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Inhibitor exhibits ‘modest’ activity in lymphoma
A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.
A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.
Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.
“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.
Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.
“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”
Patient and treatment characteristics
Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.
The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).
Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.
Safety
The maximum tolerated doses were 110 mg/m2 and 196 mg/m2 on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.
On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).
On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).
Efficacy
Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.
Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.
“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.
“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”
Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be. 
A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.
A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.
Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.
“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.
Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.
“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”
Patient and treatment characteristics
Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.
The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).
Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.
Safety
The maximum tolerated doses were 110 mg/m2 and 196 mg/m2 on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.
On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).
On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).
Efficacy
Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.
Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.
“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.
“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”
Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.
A small-molecule inhibitor has shown modest anticancer activity in a phase 1 trial of patients with relapsed/refractory lymphoma or multiple myeloma (MM), according to an investigator involved in the study.
A majority of patients who recieved the drug, pevonedistat, achieved stable disease, and a few patients with lymphoma experienced partial responses.
Investigators said pevonedistat could be given safely, although 100% of patients experienced adverse events (AEs), and a majority experienced grade 3 or higher AEs.
“The most important findings from our study are that pevonedistat hits its target in cancer cells in patients, can be given safely, and has modest activity in heavily pretreated patients with relapsed/refractory lymphoma, suggesting that we are on the right path,” said Jatin J. Shah, MD, of The University of Texas MD Anderson Cancer Center in Houston.
Dr Shah and his colleagues reported these findings in Clinical Cancer Research. The trial was sponsored by Millennium Pharmaceuticals, Inc., the company developing pevonedistat.
Pevonedistat is a first-in-class, investigational, small-molecule inhibitor of the NEDD8-activating enzyme.
“This enzyme is part of the ubiquitin-proteasome system, which is the target of a number of FDA-approved anticancer therapeutics, including bortezomib . . . ,” Dr Shah explained. “Pevonedistat also alters the ability of cancer cells to repair damaged DNA.”
Patient and treatment characteristics
Dr Shah and his colleagues enrolled 44 patients on this trial. Seventeen patients had relapsed/refractory MM, and 27 had relapsed/refractory lymphoma.
The types of lymphoma were diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=5), Hodgkin lymphoma (n=5), small lymphocytic lymphoma/chronic lymphocytic leukemia (n=2), mantle cell lymphoma (n=1), lymphoplasmacytic lymphoma (n=1), peripheral T-cell lymphoma (n=1), splenic marginal zone B-cell lymphoma (n=1), and “other” (n=1).
Twenty-seven patients received escalating doses of pevonedistat on schedule A, which was days 1, 2, 8, and 9 of a 21-day cycle, and 17 patients received escalating doses of the drug on schedule B, which was days 1, 4, 8, and 11 of a 21-day cycle.
Safety
The maximum tolerated doses were 110 mg/m2 and 196 mg/m2 on schedule A and B, respectively. The dose-limiting toxicities were febrile neutropenia, transaminase elevations, and muscle cramps on schedule A, and thrombocytopenia on schedule B.
On schedule A, 100% of patients experienced AEs, and 59% had AEs of grade 3 or higher. The grade 3 or higher AEs were anemia (19%), thrombocytopenia (4%), neutropenia (7%), fatigue (7%), ALT increase (4%), AST increase (7%), diarrhea (4%), pain (4%), dyspnea (4%), hypercalcemia (7%), hypophosphatemia (11%), hyperkalemia (4%), muscle spasms (4%), abdominal discomfort (4%), and pneumonia (4%).
On schedule B, 100% of patients experienced AEs, and 71% had grade 3 or higher AEs. The grade 3 or higher AEs were anemia (6%), thrombocytopenia (6%), neutropenia (12%), fatigue (6%), ALT increase (6%), pyrexia (6%), pain (6%), dyspnea (6%), hypophosphatemia (6%), muscle spasms (6%), upper respiratory tract infection (6%), dehydration (6%), hyperbilirubinemia (6%), and pneumonia (12%).
Efficacy
Three patients had a partial response to treatment, including 1 patient with relapsed nodular sclerosis Hodgkin lymphoma, 1 with relapsed diffuse large B-cell lymphoma, and 1 with relapsed peripheral T-cell lymphoma.
Another 30 patients, 17 with lymphoma and 13 with MM, had stable disease.
“Although pevonedistat had modest activity as a single-agent treatment, we expect greater activity when it is given in combination with standard therapy,” Dr Shah said.
“The pharmacodynamics data showed that pevonedistat hit its target in cancer cells in patients at low doses. This is important because it may mean that we do not need to escalate the dose in future trials to increase anticancer activity. This has the potential to increase the risk-benefit ratio of pevonedistat.”
Dr Shah said a limitation of this study is that it included a small number of patients, all of whom were very heavily pretreated, which may limit assessment of how active pevonedistat could be.
