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CAR T-cell trial explores new territory
Photo courtesy of
Fred Hutch News Service
Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.
And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.
The researchers detailed these conclusions in The Journal of Clinical Investigation.
This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.
The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.
Patients and treatment
The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.
The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.
To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.
Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 105/kg (DL1), 2 × 106/kg (DL2), and 2 × 107/kg (DL3).
Toxicity
The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.
Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.
The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.
However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.
Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.
Response
One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.
Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).
Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.
“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”
Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.
“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”
Lessons learned
The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.
The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.
Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.
Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.
The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.
And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide. 
Photo courtesy of
Fred Hutch News Service
Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.
And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.
The researchers detailed these conclusions in The Journal of Clinical Investigation.
This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.
The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.
Patients and treatment
The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.
The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.
To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.
Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 105/kg (DL1), 2 × 106/kg (DL2), and 2 × 107/kg (DL3).
Toxicity
The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.
Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.
The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.
However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.
Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.
Response
One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.
Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).
Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.
“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”
Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.
“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”
Lessons learned
The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.
The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.
Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.
Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.
The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.
And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.
Photo courtesy of
Fred Hutch News Service
Researchers say they have conducted the first trial of CD19-directed chimeric antigen receptor (CAR) T-cell therapy in which CD4+ and CD8+ cells were administered in equal proportions.
And the assurance that each patient received the same mixture of cells allowed the team to draw clear conclusions about the effects of administering CAR T-cell therapy at different doses.
The researchers detailed these conclusions in The Journal of Clinical Investigation.
This phase 1/2 trial (NCT01865617) was funded, in part, by Juno Therapeutics, the company developing the CAR T-cell therapy as JCAR014.
The work was also funded by the National Cancer Institute, private philanthropists, and the Life Sciences Discovery Fund.
Patients and treatment
The researchers reported data on 32 patients who had relapsed or refractory, CD19+ B-cell acute lymphoblastic leukemia and a median age of 40 (range, 20–73). Two of these patients were excluded due to complications prior to receiving treatment.
The 30 patients who were treated in this study had received a median of 3 prior intensive chemotherapy regimens (range, 1–11). Eleven patients had failed a hematopoietic stem cell transplant (HSCT). And all patients had detectable disease in the bone marrow, extramedullary sites, or cerebrospinal fluid at baseline.
To create the CAR T-cell therapy, the researchers modified CD8+ and CD4+ T-cell subsets separately to express a CD19-targeted CAR incorporating 4-1BB and CD3ζ signaling domains. The cells were then formulated in a defined ratio of CD4+:CD8+ CAR T cells.
Patients underwent lymphodepletion with a cyclophosphamide-based regimen (alone or with fludarabine or etoposide) and then received CAR T cells 48 to 96 hours later. The CAR T cells were given at 3 dose levels—2 × 105/kg (DL1), 2 × 106/kg (DL2), and 2 × 107/kg (DL3).
Toxicity
The first 2 patients who received CAR T-cell therapy at DL3 developed severe toxicities, including 1 patient who died. So DL3 was not given to any subsequent patients.
Two patients died after CAR T-cell infusion. One patient had severe cytokine release syndrome (CRS) and multiorgan failure and died on day 3. The other patient had transient severe CRS with irreversible neurologic toxicity and died on day 122.
The most common adverse event observed in the first 14 days after CAR T-cell infusion was CRS, which occurred in 25 patients. Seven patients had severe CRS that put them in the intensive care unit.
However, for the patients treated at DL1 and DL2, dexamethasone alone or with tocilizumab resolved CRS.
Fifteen patients developed severe neurotoxicity (grade 3 or higher), either with CRS or after it resolved. For all but 1 patient (the aforementioned patient who died), neurologic symptoms and signs resolved.
Response
One patient died before response assessment, so 29 patients were evaluable. Twenty-seven of these patients (93%) achieved bone marrow remission by flow cytometry.
Of the 2 patients who did not achieve a complete response (CR), 1 underwent an allogeneic HSCT after receiving CAR T cells. After HSCT, she relapsed, was re-enrolled on the trial, and achieved a CR after receiving a higher dose of CAR T cells (DL2).
Twenty-five patients (86%) achieved a CR without evidence of minimal residual disease by flow cytometry and conventional karyotyping, FISH, or QPCR.
“Patients who come onto the trial have really limited options for treatment,” said study author Cameron Turtle, MBBS, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, Washington.
“They have refractory acute leukemia. So the fact that we’re getting so many into remission is giving these people a way forward.”
Unfortunately, not all patients stayed in CR. Some relapsed and were treated again with CAR T cells, and 2 patients relapsed with leukemias that were immune to the CAR T cells. The researchers said it is still too early to know the long-term outcomes of the therapy.
“This is just the beginning,” Dr Turtle said. “It sounds fantastic to say that we get over 90% remissions, but there’s so much more work to do make sure they’re durable remissions, to work out who’s going to benefit the most, and extend this work to other diseases.”
Lessons learned
The researchers said that, because these CAR T cells had a defined CD4+:CD8+ composition, this study provides the first clear evidence of the relationships between the CAR T-cell dose patients receive and their outcomes after infusion.
The team found that high doses of CAR T cells and high tumor burden increase the risks of severe CRS and neurotoxicity. However, certain biomarkers can identify patients at the highest risk of toxicity.
Levels of IL-6, IFN-γ, and TNF-α on the first day after CAR T-cell infusion were significantly higher in patients who later developed severe neurotoxicity. Levels of these biomarkers were also higher in patients who were later sent to the intensive care unit.
Furthermore, risk-stratified CAR T-cell dosing based on bone marrow disease burden decreased toxicity.
