-4. And 85% achieved an incomplete MRD response of <10-4 with a minimum sensitivity of 10-4.
Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.
Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.
The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.
“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.
Adverse events
All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the
patients included tremor (7%), aphasia (5%), and encephalopathy (5%).
Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.
However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.
She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.
“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”
Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.
The BLAST trial was funded by Amgen Inc., the company developing blinatumomab. 
SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.
In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.
This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.
Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.
“The question,” she said, “is how to treat these patients.”
She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).
The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10-3.
Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.
Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10-2 to < 10-1, and 45% were ≥ 10-3 to < 10-2.
Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.
The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.
Patients received 15 μg/m2 of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.
Results
In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10-4. And 85% achieved an incomplete MRD response of <10-4 with a minimum sensitivity of 10-4.
Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.
Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.
The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.
“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.
Adverse events
All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the
patients included tremor (7%), aphasia (5%), and encephalopathy (5%).
Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.
However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.
She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.
“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”
Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.
The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.
SAN FRANCISCO—The first international, multicenter trial in acute lymphoblastic leukemia (ALL) using minimal residual disease (MRD) as a criterion for inclusion has confirmed clinical benefit for patients using a non-chemotherapeutic approach.
In the BLAST trial, blinatumomab, a bispecific T-cell engager antibody that directs cytotoxic T cells to CD19-positive cells, produced a complete MRD response in 80% of patients who were in complete hematologic remission but had quantifiable MRD at the time of treatment.
This echoes results of an earlier phase 2 study, in which blinatumomab produced an 80% MRD response rate in 20 patients with B-precursor ALL and persistent or relapsed MRD.
Nearly all patients with persistent or recurrent MRD relapse despite continued chemotherapy, according to Nicola Gökbuget, MD, PhD, of Goethe University Hospital in Frankfurt, Germany.
“The question,” she said, “is how to treat these patients.”
She presented one effective method, as shown by the BLAST trial, at the 2014 ASH Annual Meeting (abstract 379).
The trial enrolled 116 patients aged 18 or older with B-precursor ALL in complete hematologic remission but with MRD ≥ 10-3.
Patients could be in second or later remission, but they were excluded if they had a prior allogeneic stem cell transplant, circulating blasts or extra medullary ALL involvement, CNS pathology, prior chemotherapy within 2 weeks, or radiotherapy within 4 weeks.
Enrolled patients were a median age of 45 years (range, 18-76), and 34% were 65 or older. Most patients had high baseline MRD levels: 39% were ≥ 10-2 to < 10-1, and 45% were ≥ 10-3 to < 10-2.
Investigators evaluated MRD levels after each cycle. Analysis was performed in a central lab in Kiel, Germany, and was based on amplification of immunoglobulin and/or T-cell receptor gene rearrangements by PCR.
The primary endpoint was the proportion of patients achieving a complete MRD response after 1 cycle of blinatumomab.
Patients received 15 μg/m2 of blinatumomab per day by continuous intravenous infusion for 4 weeks, followed by a treatment-free period of 2 weeks. Responders could receive up to 4 cycles of therapy or receive a transplant any time after the first cycle.
Results
In the efficacy-evaluable population, 80% of 103 patients achieved a complete MRD response after 1 cycle, defined as MRD negative with no amplification in PCR with a minimum sensitivity of 10-4. And 85% achieved an incomplete MRD response of <10-4 with a minimum sensitivity of 10-4.
Results were similar in the full analysis set of 113 patients: 78% achieved complete MRD response after 1 cycle, and 85% achieved an incomplete MRD response.
Dr Gökbuget noted that 2 patients who initially achieved an incomplete response achieved a complete response during continued treatment in cycle 2.
The investigators analyzed the clinical characteristics of the patients and found that no factor—age, treatment interruptions, neurologic events, relapse history, nor gender—correlated with MRD response.
“I think that the good news is that it means that the compound was active in all of the patients,” Dr Gökbuget commented.
