ALL

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Red blood cells

Erytech Pharma said it plans to stop development of eryaspase for acute lymphoblastic leukemia (ALL).

This means withdrawal of the European marketing authorization application for eryaspase as a treatment for relapsed and refractory ALL.

However, Erytech will continue development of eryaspase as a treatment for certain solid tumor malignancies.

Eryaspase consists of L-asparaginase encapsulated inside donor-derived red blood cells. These enzyme-loaded red blood cells function as bioreactors to eliminate circulating asparagine and “starve” cancer cells, thereby inducing their death.

Erytech noted that eryaspase has produced favorable efficacy and safety results in ALL.

However, based on recent feedback from regulatory agencies in Europe and the US, the company believes significant additional investment would be required to seek regulatory approval of eryaspase for the treatment of ALL. Erytech also believes there would be a limited market opportunity for eryaspase in ALL.

Therefore, the company decided to cease further clinical development efforts in ALL. The resources that will become available as a result of this decision will be allocated to the development of eryaspase in solid tumors.

In 2017, Erytech announced results from a phase 2b clinical trial of eryaspase plus chemotherapy in patients with second-line metastatic pancreatic cancer. The company expects to begin enrollment in a phase 3 trial of this patient population in the third quarter of 2018.

In addition, Erytech is preparing for a pair of phase 2 proof-of-concept trials of eryaspase. One is in first-line pancreatic cancer, and the other is in metastatic triple-negative breast cancer. The company is also evaluating development options in additional solid tumor indications with high unmet medical need.

To ensure an adequate supply of eryaspase, Erytech is constructing a large-scale manufacturing facility in Princeton, New Jersey, and is expanding its manufacturing capacity in Lyon, France. The company expects both facilities to be operational for clinical production at the expanded capacity in the first quarter of 2019.

Photo courtesy of Amgen

The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.

This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).

Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.

The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.

Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).

On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.

The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).

For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).

Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.

These results were published in NEJM in March 2017.

Photo courtesy of Amgen

The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.

This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).

Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.

The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.

Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).

On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.

The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).

For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).

Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.

These results were published in NEJM in March 2017.

Photo courtesy of Amgen

The European Commission (EC) has granted a full marketing authorization for blinatumomab (BLINCYTO®) as a treatment for adults with Philadelphia chromosome-negative (Ph-), relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

The EC granted blinatumomab conditional authorization for this indication in 2015. Now, the drug has full authorization based on overall survival (OS) data from the phase 3 TOWER study.

This authorization is valid in all European Union and European Economic Area-European Free Trade Association states (Norway, Iceland, and Liechtenstein).

Blinatumomab is a bispecific CD19-directed CD3 T cell engager (BiTE®) immunotherapy construct. It binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of effector T cells.

The TOWER study was a phase 3, randomized trial in which researchers compared blinatumomab to standard of care (SOC) chemotherapy in 405 adults with Ph-, relapsed/refractory B-cell precursor ALL.

Patients were randomized in a 2:1 ratio to receive blinatumomab (n=271) or investigator’s choice of SOC chemotherapy (n=134).

On the recommendation of an independent data monitoring committee, Amgen ended the study early for evidence of superior efficacy in the blinatumomab arm.

The median OS was 7.7 months in the blinatumomab arm and 4 months in the SOC arm (hazard ratio=0.71; P=0.012).

For patients treated in first salvage, the median OS was 11.1 months in the blinatumomab arm and 5.3 months in the SOC arm (hazard ratio=0.6).

Safety results in the blinatumomab arm were comparable to those seen in previous phase 2 studies.

These results were published in NEJM in March 2017.

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

©ASCO/Zach Boyden-Holmes 2018

CHICAGO—A specific gene signature might be able to identify patients at risk of CD19 CAR T-cell associated neurotoxicity, according to results of an exploratory analysis presented at the 2018 ASCO Annual Meeting.

The analysis, based on bone marrow samples from patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated with JCAR015 in the ROCKET trial, helped identify a set of neurotoxicity-associated genes that separated patients based on molecular subtype.

“These findings suggest that patient risk stratification by molecular subtype of disease or gene expression signature may play a role in identifying patients at elevated risk of neurotoxicity,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center, New York, New York, in a presentation of the findings (abstract 7007).

The phase 2 ROCKET study included adult patients with relapsed or refractory morphological (>5% blasts in bone marrow) CD-19 positive disease in first salvage or greater, including post allogeneic hematopoietic stem cell transplantation (HSCT). Prior blinatumomab was allowed.