The researchers also said they observed CD8+ T-cell-mediated anti-CAR transgene product immune responses in some patients, which limited CAR T-cell persistence and increased the risk of relapse.
And including fludarabine in the lymphodepletion regimen resulted in better CAR T-cell persistence and disease-free survival than when cyclophosphamide was given alone or with etoposide.
Childhood cancer risk linked to mother’s birthplace
Photo by Nina Matthews
New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.
The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.
However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).
Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.
The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.
The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.
To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.
For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.
When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.
For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.
For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.
The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.
These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.
Photo by Nina Matthews
New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.
The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.
However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).
Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.
The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.
The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.
To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.
For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.
When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.
For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.
For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.
The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.
These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.
Photo by Nina Matthews
New research suggests a mother’s birthplace may affect the risk of certain cancers for Hispanic children.
The study showed that children of Hispanic mothers who were not born in the US had lower risks of brain cancers, neuroblastoma, and Wilms tumor, when compared to children of US-born Hispanic mothers and non-Hispanic white mothers born in the US.
However, all Hispanic children, regardless of where their mothers were born, had higher risks of acute leukemias and Hodgkin lymphoma but a lower risk of non-Hodgkin lymphoma (NHL).
Julia E. Heck, PhD, of the University of California, Los Angeles, and her colleagues reported these findings in JAMA Pediatrics.
The researchers used California birth records to identify children born from 1983 through 2011. Information on cancer cases came from California Cancer Registry records from 1988 to 2012.
The team restricted their analysis to children of US-born white, US-born Hispanic, and non-US-born Hispanic mothers. The study included 13,666 cases of children diagnosed with cancer before the age of 6 and 15,513,718 children who served as control subjects.
To assess the hazard ratios (HRs) for various cancers, the researchers used children of non-Hispanic white mothers as a reference (HR=1.00) and compared them to the children of non-US-born Hispanic mothers and US-born Hispanic mothers.
For children of non-US-born Hispanic mothers, the HR was 0.50 for glioma, 0.43 for astrocytoma, 0.47 for neuroblastoma, and 0.70 for Wilms tumor. For children of US-born Hispanic mothers, the HR was 0.71 for glioma, 0.62 for astrocytoma, 0.66 for neuroblastoma, and 0.88 for Wilms tumor.
When compared to non-Hispanic white children, Hispanic children had an increased risk of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and Hodgkin lymphoma but lower risks of NHL and Burkitt lymphoma.
For children of US-born Hispanic mothers, the HR was 1.20 for ALL, 1.28 for AML, 2.49 for Hodgkin lymphoma, 0.79 for NHL, and 0.69 for Burkitt lymphoma.
For children of non-US-born Hispanic mothers, the HR was 1.06 for ALL, 1.05 for AML, 2.35 for Hodgkin lymphoma, 0.76 for NHL, and 0.73 for Burkitt lymphoma.
The researchers said the differences observed between children of US-born and non-US-born Hispanic mothers may be explained by lifestyle differences and varying environmental exposures.
These factors may explain the differences in cancer incidence between Hispanic children and white children as well, but the differences may also be a result of genetic variation and infection exposures early in life.
High-dose MTX improves EFS in high-risk B-ALL
Photo by Bill Branson
High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.
Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.
In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.
The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.
Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.
“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.
“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”
Treatment
Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.
Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.
So the treatment groups were as follows:
- Prednisone and escalating MTX (n=926)
- Prednisone and high-dose MTX (n=926)
- Dexamethasone and escalating MTX (n=535)
- Dexamethasone and high-dose MTX (n=527).
MTX results
At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).
The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).
There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).
There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).
But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.
Corticosteroid results
Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.
However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.
Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.
The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).
For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).
Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).
However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).
Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).
There were no other significant differences in adverse events between the 2 corticosteroid regimens.
Photo by Bill Branson
High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.
Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.
In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.
The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.
Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.
“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.
“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”
Treatment
Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.
Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.
So the treatment groups were as follows:
- Prednisone and escalating MTX (n=926)
- Prednisone and high-dose MTX (n=926)
- Dexamethasone and escalating MTX (n=535)
- Dexamethasone and high-dose MTX (n=527).
MTX results
At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).
The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).
There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).
There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).
But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.
Corticosteroid results
Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.
However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.
Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.
The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).
For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).
Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).
However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).
Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).
There were no other significant differences in adverse events between the 2 corticosteroid regimens.
Photo by Bill Branson
High-dose methotrexate (MTX) is more effective than escalating doses of MTX for young patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL), according to a study published in the Journal of Clinical Oncology.
Patients who received high-dose MTX during interim maintenance 1 had significantly better event-free survival (EFS) than those who received escalating MTX.
In addition, the study showed that substituting dexamethasone for prednisone during induction was beneficial for younger—but not older—patients.
The high-dose MTX protocol outlined in this study, and the use of dexamethasone in younger patients, has become the standard practice for the treatment of high-risk ALL patients in North America.
Prior to the release of the initial study results, which were first presented last year at the ASCO Annual Meeting, the standard of care for high-risk ALL patients in North America was escalating MTX.
“One of the improvements in outcome for ALL overall has been using methotrexate in a more intense fashion, by giving higher doses,” said study investigator William L. Carroll, MD, of NYU Langone Medical Center in New York, New York.
“We designed this study to compare high-dose and escalating methotrexate to determine the best way to use this drug to increase the survival of high-risk ALL patients.”
Treatment
Between January 2004 and January 2011, Dr Carroll and his colleagues enrolled 3154 patients, ages 1 to 30, with newly diagnosed, high-risk B-ALL. After exclusions, 2914 patients were randomized to treatment.