Adverse events
All patients experienced at least one adverse event (AE), and 2 were fatal—subdural hemorrhage and treatment-related pneumonitis. Serious treatment-related AEs that occurred in 3% or more of the
patients included tremor (7%), aphasia (5%), and encephalopathy (5%).
Thirty-one percent of patients interrupted their treatment because of AEs, which were primarily due to cytokine-related symptoms like pyrexia and neurologic events, including tremor, aphasia, and dizziness. Seventeen percent of patients permanently discontinued treatment due to an AE.
However, Dr Gökbuget pointed out that most AEs were grade 1 or 2, and the treatment interruption did not correlate with response.
She said the next step for this trial is to investigate whether high MRD response translates into long-term clinical benefit such as continued molecular remission and long-term survival.
“For me personally, this trial is very important because it is an up-to-date trial where we used PCR-based methods to identify patients with a high risk of relapse and treat them before the relapse occurs,” Dr Gökbuget said. “[W]e used a new endpoint, which is also MRD based, and . . . we used a new, non-chemotherapy treatment to eradicate this highly resistant, persistent ALL subclone.”
Blinatumomab received US Food and Drug Administration approval a few days before the start of the ASH Annual Meeting.
The BLAST trial was funded by Amgen Inc., the company developing blinatumomab.
Researchers show CTL019 cells proliferate and persist
SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.
Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).
Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*
CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.
“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”
“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”
More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.
Updated results
At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019. He and his colleagues previously reported results in children and adults with ALL in NEJM.
Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19+ and 5 were CD19-.
Dr Grupp explained that CD19+ relapses represent waning T cells, and CD19- relapses represent true antigen escape. The latter patients still have CTL019 cells.
Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.
The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.
Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.
“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”
Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.
To date, there has been no graft-vs-host disease.
In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.
Persistence and proliferation
“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”
Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.
Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19+ recurrence is overrepresented, Dr Grupp noted.
Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.
Toxicity
Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.
Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.
The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).
“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.
Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.
Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.
“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.
B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.
Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.
Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.
CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.
*Data in the presentation differ from the abstract.
SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.
Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).
Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*
CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.
“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”
“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”
More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.
Updated results
At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019. He and his colleagues previously reported results in children and adults with ALL in NEJM.
Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19+ and 5 were CD19-.
Dr Grupp explained that CD19+ relapses represent waning T cells, and CD19- relapses represent true antigen escape. The latter patients still have CTL019 cells.
Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.
The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.
Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.
“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”
Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.
To date, there has been no graft-vs-host disease.
In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.
Persistence and proliferation
“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”
Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.
Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19+ recurrence is overrepresented, Dr Grupp noted.
Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.
Toxicity
Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.
Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.
The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).
“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.
Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.
Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.
“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.
B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.
Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.
Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.
CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.
*Data in the presentation differ from the abstract.
SAN FRANCISCO—Two goals for cell therapy with chimeric antigen receptor (CAR) T cells are significant levels of in vivo proliferation and persistence after the cells are infused.
Researchers at the University of Pennsylvania, working with CTL019 cells, are beginning to see both of these phenomena in children with relapsed, refractory acute lymphoblastic leukemia (ALL).
Stephan Grupp, MD, PhD, described these results at the 2014 ASH Annual Meeting (abstract 380).*
CTL019 is a second-generation chimeric protein engineered using a single-chain variable fragment of an antibody that targets CD19 on B cells. It is combined with the intracellular signaling domains 4-1BB and CD3 zeta and expanded ex vivo with anti-CD3/anti-CD28.
“We take T cells from the patient—this is an individualized or personalized product,” Dr Grupp explained. “We transfect the T cells with a virus, and, in our case, we are using a lentiviral vector. This permanently modifies the T cells.”
“And this allows the expression of the CAR protein in the T cells, which then drives the interaction between the T cell and the cancer cell, hopefully killing the cancer cell but also, and I think this is extraordinarily important, allowing for T-cell activation and significant proliferation.”
More than 130 patients have been treated with CTL019, including patients with CLL whose results were reported at the 2014 ASCO Annual Meeting.