Drug ‘life-changing’ for CLL patients in phase 1 trial
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
Photo courtesy of NIH
A novel Bruton’s tyrosine kinase inhibitor has proven life-changing for patients with chronic lymphocytic leukemia (CLL) who received the drug as part of a phase 1 trial, according to the study’s lead author.
The inhibitor, ONO/GS-4059, produced a response in 96% of evaluable CLL patients.
Most CLL patients are still on the study after 3 years, although a handful withdrew due to adverse events (AEs) or disease progression.
“These patients were confronted with a cruel reality: they had failed multiple chemotherapy lines, and there were no other treatment options available for them,” said lead study author Harriet Walter, MBChB, of the University of Leicester in the UK.
“This drug has changed their lives. From desperate and tired, they are now leading a normal and really active life. This is hugely rewarding and encouraging.”
Dr Walter and her colleagues reported these results in Blood. The trial was funded by ONO Pharmaceuticals, the company developing ONO/GS-4059.
This study opened in January 2012, and 90 patients were enrolled at centers in the UK and France. There were 28 patients with CLL and 62 with non-Hodgkin lymphoma (NHL), including 16 with mantle cell lymphoma (MCL) and 35 with diffuse large B-cell lymphoma (DLBCL).
The study also included patients with follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenstrom’s macroglobulinemia, but patient numbers were small for these groups, so the results were not discussed in detail.
There were 9 dose-escalation cohorts in this study. ONO/GS-4059 was given once-daily at doses ranging from 20 mg to 600 mg. Or the drug was given twice daily at doses of 240 mg or 300 mg.
Results
The maximum tolerated dose was not reached in the CLL cohort, but it was 480 mg once-daily in the NHL cohort. Four NHL patients had a dose-limiting toxicity.
In the CLL cohort, 2 patients went off study due to progression and 5 due to AEs.
In the NHL cohort, 49 patients discontinued treatment, 32 due to progression and 5 due to dose-limiting toxicities or AEs. The other 12 NHL patients discontinued due to patient or investigator decision, proceeding to transplant (n=1), or death due to progressive disease.
The median duration of follow-up was 560 days for CLL patients, 309 days for MCL patients, and 60 days for DLBCL patients.
The overall estimated mean progression-free survival was 874 days for CLL patients, 341 days for MCL patients, and 54 days for DLBCL patients.
CLL patients
Of all 28 CLL patients, 16 had relapsed CLL, 11 had refractory disease, and 1 had unknown status. The median number of prior therapies was 3.5 (range, 2-7).
Twenty-five patients were evaluable. Of the 3 who were not evaluable, 1 had not reached cycle 3 disease assessment at the time of data analysis, 1 progressed during cycle 1, and 1 was withdrawn due to an AE (idiopathic thrombocytopenia).
Of the 25 evaluable patients, 24 (96%) responded to ONO/GS-4059. The researchers said they observed rapid resolution of bulky lymphadenopathy within the first 3 months of treatment, but improvement in lymphadenopathy continued for up to 18 months in most patients.
The median treatment duration for these patients is 80 weeks, and 21 patients are still on treatment. Two of the evaluable patients progressed during therapy, one at cycle 3 and one at cycle 12.
MCL patients
Of the 16 MCL patients enrolled, 7 were refractory to their last course of immuno-chemotherapy. The median number of prior therapies was 3 (range, 2-7).
Eleven of 12 (92%) evaluable patients with MCL responded to ONO/GS-4059. Six patients had a partial response, and 5 had a complete response (CR) or unconfirmed CR.
Three patients progressed after an initial response. Four patients were not evaluable because they progressed.
The median treatment duration for MCL patients is 40 weeks, and 8 patients remain on study.
DLBCL patients
All 35 DLBCL patients had relapsed or refractory disease. The median number of prior treatments was 3
(range, 2-10), and 30 patients were refractory to their last line of chemotherapy.
Eleven of 31 (35%) patients with non-germinal center B-cell (non-GCB) DLBCL responded to ONO/GS-4059. Two non-GCB DLBCL patients had a confirmed CR, 1 had an unconfirmed CR, and the rest had partial responses.
The median duration of response was 54 days. And, among responders, the median treatment duration was 12 weeks.
The majority of non-GCB DLBCL patients progressed. There were no responses among the 2 patients with GCB DLBCL, and there were no responses among patients with primary mediastinal B-cell lymphoma or plasmablastic DLBCL.
Toxicity
AEs in this study were mostly grade 1/2—75% in the CLL cohort and 50% in the NHL cohort. However, treatment-related grade 3/4 AEs occurred in 14.3% of CLL patients and 16.1% of NHL patients.
Grade 3/4 events were mainly hematologic in nature and included neutropenia (10%), anemia (13.3%), and thrombocytopenia (13.3%).