Using a 2 × 2 factorial design, the patients were randomized to receive dexamethasone for 14 days or prednisone for 28 days during induction and high-dose MTX or Capizzi escalating-dose MTX plus pegaspargase during interim maintenance 1.
So the treatment groups were as follows:
- Prednisone and escalating MTX (n=926)
- Prednisone and high-dose MTX (n=926)
- Dexamethasone and escalating MTX (n=535)
- Dexamethasone and high-dose MTX (n=527).
MTX results
At the planned interim analysis, the 5-year EFS was 82% among patients who received high-dose MTX and 75.4% among those who received escalating MTX (P=0.006).
The final data showed 5-year EFS rates of 79.6% and 75.2%, respectively (P=0.008) and 5-year overall survival rates of 88.9% and 86.1%, respectively (P=0.025).
There was a higher rate of febrile neutropenia during interim maintenance 1 among patients who received escalating MTX than among those who received high-dose MTX—8.3% and 5.1%, respectively (P=0.003).
There were 5 cases of ischemic cerebrovascular toxicity among patients who received high-dose MTX and none among the patients who received escalating MTX (P=0.03).
But there were no other significant differences in adverse events between the high-dose and escalating-dose MTX groups.
Corticosteroid results
Patients age 10 and older saw no benefit from dexamethasone, and, in fact, were at much higher risk of developing osteonecrosis. Because of this risk, the corticosteroid induction arm of this study was closed early, in 2008.
However, the investigators found that patients younger than age 10 did benefit from dexamethasone exposure.
Specifically, patients under 10 who received dexamethasone and high-dose MTX had significantly better EFS than patients who received the other 3 treatment regimens.
The 5-year EFS rate was 91.2% in the dexamethasone and high-dose MTX arm, 83.2% in the dexamethasone and escalating MTX arm, 80.8% in the prednisone and high-dose MTX arm, and 82.1% in the prednisone and escalating MTX arm (P=0.015).
For patients of all ages, there was a higher rate of febrile neutropenia during induction among patients who received dexamethasone than among those who received prednisone—18.2% and 11.0%, respectively (P<0.001).
Patients who received dexamethasone also had a higher rate of infections/infestations—29.4% and 20.3%, respectively (P<0.001).
However, there was no significant difference in induction death rate—1.9% and 1.8%, respectively (P=0.87). The same was true when the investigators looked only at patients younger than 10 (P=0.71) or at patients 10 and older (P=0.69).
Among patients ages 10 and older who participated in the induction corticosteroid randomization before it was closed, the 5-year cumulative incidence of osteonecrosis was 24.3% for patients who received dexamethasone and 15.9% for those who received prednisone (P=0.001).
There were no other significant differences in adverse events between the 2 corticosteroid regimens.
Factors may increase risk of asparaginase-induced pancreatitis in ALL
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
Method detects SNVs better, group says
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Researchers have developed a new method for detecting single-nucleotide variants (SNVs) in a single cell, and they believe it could have applications for cancer diagnosis and treatment.
The team said the method, known as Monovar, improves upon current single-cell sequencing (SCS) by more accurately detecting SNVs.
During testing, Monovar identified 28 new somatic SNVs in cells from a patient with acute lymphoblastic leukemia (ALL).
The researchers described Monovar in Nature Methods.
“To improve the SNVs in SCS datasets, we developed Monovar,” said study author Nicholas Navin, PhD, of the University of Texas MD Anderson Cancer Center in Houston.
“Monovar is a novel statistical method able to leverage data from multiple single cells to discover SNVs and provides highly detailed genetic data.”
Dr Navin and his colleagues found Monovar superior to standard algorithms for analyzing cells from previously studied patients with 3 different cancer types.
The team analyzed single cells from a patient with triple-negative breast cancer, a patient with muscle-invasive bladder cancer, and a child with ALL.
In cells from the ALL patient, Monovar discovered 57 somatic mutations, including 28 new somatic SNVs.
The researchers said Monovar identified significant mutations in OR4C3 and GPR107 (all subclones); LRFN5, PKD2L1, and ZNF781 (in subs 2, 4 and 5); DNAH7 (sub 1); LYAR and FMNL1 (sub 2); RGS3 (subs 4 and 5); and ADAMTS13, PRSS3, and PKD2L1 (subs 2-5).
The clonal mutations in OR4C3 and GPR107 and the subclonal mutations in PKD2L1, ADAMTS13, PRSS3, and RGS3 were not identified in the original study of the ALL patient (C Gawad et al. PNAS 2014).
Dr Navin and his colleagues said Monovar could have significant translational applications in cancer diagnosis and treatment, personalized medicine, and prenatal genetic diagnosis, where the accurate detection of SNVs is critical for patient care.
The researchers also believe Monovar could be used for studies in a range of biomedical fields.
“With the recent innovations in SCS methods to analyze thousands of single cells in parallel with RNA analysis, which will soon be extended to DNA analysis, the need for accurate DNA variant detection will continue to grow,” said Ken Chen, PhD, also of MD Anderson Cancer Center.
“Monovar is capable of analyzing large-scale datasets and handling different whole-genome protocols. Therefore, it is well-suited for many types of studies.”
Antibody shows activity against ALL, CLL
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Photo by Aaron Logan
NEW ORLEANS—Preclinical data suggest IMMU-114, a humanized anti-HLA-DR IgG4 antibody, is active against acute and chronic leukemias.
In a mouse model of chronic lymphocytic leukemia (CLL), IMMU-114 significantly prolonged survival when compared to rituximab.