Updated results
At ASH, Dr Grupp provided an update on the 39 children with relapsed, refractory ALL treated with CTL019. He and his colleagues previously reported results in children and adults with ALL in NEJM.
Thirty-six patients (92%) achieved complete remission within a month after infusion. Ten patients relapsed, of whom 5 were CD19+ and 5 were CD19-.
Dr Grupp explained that CD19+ relapses represent waning T cells, and CD19- relapses represent true antigen escape. The latter patients still have CTL019 cells.
Patients were followed for a median of 6 months, ranging from 6 weeks to 31 months. And 15 patients have been followed for more than 1 year.
The patient followed for 31 months “represents the first patient treated who remains in remission with no further therapy,” Dr Grupp said.
Three patients went on to have a stem cell transplant, and 2 had other treatments. One patient had a donor-lymphocyte infusion, and 1 patient who developed myelodysplastic syndrome received treatment for that condition.
“And I think this is a key point,” Dr Grupp noted. “[I]t was a possibility to consider not continuing with a second, third, or, in one case, a fourth transplant.”
Another important point is disease burden, he said. Patients with more than 50% bone marrow blasts at the time of their T-cell infusion had a similar response rate (82%) to those patients who had a lower disease burden of 5% blasts or more (88%). Relapse occurred in all levels of disease burden in a small number of patients.
To date, there has been no graft-vs-host disease.
In terms of efficacy, there appeared to be no significant difference if the patient had received a transplant before CAR therapy or not. Eighty-nine percent of patients who had received an allogeneic transplant responded, compared to 100% who had not had a transplant.
Persistence and proliferation
“Q-PCR detection of CAR cells shows enormous proliferation,” Dr Grupp said. “We have an extraordinary amount of expansion of these cells that’s nearly universal.”
Specifically, the researchers saw 100,000- to 110,000-fold expansions of CAR-positive cells.
Two-thirds of patients have circulating CAR cells 6 months out from their CTL019 infusion. And a group of patients have kept their CAR cells for longer than 12 months. In the group that loses their cells more quickly, CD19+ recurrence is overrepresented, Dr Grupp noted.
Event-free survival is 70% at 6 months, and 76% of patients had a 6-month duration of response.
Toxicity
Cytokine release syndrome (CRS) is a “significant toxicity,” Dr Grupp said, but investigators are beginning to understand some correlates that impact treatment.
Patients with extraordinary levels of the cytokine interleukin-6 (IL-6)—those who require blood pressure or respiratory support—have significantly more severe CRS than those with lower IL-6 levels (P<0.001). Responding patients have high IL-6 levels as well, but patients with severe CRS have very high levels.
The effector cytokine IFNγ, which may be required for the T-cell response, is also elevated in patients with severe CRS compared to those without CRS (P<0.001).
“The thing that I think we’ve really learned from these patients is the impact of disease burden,” Dr Grupp said.
Patients with high disease burden—those with more than 50% bone marrow blasts—have a high likelihood of developing severe CRS. Patients with less burden—fewer than 50% blasts—have a low likelihood.
Dr Grupp pointed out that only 2 patients with more than 50% blasts did not have severe CRS, and they did not respond to therapy.
“This is highly significant and quite predictive for our patients,” he said, adding that CRS is quite controllable via IL-6 blockade with tocilizumab.
B-cell aplasia is “inevitable” as long as these patients have their CAR T cells, Dr Grupp noted. Patients require IVIg replacement therapy for the entire period.
Macrophage activation syndrome, the flip side of CRS, is also a concern, and neurotoxicity, consisting of confusion and aphasia, occurred in a small number of patients and required no therapy.
Given these results, the investigators believe that CTL019 cells may be able to provide long-term response without subsequent therapy.
CTL019 recently received breakthrough therapy designation from the US Food and Drug Administration.
CTL019 was invented at The University of Pennsylvania but has been licensed to Novartis. Several researchers involved in this study reported research funding and/or consultancy payments from Novartis, and 2 researchers are employed by the company.
*Data in the presentation differ from the abstract.