There was a grade 3 episode of drug-related hemorrhage in a CLL patient, which resulted in a psoas hematoma (with concomitant CLL progression) in the presence of a normal platelet count. This patient was among those taken off the study.
“The next step is now to see how best we can improve on these outstanding results,” said study author Martin Dyer, DPhil, of the University of Leicester.
“A further study using this drug in combination with additional targeted agents is shortly to open in Leicester with the aim of achieving cure. In parallel with the clinical development of the drug, our team of scientists at the Haematological Research Institute are studying how this drug is working and how to overcome potential resistance.”
CCSs have increased risk of autoimmune diseases
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
Photo by Bill Branson
Childhood cancer survivors (CCSs) have an increased risk of developing autoimmune diseases, according to research published in the Annals of the Rheumatic Diseases.
CCSs had a significantly increased risk for 11 of 33 autoimmune diseases studied, and the highest risk was observed for autoimmune hemolytic anemia.
Survivors of leukemia and Hodgkin lymphoma were among those CCSs at the greatest risk of developing
an autoimmune disease.
Anna Sällfors Holmqvist, MD, of Lund University in Sweden, and her colleagues conducted this research.
They used national cancer registry data from Denmark, Iceland, and Sweden, spanning the period from the 1940s to 2008, to identify subjects who had cancer as a child.
The researchers identified 20,361 adults who had cancer before the age of 20 and survived for at least a year. These subjects were matched (for age, gender, and country of birth) to 125,794 individuals who had not had cancer as children.
The health of all participants was tracked for an average of 15 to 19 years. The researchers used hospital records to determine the difference between the expected and excess number of autoimmune diseases, expressed as a standardized hospitalization rate ratio (SHRR).
In all, 724 (3.6%) CCSs had at least 1 episode of hospital treatment for any autoimmune condition, but only 516 would have been expected.
So CCSs had an SHRR for autoimmune diseases of 1.4. This corresponds to an absolute excess risk of 67 per 100,000 person-years.
SHRRs were significantly higher for 11 autoimmune diseases, including autoimmune hemolytic anemia (16.3), Addison’s disease (13.9), polyarteritis nodosa (5.8), chronic rheumatic heart disease (4.5), localized scleroderma (3.6), idiopathic thrombocytopenia (3.4), Hashimoto’s thyroiditis (3.1), pernicious anemia (2.7), sarcoidosis (2.2), Sjögren’s syndrome (2.0), and insulin-dependent diabetes mellitus (1.6).
SHRRs for any autoimmune disease were significantly increased for survivors of leukemia (1.6), Hodgkin lymphoma (1.6), renal tumors (1.6), and central nervous system neoplasms (1.4).
The excess risk for all autoimmune diseases combined peaked in the first 5 years after a cancer diagnosis. However, the risk persisted for up to 30 years later for most conditions and up to 50 years later for some conditions.
The researchers said the peak observed in the first 5 years may be a consequence of closer medical monitoring during this time period.
They added that a possible explanation for these findings is that persistent immune abnormalities after chemotherapy predispose CCSs to develop autoantibodies, which are central to the pathogenesis of many autoimmune diseases.
The team said the cancer itself, immunosuppressive treatment, and the increased number and types of infections during cancer treatment could alter the immune system as a whole and result in immunologically different antigens, leading to the production of autoantibodies.
Drug protects fertility in chemo-treated mice
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
Photo courtesy of UW Health
The heart medication dexrazoxane can protect fertility and improve survival in female mice receiving the chemotherapeutic agent doxorubicin, according to research published in PLOS ONE.
Dexrazoxane prevented ovarian damage, increased the number of healthy offspring mice had, and prolonged their survival.
If dexrazoxane has the same effects in humans, it could save young lives while also overcoming limitations to fertility treatments currently used during cancer treatment, according to study author Sana Salih, MD, of the University of Wisconsin School of Medicine and Public Health in Madison.
“Fertility preservation following chemotherapy for children and women diagnosed with cancer is a formidable challenge,” Dr Salih said. “For pre-pubescent girls, the only option to prevent chemo-induced ovarian failure is to preserve ovarian tissue by freezing.”
Unfortunately, that is an experimental procedure that requires surgery to harvest and again to re-implant the tissue after cancer treatment. The transplantation carries a small risk of cancer recurrence and provides only a short-term solution.
“The transplanted ovarian tissue can only function for 3 to 7 years,” Dr Salih said.
So she was pleased to discover that pre-administration of dexrazoxane diminished ovarian damage and preserved ovarian function and fertility in mice whose ovaries were exposed to doxorubicin.
“What really surprised us is that a very small dose of dexrazoxane was enough to give full ovarian protection,” Dr Salih said.
Mice treated with dexrazoxane also gave birth to healthier litters, with more pups and higher birth weights than mice that received doxorubicin alone.
In addition, the mice that received dexrazoxane and doxorubicin lived much longer than mice that only received doxorubicin. And mice given only dexrazoxane lived longer than control mice receiving no interventions.