IMMU-114 also produced a significant survival benefit in a mouse model of acute lymphoblastic leukemia (ALL) that is refractory to doxorubicin.
These results were presented at the 2016 AACR Annual Meeting (abstract 587). The research was carried out by employees of Immunomedics, Inc., the company developing IMMU-114.
The researchers generated a mouse model of human CLL by growing the cell line JVM-3 in SCID mice. The team noted that this model has similar HLA-DR and CD20 expression.
So they compared the efficacy of IMMU-114 and the anti-CD20 antibody rituximab in these mice and found that, at all doses tested, IMMU-114 significantly improved the median survival time (MST).
When both drugs were given at 50 µg, the MST was 42 days with IMMU-114 and 19 days with rituximab (P<0.0001).
When both drugs were given at 100 µg, the MSTs were 54 days and 18 days, respectively (P=0.017). And when both drugs were given at 200 µg, the MSTs were 46 days and 18 days, respectively (P<0.0001).
In control mice that received only saline, the MST was 14 days.
In in vitro experiments with the cell line JVM-3, IMMU-114 and the BTK inhibitor ibrutinib exhibited synergy fighting against the CLL cells. When given with the PI3K inhibitor idelalisib, IMMU-114 produced an additive effect.
In a doxorubicin-refractory mouse model of ALL (MN 60), IMMU-114 provided a significant survival benefit over doxorubicin and saline controls.
The MSTs were 21 days with saline, 23 days with doxorubicin, 39 days with IMMU-114 at 25 µg (P<0.0001), and 42.5 days with IMMU-114 at 50 µg (P<0.0001).
The researchers said IMMU-114 was well tolerated in these experiments, as evidenced by no significant weight loss in the mice.
Targeted corticosteroids cut GVHD incidence
Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.
The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.
The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.
The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).
Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.
The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.
“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.
Despite the encouraging results of Chang et al, it would be premature to routinely use corticosteroid prophylaxis to prevent GVHD until further studies are completed.
This study wasn’t sufficiently powered to determine whether corticosteroids reduced treatment-specific mortality or improved overall survival. Future studies must examine these end points, as well as relapse rates, before this method of prophylaxis is widely adopted.
Dr. Edwin P. Alyea is at Dana-Farber Cancer Institute, Boston. He reported having no relevant financial disclosures. Dr. Alyea made these remarks in an editorial accompanying Dr. Chang’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.66.0902).
Despite the encouraging results of Chang et al, it would be premature to routinely use corticosteroid prophylaxis to prevent GVHD until further studies are completed.
This study wasn’t sufficiently powered to determine whether corticosteroids reduced treatment-specific mortality or improved overall survival. Future studies must examine these end points, as well as relapse rates, before this method of prophylaxis is widely adopted.
Dr. Edwin P. Alyea is at Dana-Farber Cancer Institute, Boston. He reported having no relevant financial disclosures. Dr. Alyea made these remarks in an editorial accompanying Dr. Chang’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.66.0902).
Despite the encouraging results of Chang et al, it would be premature to routinely use corticosteroid prophylaxis to prevent GVHD until further studies are completed.
This study wasn’t sufficiently powered to determine whether corticosteroids reduced treatment-specific mortality or improved overall survival. Future studies must examine these end points, as well as relapse rates, before this method of prophylaxis is widely adopted.
Dr. Edwin P. Alyea is at Dana-Farber Cancer Institute, Boston. He reported having no relevant financial disclosures. Dr. Alyea made these remarks in an editorial accompanying Dr. Chang’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.66.0902).
Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.
The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.
The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.
The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).
Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.
The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.
“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.
Short-term low-dose corticosteroid prophylaxis reduces the incidence of graft-vs.-host disease in patients who undergo allogeneic haploidentical stem-cell transplantation to treat hematologic neoplasms, according to a report published online April 18 in the Journal of Clinical Oncology.
The key to selecting patients most likely to benefit from the corticosteroid therapy is to identify those at high risk for graft-vs.-host disease (GVHD) using two biomarkers: high levels of CD56bright natural killer cells in allogeneic grafts or high CD4:CD8 ratios in bone marrow grafts, according to Dr. Ying-Jun Chang of Peking University People’s Hospital, Beijing, and associates.
The investigators performed an open-label trial involving 228 patients aged 15-60 years treated at a single medical center during an 18-month period for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, or other hematologic neoplasms. Using the two biomarkers, the patients were categorized as either high or low risk for developing GVHD. They were randomly assigned to three study groups: 72 high-risk patients who received short-term low-dose corticosteroids, 73 high-risk patients who received usual care, and 83 low-risk patients who received usual care.
The cumulative 100-day incidence of acute grade-II to grade-IV GVHD was significantly lower in the high-risk patients who received prophylaxis (21%) than in the high-risk patients who did not receive prophylaxis (48%). In fact, corticosteroids decreased the rate of GVHD so that it was comparable with that in the low-risk patients (26%), Dr. Chang and associates said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.63l.8817).
Moreover, in the high-risk patients the median interval until GVHD developed was 25 days for those who took corticosteroids, compared with only 15 days for those who did not. Median times to myeloid recovery and platelet recovery were significantly shorter for high-risk patients who received corticosteroids than for either of the other study groups. However, 3-year overall survival and leukemia-free survival were comparable among the three study groups.
The short-term low-dose regimen of corticosteroids did not raise the rate of adverse events, including infection, which suggests that it is preferable to standard corticosteroid regimens in this patient population. The incidences of cytomegalovirus or Epstein-Barr virus reactivation, post-transplantation lymphoproliferative disorder, hemorrhagic cystitis, bacteremia, and invasive fungal infections were comparable among the three study groups. Of note, the incidences of osteonecrosis of the femoral head and secondary hypertension were significantly lower among high-risk patients who received corticosteroid prophylaxis than among those who did not.