The tumor gene expression study presented at ASCO was based on sequenced RNA from pre-apheresis bone marrow samples available for 31 patients in the ROCKET study.

Investigators identified a set of 10 genes expressed more frequently in bone marrow samples from patients in ROCKET with low (grade 0-1) neurotoxicity, and 7 that were more frequent in those who had severe (grade 4-5) neurotoxicity.

Looking at B-cell ALL samples in public datasets by molecular subtype, they found genes highly expressed in the low neurotoxicity ROCKET patients were also highly expressed in Philadelphia chromosome-positive (Ph+) and Ph-like subtypes.

Conversely, the genes highly expressed in the severe neurotoxicity patients were also highly expressed in non-Ph-like samples.

A total of 16 ROCKET patients were classified as having Ph-like gene expression and 15 as having non-Ph-like expression.

There were no grade 4-5 neurotoxicity events in the Ph-like patients, while both grade 3+ and grade 4+ neurotoxicity were significantly more prevalent in the non-Ph-like patients, investigators reported.

One of the most differentially expressed genes in the set was CCL17, which was higher in the low-neurotoxicity tumor samples, and likewise highly expressed in Ph-like B-cell ALL, according to the report.

“[CCL17] may serve as an early biomarker for differentiating severe neurotoxicity,” Dr Park said.

These findings are now being validated in the previously mentioned data set, as well as other studies to see if the findings can be replicated, according to Dr Park.

Juno Therapeutics, a Celgene company, shut down the phase 2 ROCKET trial of JCAR015 in 2017 after 2 clinical holds in 2016 and 5 patient deaths. 

STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.

Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.

Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.

“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.

She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).

Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.

Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 10⁵/kg in patients who had not undergone HCT, and 0.9 x 10⁵ in patients who had received a transplant.

The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).

Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.

Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.

One of the two patients with extramedullary disease had a CR, and the other had a partial response.

Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.

All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.

At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.

Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.

It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.

SOURCE: Pan J et al. EHA Congress, Abstract S832.

STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.

Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.

Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.

“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.

She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).

Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.

Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 10⁵/kg in patients who had not undergone HCT, and 0.9 x 10⁵ in patients who had received a transplant.

The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).

Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.

Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.

One of the two patients with extramedullary disease had a CR, and the other had a partial response.

Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.

All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.

At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.

Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.

It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.

SOURCE: Pan J et al. EHA Congress, Abstract S832.

STOCKHOLM, SWEDEN – A novel chimeric antigen receptor T-cell construct directed against CD22 was able to rescue children with relapsed or refractory B-cell acute lymphoblastic leukemia for whom CD19-directed CAR T therapy had failed, investigators from China reported.

Thirty days after CAR T cell infusion, 12 of 15 children (80%) treated with the unnamed CD22 CAR T product had a complete response (CR) and one (6.7%) had a partial response (PR), for an overall response rate (ORR) of 86.7%, said Jing Pan, MD, from the Beijing Boren Hospital in China.

Surprisingly for a therapy of its type, the CD22 CAR T was well tolerated, with only mild cases of the cytokine release syndrome (CRS), and it could be delivered safely in children with relapsed disease after hematopoietic cell transplants (HCT), she reported in a briefing and in an oral abstract session at the annual congress of the European Hematology Association.

“CD22 CAR T immunotherapy brings hope for patients with refractory or relapsed B-ALL who failed on CD19 CAR T immunotherapy, and we think it’s quite safe. No children died and no children had severe side effects during the study, even in post-HCT patients,” Dr. Pan said.

She noted that in a previous clinical trial by her group, some patients experienced relapses and were resistant to retreatment with CD19-directed CAR T therapy due to mutations or loss of the CD19 antigen (Leukemia. 2017 Dec;31[12]:2587-93).

Since CD22 is highly expressed on leukemic cells in children with B-ALL, the investigators decided to evaluate the safety and efficacy of a CD22 CAR T as a rescue strategy. They enrolled 15 patients who either experienced relapse or did not have a response to CD19 CAR T immunotherapy. The CAR T construct they used contains an anti-CD22 single-chain variable fragment derived from a humanized CD22 antibody.

Patient conditioning with fludarabine and cyclophosphamide was performed simultaneously with CAR T transfection and expansion. After about 7 days, the expanded and transformed CAR T cells were infused at a dose of 8.2 x 10⁵/kg in patients who had not undergone HCT, and 0.9 x 10⁵ in patients who had received a transplant.