“The [US Food and Drug Administration] currently limits the use of dexrazoxane to adults to protect their hearts from the toxic side effects of chemotherapy,” Dr Salih said. “But these patients are receiving very high doses of dexrazoxane that may actually be contributing to increased toxicity, leading to decreased survival in some patients.”
Dr Salih and her colleagues found they could achieve high mouse survival rates, ovarian protection, and birthing successes using a dose of dexrazoxane 10 times lower than what is used for adult human cardiac protection. Post-mortem studies on the mice showed protection of ovarian, heart, and other cells and tissues.
“This is exciting,” Dr Salih said. “We are now submitting a grant to look at low-dose dexrazoxane protection in nonhuman primates as a stepping stone to clinical translation in pediatric cancer patients.”
Dr Salih has begun studies needed to show that safe doses of dexrazoxane can protect developing primate ovaries. Nonhuman primate ovarian development, cycle time, and gestation are very similar to that of humans.
“My goal is to present data so that physicians can come up with dosage recommendations and safety profiles for early clinical trials in humans,” Dr Salih said. “Up to 6% of young girls with childhood cancers and 50% of women with breast cancer who endure chemotherapy face ovarian failure. We need to give more cancer survivors real hope that they can conceive a healthy child.”
Donor CAR T cells treat aggressive ALL in infant
person treated with UCART19
Photo courtesy of GOSH
A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.
The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.
Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla
is now free of leukemia.
“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.
“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”
Layla’s history
Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”
Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.
A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.
Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.
“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.
“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”
UCART19 treatment
Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.
UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.
But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.
Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 106/kg) of UCART19.
After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.
The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.
She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.
More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.
person treated with UCART19
Photo courtesy of GOSH
A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.
The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.
Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla
is now free of leukemia.
“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.
“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”
Layla’s history
Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”
Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.
A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.
Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.
“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.
“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”
UCART19 treatment
Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.
UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.
But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.
Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 106/kg) of UCART19.
After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.
The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.
She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.
More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.
person treated with UCART19
Photo courtesy of GOSH
A hospital in the UK has reported success with the first-in-human use of an allogeneic chimeric antigen receptor (CAR) T-cell treatment.
The therapy, UCART19, helped treat an aggressive case of acute lymphoblastic leukemia (ALL) in an infant named Layla Richards.
Chemotherapy, a first transplant, and blinatumomab all failed to treat Layla’s disease. But UCART19 provided a bridge to a second transplant, and Layla
is now free of leukemia.
“We have only used this treatment on one very strong little girl, and we have to be cautious about claiming that this will be a suitable treatment option for all children,” said Waseem Qasim, MBBS, PhD, a professor at University College London’s Institute of Child Health and a consultant immunologist at Great Ormond Street Hospital (GOSH) in London, where Layla was treated.
“But this is a landmark in the use of new gene-engineering technology, and the effects for this child have been staggering. If replicated, it could represent a huge step forward in treating leukemia and other cancers.”
Layla’s history
Layla was born in June 2014 and, at 14 weeks old, was diagnosed with CD19+ ALL (t[11;19] rearrangement). Doctors at GOSH described her leukemia as “one of the most aggressive forms of the disease we have ever seen.”
Layla underwent several rounds of chemotherapy at GOSH and then received a transplant from a mismatched, unrelated donor. Seven weeks later, her leukemia had returned.
A second round of chemotherapy wasn’t an option, so Layla went on to receive blinatumomab. This, too, ultimately failed.
Layla’s family was unwilling to accept palliative care, so her doctors mentioned the possibility of using UCART19.
“The approach was looking incredibly successful in laboratory studies, and so when I heard there were no options left for treating this child’s disease, I thought, ‘Why don’t we use the new UCART19 cells?’” Dr Qasim said.
“The treatment was highly experimental, and we had to get special permissions, but she appeared ideally suited for this type of approach.”
UCART19 treatment
Before Layla received UCART19, investigators from GOSH, University College London, and the biotech company Cellectis had been developing off-the-shelf banks of the cells for use in clinical trials.
UCART19 consists of donor T cells modified using transcription activator-like effector nucleases (TALEN). Like some other CAR T-cell products, UCART19 is designed to target CD19+ cancer cells.
But UCART19 cells are also programmed to be insensitive to alemtuzumab. That way, a patient can receive the drug to prevent rejection of HLA-mismatched cells.
Before receiving UCART19, Layla was given vincristine, dexamethasone, and asparaginase, followed by fludarabine, cyclophosphamide, and alemtuzumab. She then received a single dose (4.5 x 106/kg) of UCART19.
After this, Layla spent several months in isolation to protect her from infections while her immune system was extremely weak. Within weeks of receiving UCART19, Layla demonstrated an immune response in the form of a rash.
The rash worsened, but, aside from that, Layla appeared to be well. To date, she has shown no signs of cytokine release syndrome.