“These results provide the first test, to our knowledge, of a novel risk-stratification-directed prophylaxis strategy that effectively prevented acute GVHD among patients who were at high risk for GVHD, without unnecessarily exposing patients who were at low risk to excessive toxicity from additional immunosuppressive agents,” Dr. Chang and associates said.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Short-term low-dose corticosteroid prophylaxis reduces the incidence of the GVHD in patients who undergo haploidentical stem-cell transplantation to treat hematologic neoplasms.
Major finding: The 100-day incidence of acute GVHD was significantly lower in the high-risk patients who received corticosteroid prophylaxis (21%) than in the high-risk patients who did not (48%).
Data source: An open-label randomized controlled trial involving 228 Chinese patients who underwent stem-cell transplantation.
Disclosures: This study was supported by the Beijing Committee of Science and Technology, the National High Technology Research and Development Program of China, and the National Natural Science Foundation of China. Dr. Chang and associates reported having no relevant financial disclosures.
Donor EBV status affects recipient graft-vs-host disease risk
In allogeneic hematopoietic stem-cell transplantation, the donor’s status regarding Epstein-Barr virus affects the recipient’s risk of developing graft-vs-host disease – a “completely new and striking” finding, according to a report published online April 18 in the Journal of Clinical Oncology.
Approximately 80% of the general population has been infected with EBV and carries persistent virus in memory B cells. When viral material is transmitted to stem-cell recipients, it is known to cause posttransplantation lymphoproliferative disorder. Until now, however, no data were available to examine EBV serology’s effect on other posttransplantation outcomes, said Dr. Jan Styczynski of the department of pediatric hematology and oncology at Nicolaus Copernicus University, Bydgoszcz, Poland, and his associates.
They analyzed information in the European Society of Blood and Marrow Transplantation database for 11,364 patients with acute lymphoblastic leukemia or acute myeloblastic leukemia who underwent stem-cell transplantation between 1997 and 2012 and who were followed for approximately 5 years. Most of the donors (82%) were seropositive for EBV. Acute graft-vs-host disease (GVHD) developed in 32% and chronic GVHD developed in 40% of these stem cell–transplant recipients.
The incidence of chronic GVHD was significantly higher when the donor was EBV-seropositive (41%) than when the donor was EBV-seronegative (31%). Similarly, the incidence of acute GVHD was significantly higher when the donor was EBV-seropositive (32% vs 30%), but the magnitude of the difference between the two groups was smaller. The risk for GVHD increased even though patients receiving transplants from EBV-seropositive donors underwent more intensive GVHD prophylaxis than did those who had seronegative donors, the investigators said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.64.2405).
In contrast, the transplant recipients’ EBV status did not affect their risk of developing GVHD.
“Despite the effect of donor EBV serostatus on GVHD, we did not observe a corresponding GVHD-related death rate, and as a result, there was no effect on overall survival, relapse-free survival, relapse incidence, and nonrelapse mortality. However, it should be kept in mind that many other pre- and posttransplantation factors play a role in contributing to final transplantation outcomes,” Dr. Styczynski and his associates noted.
The current recommendation to monitor transplantation recipients for EBV and to give them “preemptive” rituximab to stave off the development of posttransplantation lymphoproliferative disorder might prove useful in also preventing GVHD, they added.
The findings of Dr. Styczynski and his associates raise the possibility that we may be able to prevent or treat GVHD in transplant recipients by controlling EBV infection.
Selecting only EBV-negative donors would be one way to accomplish this, but that would be impractical given the high seroprevalence of EBV in the general population. Depleting memory B cells, the reservoir of EBV infection, using monoclonal antibodies may prove helpful, and these agents might provide additional therapeutic effects. And novel antivirals such as retroviral integrase inhibitors may be more specific at targeting EBV than acyclovir and related agents, which have limited activity against latently infected B cells. These novel drugs, however, are not without risks and adverse effects.
A promising alternative might be to boost immunity to EBV using vaccination or adoptive transfer of ex vivo expanded EBV-specific cytotoxic T cells.
Dr. Katayoun Rezvani and Dr. Richard E. Champlin are with the University of Texas MD Andersen Cancer Center, Houston. Their financial disclosures are available at www.jco.org. They made these remarks in an editorial accompanying Dr. Styczynski’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2016.66.6099).
The findings of Dr. Styczynski and his associates raise the possibility that we may be able to prevent or treat GVHD in transplant recipients by controlling EBV infection.
Selecting only EBV-negative donors would be one way to accomplish this, but that would be impractical given the high seroprevalence of EBV in the general population. Depleting memory B cells, the reservoir of EBV infection, using monoclonal antibodies may prove helpful, and these agents might provide additional therapeutic effects. And novel antivirals such as retroviral integrase inhibitors may be more specific at targeting EBV than acyclovir and related agents, which have limited activity against latently infected B cells. These novel drugs, however, are not without risks and adverse effects.
A promising alternative might be to boost immunity to EBV using vaccination or adoptive transfer of ex vivo expanded EBV-specific cytotoxic T cells.
Dr. Katayoun Rezvani and Dr. Richard E. Champlin are with the University of Texas MD Andersen Cancer Center, Houston. Their financial disclosures are available at www.jco.org. They made these remarks in an editorial accompanying Dr. Styczynski’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2016.66.6099).
The findings of Dr. Styczynski and his associates raise the possibility that we may be able to prevent or treat GVHD in transplant recipients by controlling EBV infection.