The patients ranged from 2 to 18 years old (median 8 years), had a median disease course of 21 months (range 5-84 months), and had a median of 42% bone marrow blasts (range 5%-95.5%).

Four of the 15 patients had relapses following allogeneic HCT, and the remaining 11 had relapses following chemotherapy. Two of the patients were found to be minimal residual disease (MRD)-positive by flow cytometry. Two patients had extramedullary disease only at relapse.

Ten of 11 patients who had experienced a hematologic relapse had either a CR or CR with incomplete recovery of counts (CRi), and of these 10 patients, nine were determined on follow-up to be MRD-negative by flow cytometry.

One of the two patients with extramedullary disease had a CR, and the other had a partial response.

Although two patients had no response to CD22 CAR T therapy, expression of the antigen was strong on leukemia cells from these patients, Dr. Pan said.

All patients experienced CRS, but none had greater than grade 2, Dr. Pan said, although she did not provide give specific numbers. Two patients had grade 1 neurotoxicity, two patients had grade 2 hypoxemia, and one patient had grade 2 liver enzyme elevation.

At a median follow-up of 108 days, six patients had been bridged to allogeneic HCT, and eleven of 12 patients who had a CR or CRi at 30 days had no evidence of disease progression. The remaining patient with an initial CR or CRi had a relapse at day 50. The 6-month progression-free survival rate was 91.7%.

Anton Hagenbeek, MD, PhD, from the Academic Medical Center at the University of Amsterdam, the Netherlands, who moderated the briefing but was not involved in the study, commented that given the high leukemia burden of the patients and the apparent efficacy of the therapy, one would expect to see higher grades of CRS, and asked Dr. Pan whether she could account for the CRS findings in her study, compared with those of trials for CD19-directed CAR T therapy.

It may have to do with differences in density of CD22 expression, compared with CD19 expression on leukemia cells, or on differences in the antibody used to target the cells, Dr. Pan said.

SOURCE: Pan J et al. EHA Congress, Abstract S832.

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

©ASCO/Rodney White 2018

CHICAGO—Prior exposure to blinatumomab does not appear to affect the successful manufacture of KTE-C19 or its efficacy in patients with relapsed/refractory acute lymphoblastic leukemia (ALL), an investigator reported at the 2018 ASCO Annual Meeting.

The clinical benefit of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, was preserved regardless of whether patients were exposed to blinatumomab, said Bijal D. Shah, MD, of Moffitt Cancer Center in Tampa, Florida.

High rates of complete response and undetectable minimal residual disease (MRD) were independent of exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager.

“We feel the results of these data support KTE-C19 as an effective option for adults with refractory leukemia, regardless of prior exposure to CD19-directed therapy,” Dr Shah reported at the meeting (abstract 7006*).

The current standard of care for adults with relapsed/refractory ALL includes blinatumomab, raising the question of whether prior exposure to this CD19-directed treatment could influence the manufacture or efficacy of KTE-C19.

Sara Cooley, MD, of Masonic Medical Center, University of Minnesota in Minneapolis, said results of this analysis suggest prior blinatumomab should not be a contraindication or concern in the context of KTE-C19.

“This remains to be shown with other CAR T-cell therapies,” she said in a presentation at ASCO on cellular therapy in leukemia.

The analysis by Dr Shah and co-investigators was based on ZUMA-3 (NCT02614066), a phase 1 study including adults with relapsed/refractory ALL who received KTE-C19 at doses of 0.5, 1, or 2 x 10⁶ cells/kg.

They excluded patients in the highest dose cohort, who were required to be blinatumomab naïve, per protocol. That left 23 patients who received 0.5 or 1 x 10⁶ cells/kg, of whom 11 had prior blinatumomab exposure and 12 did not.

Best overall response appeared to be independent of prior blinatumomab treatment, with a CR rate of 72% overall, and 63% and 80% for blinatumomab-exposed and blinatumomab-naïve patients, respectively.

The rate of undetectable MRD was likewise high at 88% in the prior blinatumomab group and 100% in the no-blinatumomab group.

Product characteristics did not vary according to blinatumomab exposure, though there was a trend toward a more differentiated phenotype in those patients who had received prior CD19-directed treatment, he said.

There were no significant differences between groups in the rate of grade 3 or greater cytokine release syndrome. Neurologic events were higher in the blinatumomab-naïve patients, though a higher percentage of those patients received the 1 x 10⁶ cells/kg dose, Dr Shah reported.