She did, however, show signs of molecular and cytogenetic remission. Once she was deemed leukemia-free, Layla underwent a second transplant. One month later, she was well enough to go home. Today, Layla is still free of ALL.
More details on Layla’s story and UCART19 are scheduled to be presented at the 2015 ASH Annual Meeting (abstract 2046). Clinical trials of UCART19 (funded by Cellectis) are set to begin early next year.
RIC can improve HSCT outcomes in older AML patients
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
Photo by Chad McNeeley
Results of a phase 2 study suggest that reduced-intensity conditioning (RIC) may allow older patients with acute myeloid leukemia (AML) to remain in long-term remission after allogeneic hematopoietic stem cell transplant (HSCT).
The study included patients age 60 and older who were in their first complete remission (CR1) at transplant.
Two years later, the probability of overall survival was 48%, and the probability of disease-free survival was 42%.
“This new data offers strong support against using biological age as a limiting factor for stem cell transplantation in AML patients who are otherwise well positioned to tolerate and achieve long-term remission with this approach,” said Steven Devine, MD, of The Ohio State University in Columbus.
He and his colleagues shared the data in the Journal of Clinical Oncology.
The researchers wanted to determine whether RIC could improve long-term remission rates after HSCT for older patients with AML.
So the team studied 114 patients with a median age of 65 (range, 60-74) who were treated at 21 US hospitals between November 2004 and November 2011. Most patients were male (62%), and most had intermediate cytogenetics (70%).
All of the patients were in CR1 according to International Working Group criteria. The CR had to be achieved after no more than 2 cycles of induction chemotherapy, and patients were required to undergo HSCT within 6 months of the initial documentation of morphologic CR.
The median time from CR1 documentation to HSCT was 85 days (range, 9-184), and the median time from AML diagnosis to HSCT was 138 days (range, 61-265).
All patients received RIC (fludarabine followed by busulfan) prior to HSCT, which essentially cut treatment strength by half compared to traditional high-dose conditioning. The patients received tacrolimus and methotrexate as graft-versus-host disease (GVHD) prophylaxis.
Forty-eight percent of patients underwent HSCT from a matched, related donor, and 52% had a matched, unrelated donor.
At 2 years, disease-free survival was 42%, and overall survival was 48%. Among patients with unrelated donors, disease-free survival was 40%, and overall survival was 50%.
The cumulative incidence of relapse was 44%, and non-relapse mortality was 15%. Twenty-eight percent of patients had chronic GVHD, and 9.6% had grade 2-4 acute GVHD.
“Close to half of the patients treated in this study achieved long-term, cancer-free survival after 2 years,” Dr Devine noted. “These outcomes are similar to what we would expect to see in younger patients and appear to be better results than those that can be achieved with conventional chemotherapy-based approaches typically used in AML patients over 60.”
HSC self-renewal depends on surroundings
in the bone marrow
Scientists say that, using a model of the hematopoietic system, they have determined which signaling pathways play an essential role in the self-renewal of hematopoietic stem cells (HSCs).
They found that a particularly important role in this process is the interactive communication with surrounding tissue cells in the bone marrow.
Robert Oostendorp, PhD, of Klinikum Rechts der Isar der Technischen Universität München in Munich, Germany, and his colleagues described these findings in Stem Cell Reports.
The team noted that, in steady-state conditions, HSCs are maintained as slow-dividing clones of quiescent cells. However, when stress occurs, such as an accident that leads to substantial blood loss or the defense against a pathogen requires more blood cells in the course of an infection, HSCs are activated.
In response, the entire hematopoietic system switches from “standby” mode into a state of alert. The activated HSCs generate new blood cells to counteract the blood loss or combat the pathogen. At the same time, self-renewal keeps the stem cell pool replenished.
This switch is accompanied by a complex communication process between the HSCs and tissue cells—an area that had not previously been examined in depth.
“In our study, we set out to establish which tissue signals are important to stem cell maintenance and functionality, and which HSC signals influence the microenvironment,” Dr Oostendorp said.
He and his colleagues used mixed cultures of tissue cells and HSCs to investigate how these cell types interact.
The scientists analyzed factors that are upregulated or downregulated in the interplay between tissue cells and HSCs. And they linked these findings with the signaling pathways described in existing literature.
The team then consolidated this information in a bioinformatics computer model. And they conducted extensive cell experiments to confirm the computer-generated signaling pathway model.
“The outcome was very interesting indeed,” Dr Oostendorp said. “The entire system operates in a feedback loop. In ‘alert’ mode, the stem cells first influence the behavior of the tissue cells, which, in turn, impact on the stem cells, triggering the self-renewal step.”
In alert mode, HSCs emit signaling substances, which induce tissue cells to release the connective tissue growth factor (CTGF) messenger. This is essential to maintain the HSCs through self-renewal. In the absence of CTGF, HSCs age and cannot replenish the stem cell pool.