Selecting only EBV-negative donors would be one way to accomplish this, but that would be impractical given the high seroprevalence of EBV in the general population. Depleting memory B cells, the reservoir of EBV infection, using monoclonal antibodies may prove helpful, and these agents might provide additional therapeutic effects. And novel antivirals such as retroviral integrase inhibitors may be more specific at targeting EBV than acyclovir and related agents, which have limited activity against latently infected B cells. These novel drugs, however, are not without risks and adverse effects.
A promising alternative might be to boost immunity to EBV using vaccination or adoptive transfer of ex vivo expanded EBV-specific cytotoxic T cells.
Dr. Katayoun Rezvani and Dr. Richard E. Champlin are with the University of Texas MD Andersen Cancer Center, Houston. Their financial disclosures are available at www.jco.org. They made these remarks in an editorial accompanying Dr. Styczynski’s report (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2016.66.6099).
In allogeneic hematopoietic stem-cell transplantation, the donor’s status regarding Epstein-Barr virus affects the recipient’s risk of developing graft-vs-host disease – a “completely new and striking” finding, according to a report published online April 18 in the Journal of Clinical Oncology.
Approximately 80% of the general population has been infected with EBV and carries persistent virus in memory B cells. When viral material is transmitted to stem-cell recipients, it is known to cause posttransplantation lymphoproliferative disorder. Until now, however, no data were available to examine EBV serology’s effect on other posttransplantation outcomes, said Dr. Jan Styczynski of the department of pediatric hematology and oncology at Nicolaus Copernicus University, Bydgoszcz, Poland, and his associates.
They analyzed information in the European Society of Blood and Marrow Transplantation database for 11,364 patients with acute lymphoblastic leukemia or acute myeloblastic leukemia who underwent stem-cell transplantation between 1997 and 2012 and who were followed for approximately 5 years. Most of the donors (82%) were seropositive for EBV. Acute graft-vs-host disease (GVHD) developed in 32% and chronic GVHD developed in 40% of these stem cell–transplant recipients.
The incidence of chronic GVHD was significantly higher when the donor was EBV-seropositive (41%) than when the donor was EBV-seronegative (31%). Similarly, the incidence of acute GVHD was significantly higher when the donor was EBV-seropositive (32% vs 30%), but the magnitude of the difference between the two groups was smaller. The risk for GVHD increased even though patients receiving transplants from EBV-seropositive donors underwent more intensive GVHD prophylaxis than did those who had seronegative donors, the investigators said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.64.2405).
In contrast, the transplant recipients’ EBV status did not affect their risk of developing GVHD.
“Despite the effect of donor EBV serostatus on GVHD, we did not observe a corresponding GVHD-related death rate, and as a result, there was no effect on overall survival, relapse-free survival, relapse incidence, and nonrelapse mortality. However, it should be kept in mind that many other pre- and posttransplantation factors play a role in contributing to final transplantation outcomes,” Dr. Styczynski and his associates noted.
The current recommendation to monitor transplantation recipients for EBV and to give them “preemptive” rituximab to stave off the development of posttransplantation lymphoproliferative disorder might prove useful in also preventing GVHD, they added.
In allogeneic hematopoietic stem-cell transplantation, the donor’s status regarding Epstein-Barr virus affects the recipient’s risk of developing graft-vs-host disease – a “completely new and striking” finding, according to a report published online April 18 in the Journal of Clinical Oncology.
Approximately 80% of the general population has been infected with EBV and carries persistent virus in memory B cells. When viral material is transmitted to stem-cell recipients, it is known to cause posttransplantation lymphoproliferative disorder. Until now, however, no data were available to examine EBV serology’s effect on other posttransplantation outcomes, said Dr. Jan Styczynski of the department of pediatric hematology and oncology at Nicolaus Copernicus University, Bydgoszcz, Poland, and his associates.
They analyzed information in the European Society of Blood and Marrow Transplantation database for 11,364 patients with acute lymphoblastic leukemia or acute myeloblastic leukemia who underwent stem-cell transplantation between 1997 and 2012 and who were followed for approximately 5 years. Most of the donors (82%) were seropositive for EBV. Acute graft-vs-host disease (GVHD) developed in 32% and chronic GVHD developed in 40% of these stem cell–transplant recipients.
The incidence of chronic GVHD was significantly higher when the donor was EBV-seropositive (41%) than when the donor was EBV-seronegative (31%). Similarly, the incidence of acute GVHD was significantly higher when the donor was EBV-seropositive (32% vs 30%), but the magnitude of the difference between the two groups was smaller. The risk for GVHD increased even though patients receiving transplants from EBV-seropositive donors underwent more intensive GVHD prophylaxis than did those who had seronegative donors, the investigators said (J Clin Oncol. 2016 Apr 18. doi: 10.1200/JCO.2015.64.2405).
In contrast, the transplant recipients’ EBV status did not affect their risk of developing GVHD.
“Despite the effect of donor EBV serostatus on GVHD, we did not observe a corresponding GVHD-related death rate, and as a result, there was no effect on overall survival, relapse-free survival, relapse incidence, and nonrelapse mortality. However, it should be kept in mind that many other pre- and posttransplantation factors play a role in contributing to final transplantation outcomes,” Dr. Styczynski and his associates noted.
The current recommendation to monitor transplantation recipients for EBV and to give them “preemptive” rituximab to stave off the development of posttransplantation lymphoproliferative disorder might prove useful in also preventing GVHD, they added.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: In allogeneic hematopoietic stem-cell transplantation, the donor’s EBV status affects the recipient’s risk of developing GVHD.
Major finding: Chronic GVHD was significantly more likely to develop when the donor was EBV-seropositive (41%) than EBV-seronegative (31%).
Data source: A retrospective analysis of data regarding 11,364 European patients with acute leukemia who underwent stem-cell transplantation and were followed for 5 years.
Disclosures: No study sponsor was identified. Dr. Styczynski reported having no relevant financial disclosures; his associates reported ties to numerous industry sources.
Prelabor cesarean delivery linked to increased risk of childhood ALL
An increased risk of acute lymphoblastic leukemia (ALL) was seen in young children born by prelabor cesarean delivery, in a pooled analysis of 13 case-control studies from nine countries.
The odds ratio was significant at 1.23 for an association between prelabor cesarean delivery and ALL (P = .018); there was not a significant association between ALL and all indications of cesarean delivery nor was there an association with emergency cesarean delivery. Further, the risk for childhood AML was not associated with cesarean delivery, prelabor cesarean delivery, or emergency cesarean delivery, reported Erin L. Marcotte, Ph.D., of the University of Minnesota, Minneapolis, and her associates.
The association between ALL and prelabor cesarean delivery is based on 13 case-control studies from the Childhood Leukemia International Consortium. Birth delivery method was known for 97%-99% of 8,780 ALL cases, 1,332 AML cases, and 23,459 controls in those studies. In four of the studies, the indications for cesarean delivery were known for 1,061 of 4,313 ALL cases, 138 of 664 AML cases, and 1,401 of 5,884 controls. The multivariable logistic regression models used for the analysis were adjusted for birth weight, sex, age, ethnic origin, parental education, maternal age, and study.
If the association proves to be causal, “maladaptive immune activation due to an absence of stress response before birth in children born by prelabor caesarean delivery could be considered as a potential mechanism,” the researchers wrote (Lancet Haematol. 2016;3[4]:e176–e185).
ALL involves genetic and developmental aberrations that are probably modified by exposure and response to infectious agents. Early exposure to a variety of infections seems to decrease risk, and a vigorous response to infections (quantified by physician visits for infections) increases risk. During vaginal birth, the newborn is exposed to commensal bacteria that modulate immune development, Joseph Weimels, Ph.D., of the University of California at San Francisco, and Xiaomei Ma, Ph.D., of the Yale School of Public Health, New Haven, Conn., wrote in an editorial published in the same issue of The Lancet Haematology. Children delivered vaginally have different gut microbiomes and T-cell reactivity persisting up to age 2 years compared with children born by cesarean, they wrote.
The National Cancer Institute funded the study. The researchers had no relevant disclosures.
On Twitter @maryjodales
An increased risk of acute lymphoblastic leukemia (ALL) was seen in young children born by prelabor cesarean delivery, in a pooled analysis of 13 case-control studies from nine countries.
The odds ratio was significant at 1.23 for an association between prelabor cesarean delivery and ALL (P = .018); there was not a significant association between ALL and all indications of cesarean delivery nor was there an association with emergency cesarean delivery. Further, the risk for childhood AML was not associated with cesarean delivery, prelabor cesarean delivery, or emergency cesarean delivery, reported Erin L. Marcotte, Ph.D., of the University of Minnesota, Minneapolis, and her associates.
The association between ALL and prelabor cesarean delivery is based on 13 case-control studies from the Childhood Leukemia International Consortium. Birth delivery method was known for 97%-99% of 8,780 ALL cases, 1,332 AML cases, and 23,459 controls in those studies. In four of the studies, the indications for cesarean delivery were known for 1,061 of 4,313 ALL cases, 138 of 664 AML cases, and 1,401 of 5,884 controls. The multivariable logistic regression models used for the analysis were adjusted for birth weight, sex, age, ethnic origin, parental education, maternal age, and study.
If the association proves to be causal, “maladaptive immune activation due to an absence of stress response before birth in children born by prelabor caesarean delivery could be considered as a potential mechanism,” the researchers wrote (Lancet Haematol. 2016;3[4]:e176–e185).
ALL involves genetic and developmental aberrations that are probably modified by exposure and response to infectious agents. Early exposure to a variety of infections seems to decrease risk, and a vigorous response to infections (quantified by physician visits for infections) increases risk. During vaginal birth, the newborn is exposed to commensal bacteria that modulate immune development, Joseph Weimels, Ph.D., of the University of California at San Francisco, and Xiaomei Ma, Ph.D., of the Yale School of Public Health, New Haven, Conn., wrote in an editorial published in the same issue of The Lancet Haematology. Children delivered vaginally have different gut microbiomes and T-cell reactivity persisting up to age 2 years compared with children born by cesarean, they wrote.
The National Cancer Institute funded the study. The researchers had no relevant disclosures.
On Twitter @maryjodales
An increased risk of acute lymphoblastic leukemia (ALL) was seen in young children born by prelabor cesarean delivery, in a pooled analysis of 13 case-control studies from nine countries.
The odds ratio was significant at 1.23 for an association between prelabor cesarean delivery and ALL (P = .018); there was not a significant association between ALL and all indications of cesarean delivery nor was there an association with emergency cesarean delivery. Further, the risk for childhood AML was not associated with cesarean delivery, prelabor cesarean delivery, or emergency cesarean delivery, reported Erin L. Marcotte, Ph.D., of the University of Minnesota, Minneapolis, and her associates.
The association between ALL and prelabor cesarean delivery is based on 13 case-control studies from the Childhood Leukemia International Consortium. Birth delivery method was known for 97%-99% of 8,780 ALL cases, 1,332 AML cases, and 23,459 controls in those studies. In four of the studies, the indications for cesarean delivery were known for 1,061 of 4,313 ALL cases, 138 of 664 AML cases, and 1,401 of 5,884 controls. The multivariable logistic regression models used for the analysis were adjusted for birth weight, sex, age, ethnic origin, parental education, maternal age, and study.