“Our findings could prove significant in treating leukemia,” Dr Oostendorp noted. “In this condition, the stem cells are hyperactive, and their division is unchecked. Leukemic blood cells are in a constant state of alert, so we would expect a similar interplay with the tissue cells.”
To date, however, the focus here has been limited to stem cells as the actual source of the defect.
“Given what we know now about feedback loops, it would be important to integrate the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division,” Dr Oostendorp concluded.
in the bone marrow
Scientists say that, using a model of the hematopoietic system, they have determined which signaling pathways play an essential role in the self-renewal of hematopoietic stem cells (HSCs).
They found that a particularly important role in this process is the interactive communication with surrounding tissue cells in the bone marrow.
Robert Oostendorp, PhD, of Klinikum Rechts der Isar der Technischen Universität München in Munich, Germany, and his colleagues described these findings in Stem Cell Reports.
The team noted that, in steady-state conditions, HSCs are maintained as slow-dividing clones of quiescent cells. However, when stress occurs, such as an accident that leads to substantial blood loss or the defense against a pathogen requires more blood cells in the course of an infection, HSCs are activated.
In response, the entire hematopoietic system switches from “standby” mode into a state of alert. The activated HSCs generate new blood cells to counteract the blood loss or combat the pathogen. At the same time, self-renewal keeps the stem cell pool replenished.
This switch is accompanied by a complex communication process between the HSCs and tissue cells—an area that had not previously been examined in depth.
“In our study, we set out to establish which tissue signals are important to stem cell maintenance and functionality, and which HSC signals influence the microenvironment,” Dr Oostendorp said.
He and his colleagues used mixed cultures of tissue cells and HSCs to investigate how these cell types interact.
The scientists analyzed factors that are upregulated or downregulated in the interplay between tissue cells and HSCs. And they linked these findings with the signaling pathways described in existing literature.
The team then consolidated this information in a bioinformatics computer model. And they conducted extensive cell experiments to confirm the computer-generated signaling pathway model.
“The outcome was very interesting indeed,” Dr Oostendorp said. “The entire system operates in a feedback loop. In ‘alert’ mode, the stem cells first influence the behavior of the tissue cells, which, in turn, impact on the stem cells, triggering the self-renewal step.”
In alert mode, HSCs emit signaling substances, which induce tissue cells to release the connective tissue growth factor (CTGF) messenger. This is essential to maintain the HSCs through self-renewal. In the absence of CTGF, HSCs age and cannot replenish the stem cell pool.
“Our findings could prove significant in treating leukemia,” Dr Oostendorp noted. “In this condition, the stem cells are hyperactive, and their division is unchecked. Leukemic blood cells are in a constant state of alert, so we would expect a similar interplay with the tissue cells.”
To date, however, the focus here has been limited to stem cells as the actual source of the defect.
“Given what we know now about feedback loops, it would be important to integrate the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division,” Dr Oostendorp concluded.
in the bone marrow
Scientists say that, using a model of the hematopoietic system, they have determined which signaling pathways play an essential role in the self-renewal of hematopoietic stem cells (HSCs).
They found that a particularly important role in this process is the interactive communication with surrounding tissue cells in the bone marrow.
Robert Oostendorp, PhD, of Klinikum Rechts der Isar der Technischen Universität München in Munich, Germany, and his colleagues described these findings in Stem Cell Reports.
The team noted that, in steady-state conditions, HSCs are maintained as slow-dividing clones of quiescent cells. However, when stress occurs, such as an accident that leads to substantial blood loss or the defense against a pathogen requires more blood cells in the course of an infection, HSCs are activated.
In response, the entire hematopoietic system switches from “standby” mode into a state of alert. The activated HSCs generate new blood cells to counteract the blood loss or combat the pathogen. At the same time, self-renewal keeps the stem cell pool replenished.
This switch is accompanied by a complex communication process between the HSCs and tissue cells—an area that had not previously been examined in depth.
“In our study, we set out to establish which tissue signals are important to stem cell maintenance and functionality, and which HSC signals influence the microenvironment,” Dr Oostendorp said.
He and his colleagues used mixed cultures of tissue cells and HSCs to investigate how these cell types interact.
The scientists analyzed factors that are upregulated or downregulated in the interplay between tissue cells and HSCs. And they linked these findings with the signaling pathways described in existing literature.
The team then consolidated this information in a bioinformatics computer model. And they conducted extensive cell experiments to confirm the computer-generated signaling pathway model.
“The outcome was very interesting indeed,” Dr Oostendorp said. “The entire system operates in a feedback loop. In ‘alert’ mode, the stem cells first influence the behavior of the tissue cells, which, in turn, impact on the stem cells, triggering the self-renewal step.”
In alert mode, HSCs emit signaling substances, which induce tissue cells to release the connective tissue growth factor (CTGF) messenger. This is essential to maintain the HSCs through self-renewal. In the absence of CTGF, HSCs age and cannot replenish the stem cell pool.
“Our findings could prove significant in treating leukemia,” Dr Oostendorp noted. “In this condition, the stem cells are hyperactive, and their division is unchecked. Leukemic blood cells are in a constant state of alert, so we would expect a similar interplay with the tissue cells.”
To date, however, the focus here has been limited to stem cells as the actual source of the defect.
“Given what we know now about feedback loops, it would be important to integrate the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division,” Dr Oostendorp concluded.
EC expands indication for azacitidine in AML
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
The European Commission (EC) has expanded the approved indication for azacitidine for injection (Vidaza) in acute myeloid leukemia (AML).
Now, the drug is approved to treat AML patients age 65 and older who are ineligible for hematopoietic stem cell transplant (HSCT) and have more than 30% myeloblasts according to the WHO classification.
Previously, HSCT-ineligible elderly AML patients could only receive azacitidine if they had less than 30% blasts.
Because this new indication for azacitidine is thought to bring significant clinical benefit in comparison with existing therapies, the drug will receive extended market protection in all its indications for an additional year throughout the European Economic Area.
In addition to the aforementioned AML indications, azacitidine is approved in the European Economic Area to treat HSCT-ineligible adults with intermediate-2- and high-risk myelodysplastic syndromes and HSCT-ineligible adults who have chronic myelomonocytic leukemia and 10%-29% marrow blasts without myeloproliferative disorder.
Azacitidine is marketed as Vidaza by Celgene.
AML-001 trial
The EC’s recommendation to expand the indication of azacitidine in AML was based on data from the AML-001 trial. This randomized study included patients age 65 and older with newly diagnosed or secondary AML with greater than 30% blasts.
Patients were pre-selected to receive 1 of 3 regimens per investigator’s choice. This included intensive chemotherapy (standard 7+3 regimen), low-dose cytarabine (20 mg subcutaneously twice a day for 10 days of each 28-day cycle), or best supportive care only.
Patients were then randomized to receive either azacitidine (75 mg/m2/day subcutaneously for 7 days of each 28-day cycle, n=241) or their predetermined conventional care regimen (CCR, n=247).
Median overall survival, the study’s primary endpoint, was 10.4 months for patients receiving azacitidine and 6.5 months for patients receiving CCR (hazard ratio=0.85, P=0.1009).
One-year survival rates with azacitidine and CCR were 46.5% and 34.2%, respectively.
Grade 3/4 anemia occurred in 16% of patients who received azacitidine, 5% who received best supportive care, 23% who received low-dose cytarabine, and 14% who received intensive chemotherapy.
Grade 3/4 neutropenia occurred in 26%, 5%, 25%, and 33% of patients, respectively. Grade 3/4 febrile neutropenia occurred in 28%, 28%, 30%, and 31%, respectively. And grade 3/4 thrombocytopenia occurred in 24%, 5%, 28%, and 21%, respectively.
A new category of cytopenias
New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).
So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).
The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.
“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.
“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”
Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.
The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.
The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.
Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.
To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.
The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.
The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.
The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.
Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.
New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).
So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).
The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.
“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.
“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”
Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.
The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.
The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.
Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.
To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.
The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.
The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.
The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.
Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.
New research suggests that clonality may underlie the cytopenias observed in patients with idiopathic cytopenias of undetermined significance (ICUS).
So researchers say these patients should be classified as having clonal cytopenias of undetermined significance (CCUS).
The team believes that recognition of CCUS as a clinical entity would help identify it as a formally defined diagnostic group and could aid future studies.
“We don’t know to what extent patients who have low blood counts and mutations are at increased risk of developing an overt malignancy,” said Rafael Bejar, MD, PhD, of the UCSD Moores Cancer Center in La Jolla, California.
“We hope that by defining CCUS, future studies will follow these patients to learn what these mutations mean for their future, as their genetically abnormal cells may represent early stages of subsequent blood cancers.”
Dr Bejar and his colleagues defined CCUS in Blood. Their research was funded, in part, by Genoptix Medical Laboratory, and several study authors are employees of Genoptix.
The researchers prospectively examined bone marrow samples from 144 patients with unexplained cytopenias. Seventeen percent of these patients were diagnosed with myelodysplastic syndromes (MDS), 15% with ICUS and some evidence of dysplasia, and 69% with ICUS and no dysplasia.
The team then sequenced patient samples looking for mutations in 22 frequently mutated myeloid malignancy genes. They identified somatic mutations in 71% of MDS patients, 62% of patients with ICUS and some dysplasia, and 20% of ICUS patients with no dysplasia.
Overall, 35% of ICUS patients carried a somatic mutation or chromosomal abnormality indicative of clonal hematopoiesis.