If the association proves to be causal, “maladaptive immune activation due to an absence of stress response before birth in children born by prelabor caesarean delivery could be considered as a potential mechanism,” the researchers wrote (Lancet Haematol. 2016;3[4]:e176–e185).
ALL involves genetic and developmental aberrations that are probably modified by exposure and response to infectious agents. Early exposure to a variety of infections seems to decrease risk, and a vigorous response to infections (quantified by physician visits for infections) increases risk. During vaginal birth, the newborn is exposed to commensal bacteria that modulate immune development, Joseph Weimels, Ph.D., of the University of California at San Francisco, and Xiaomei Ma, Ph.D., of the Yale School of Public Health, New Haven, Conn., wrote in an editorial published in the same issue of The Lancet Haematology. Children delivered vaginally have different gut microbiomes and T-cell reactivity persisting up to age 2 years compared with children born by cesarean, they wrote.
The National Cancer Institute funded the study. The researchers had no relevant disclosures.
On Twitter @maryjodales
THE LANCET HAEMATOLOGY
Key clinical point: Prelabor cesarean delivery was associated with an increased risk of childhood ALL, but not AML.
Major finding: The odds ratio was significant at 1.23 for an association between prelabor cesarean delivery and ALL (P = .018).
Data source: Thirteen case-control studies from the Childhood Leukemia International Consortium.
Disclosures: The National Cancer Institute funded the study. The researchers had no relevant disclosures.
TKI trial leaves questions unanswered
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.
Image by Difu Wu
The phase 3 EPIC trial, a comparison of tyrosine kinase inhibitors (TKIs), has left some questions unanswered.
The trial did not determine whether the third-generation TKI ponatinib is more effective than the first-generation TKI imatinib for patients with previously untreated chronic myeloid leukemia (CML).
The study was terminated early due to safety concerns associated with ponatinib, so the primary endpoint could only be analyzed in a small number of patients.
Results in these patients showed no significant difference in that endpoint—major molecular response (MMR) at 12 months—between the imatinib and ponatinib arms.
Results in the entire study cohort suggested that, overall, ponatinib was more toxic than imatinib. In particular, ponatinib produced more arterial occlusive events.
However, the trial’s investigators have questioned whether reducing the dose of ponatinib might change that.
Jeffrey H. Lipton, MD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada, and his colleagues reported results from the EPIC trial in The Lancet Oncology. The trial was supported by Ariad Pharmaceuticals.
Problems with ponatinib
Ponatinib was approved by the US Food and Drug Administration (FDA) in December 2012 to treat adults with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia that is resistant to or intolerant of other TKIs.
In October 2013, follow-up results from the phase 2 PACE trial suggested ponatinib can increase a patient’s risk of arterial and venous thrombotic events. So all trials of the drug were placed on partial clinical hold, with the exception of the EPIC trial, which was terminated.
That November, the FDA suspended sales and marketing of ponatinib, pending results of a safety evaluation. In December, the agency decided ponatinib could return to the market if new safety measures were implemented. In January 2014, ponatinib was put back on the market in the US.
EPIC trial
The trial enrolled 307 patients with newly diagnosed, chronic-phase CML. Patients were randomized to receive ponatinib at 45 mg (n=155) or imatinib at 400 mg (n=152) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met.
The median age was 55 (range, 18-89) in the ponatinib arm and 52 (range, 18-86) in the imatinib arm. Most patients were male—63% and 61%, respectively—and most had an ECOG performance status of 0—75% and 78%, respectively.
Patients were randomized between August 14, 2012, and October 9, 2013, and the trial was terminated on October 17, 2013.
Because of the early termination, only 10 patients in the ponatinib arm and 13 in the imatinib arm were evaluable for the primary endpoint—MMR at 12 months. Eighty percent (8/10) of the evaluable patients in the ponatinib arm and 38% (5/13) of those in the imatinib arm achieved an MMR at 12 months (P=0.074).
The investigators also evaluated the incidence of MMR at any time in patients with any post-baseline molecular response assessment. This time, the incidence of MMR was significantly higher in the ponatinib arm than the imatinib arm—41% (61/149) and 18% (25/142), respectively (P<0.0001).
All of the patients were evaluable for safety—154 in the ponatinib arm and 152 in the imatinib arm.
Arterial occlusive events occurred in 7% (n=11) of patients in the ponatinib arm and 2% (n=3) in the imatinib arm (P=0.052). These events were considered serious in 6% (n=10) and 1% (n=1), respectively (P=0.010).
Common grade 3/4 adverse events—in the ponatinib and imatinib arms, respectively—were increased lipase (14% vs 2%), thrombocytopenia (12% vs 7%), rash (6% vs 1%), and neutropenia (3% vs 8%).
Serious adverse events that occurred in 3 or more patients in the ponatinib arm were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). There were no serious adverse events that occurred in 3 or more patients in the imatinib arm.
Dr Lipton and his colleagues said the premature termination of the EPIC trial restricts the interpretation of its results, but the available data provide some insight into the activity and safety of ponatinib in previously untreated CML.
The investigators also noted that data from this trial and the clinical development program for ponatinib suggest that lowering doses of the drug could improve its vascular safety profile and, therefore, the benefit-risk balance.
Two ongoing trials (NCT02467270 and NCT02627677) may provide more insight. Both are investigating starting doses of ponatinib at 15 mg or 30 mg.