To build upon these findings, the researchers performed a retrospective analysis of data from 91 patients with lower-risk MDS and 249 patients with ICUS.
The team identified mutations in 79% of patients with MDS, 45% of patients with ICUS and dysplasia, and 17% of patients with ICUS and no dysplasia.
The researchers said the spectrum of mutated genes was similar among the 3 groups. The exception was SF3B1, which was rarely mutated in patients without dysplasia.
The team added that variant allele fractions were comparable between clonal ICUS (CCUS) and MDS, and the same was true for the patients’ mean age and blood counts. But CCUS was a more frequent diagnosis than MDS.
Dr Bejar and his colleagues said larger, carefully controlled studies will be needed to confirm the findings of this research.
Drug gets orphan designation for BPDCN
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.
The European Medicines Agency (EMA) has granted orphan drug designation to SL-401 for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).
SL-401 is a targeted therapy directed to the interleukin-3 receptor (IL-3R), which is present on cancer stem cells and tumor bulk in a range of hematologic malignancies.
The drug is composed of human IL-3 coupled to a truncated diphtheria toxin payload that inhibits protein synthesis.
SL-401 already has orphan designation from the EMA to treat acute myeloid leukemia (AML) and from the US Food and Drug Administration (FDA) for the treatment of AML and BPDCN. The drug is under development by Stemline Therapeutics, Inc.
SL-401 research
At ASH 2012 (abstract 3625), researchers reported results with SL-401 in a study of patients with AML, BPDCN, and myelodysplastic syndromes (MDS).
At that time, the study had enrolled 80 patients, including 59 with relapsed or refractory AML, 11 with de novo AML unfit for chemotherapy, 7 with high-risk MDS, and 3 with relapsed/refractory BPDCN.
Patients received a single cycle of SL-401 as a 15-minute intravenous infusion in 1 of 2 dosing regimens to determine the maximum tolerated dose (MTD) and assess antitumor activity.
With regimen A, 45 patients received doses ranging from 4 μg/kg to 12.5 μg/kg every other day for up to 6 doses. With regimen B, 35 patients received doses ranging from 7.1 μg/kg to 22.1 μg/kg daily for up to 5 doses.
Of the 59 patients with relapsed/refractory AML, 2 achieved complete responses (CRs), 5 had partial responses (PRs), and 8 had minor responses (MRs). One CR lasted more than 8 months, and the other lasted more than 25 months.
Of the 11 patients with AML who were not candidates for chemotherapy, 2 had PRs and 1 had an MR. Among the 7 patients with high-risk MDS, there was 1 PR and 1 MR.
And among the 3 patients with BPDCN, there were 2 CRs. One CR lasted more than 2 months, and the other lasted more than 4 months.
The MTD was not achieved with regimen A, but the MTD for regimen B was 16.6 μg/kg/day. The dose-limiting toxicities were a gastrointestinal bleed (n=1), transaminase and creatinine kinase elevations (n=1), and capillary leak syndrome (n=3). There was no evidence of treatment-related bone marrow suppression.
Last year, researchers reported additional results in BPDCN patients (Frankel et al, Blood 2014).
Eleven BPDCN patients received a single course of SL-401 (at 12.5 μg/kg intravenously over 15 minutes) daily for up to 5 doses. Three patients who had initial responses to SL-401 received a second course while in relapse.
Seven of 9 evaluable (78%) patients responded to a single course of SL-401. There were 5 CRs and 2 PRs. The median duration of responses was 5 months (range, 1-20+ months).
The most common adverse events were transient and included fever, chills, hypotension, edema, hypoalbuminemia, thrombocytopenia, and transaminasemia.
Three multicenter clinical trials of SL-401 are currently open in the following indications:
- BPDCN and relapsed/refractory AML
- AML patients in first complete remission with minimal residual disease
- Four types of advanced, high-risk myeloproliferative neoplasms, including systemic mastocytosis, advanced symptomatic hypereosinophilic disorder, myelofibrosis, and chronic myelomonocytic leukemia.
Additional SL-401 studies are planned for patients with myeloma, lymphomas, and other leukemias.
About orphan designation
In the European Union, orphan designation is granted to therapies intended to treat a life-threatening or chronically debilitating condition that affects no more than 5 in 10,000 persons and where no satisfactory treatment is available.
Companies that obtain orphan designation for a drug in the European Union benefit from a number of incentives, including protocol assistance, a type of scientific advice specific for designated orphan medicines, and 10 years of market exclusivity once the medicine is on the market. Fee reductions are also available, depending on the status of the sponsor and the type of service required.
The FDA grants orphan designation to drugs that are intended to treat diseases or conditions affecting fewer than 200,000 patients in the US.
In the US, orphan designation provides the sponsor of a drug with various development incentives, including opportunities to apply for research-related tax credits and grant funding, assistance in designing clinical trials, and 7 years of US market exclusivity if the drug is approved.