Investigators also looked at CAR T levels by treatment.

“We cannot appreciate any significant differences between the blinatumomab-naïve and the blinatumomab-exposed groups,” Dr Shah told ASCO attendees.

The ZUMA-3 trial was sponsored by Kite, a Gilead Company. 

*Data in the abstract differ from the presentation.

Photo by Bill Branson

Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.

But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.

Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.

The investigators believe the incidence of cranial relapse may explain the results of AALL0622.

“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.

AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.

In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.

Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.

As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.

In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.

For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.

In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.

However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.

HSCT

AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.

Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.

Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.

Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.

Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).

Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.

The investigators reported their findings in The Journal of Clinical Oncology. 

Photo by Bill Branson

Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.

But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.

Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.

The investigators believe the incidence of cranial relapse may explain the results of AALL0622.

“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.

AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.

In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.

Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.

As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.

In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.

For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.

In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.

However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.

HSCT

AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.

Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.

Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.

Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.

Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).

Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.

The investigators reported their findings in The Journal of Clinical Oncology. 

Photo by Bill Branson

Dasatinib used during induction and consolidation in the Children’s Oncology Group (COG) AALL0622 trial provided early response rates for children with Ph-positive (Ph+) acute lymphoblastic leukemia (ALL), according to investigators.

But the early response rates did not improve event-free survival (EFS) compared to the use of consolidation imatinib in the AALL0031 study.

Incidence of cranial relapse was more than doubled in AALL0622 compared to AALL0031.

The investigators believe the incidence of cranial relapse may explain the results of AALL0622.

“We cannot yet conclude that the current dasatinib plus chemotherapy combination is better than imatinib plus chemotherapy,” the authors stated.

AALL0622 was designed to be an improvement on AALL0031, which demonstrated that adding the tyrosine kinase inhibitor (TKI) imatinib to intensive chemotherapy in the consolidation phase significantly improved survival for children with Ph+ ALL.

In AALL0622 dasatinib was given early in induction (day 15) and then in consolidation with the hope that patients could achieve early remission.

Another departure from AALL0031 was that cranial irradiation was not provided for control of central nervous system (CNS) metastasis. Because dasatinib accumulates in the CNS, which is a ‘sanctuary site’ for leukemia, it was presumed that patients could benefit from a TKI yet be spared from cranial irradiation.

As expected, adding dasatinib mid-induction provided a complete remission rate of 98% at the end of induction (day 29), which was better than the 89% seen in AALL0031.

In addition, more patients in AALL0622 showed minimal residual disease (MRD) <0.01% at the end of induction: 59% vs 25% in AALL0031 (P <0.001). At the end of consolidation, corresponding rates were 89% vs 71% for AALL0031.

For the primary outcome, 3-year EFS was 84.6% for patients in AALL0622 in standard-risk patients. Five-year OS and EFS rates were 86% and 60%, respectively.

In patients with overt brain metastasis (CNS3 status), 5-year CNS relapse was 15% for patients in the AALL0622 study vs 6.6% for patients in the AALL031 study.

However, 5-year OS rates were similar in the two groups of patients: 86% for AALL0622 vs 81% for AALL0031.

HSCT

AALL0622 allowed the use of hematopoietic stem cell transplantation (HSCT) in high-risk patients as well as in standard-risk patients with a sibling donor.

Five-year OS and EFS for standard-risk patients (19% underwent HSCT at first remission) and high-risk patients (91% underwent HSCT in first remission) were similar.

Children who did not undergo HSCT had a similar 5-year OS of 88%, which suggested that children with Ph+ ALL should not undergo transplantation at first remission.

Samples from a subset of patients was analyzed for IKZF1 mutations and correlated with outcomes.

Five-year OS was 80% in those harboring the mutation versus 100% who had the wild-type gene (P=0.04); 4-year EFS was also significantly lower—10% vs 82% (P=0.04).

Screening for IKZF1 may be used to identify high-risk patients suitable for HSCT and/or alternate treatment, the authors note.

The investigators reported their findings in The Journal of Clinical Oncology. 

CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.

Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.

“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.

In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.

“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.

The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.

Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).

SOURCE: Hay KA. ASCO 2018, Abstract 7005.

CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.

Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.

“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.

In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.

“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.

The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.

Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).

SOURCE: Hay KA. ASCO 2018, Abstract 7005.

CHICAGO – Minimal residual disease (MRD)–negative complete remission was strongly associated with improved survival outcomes in patients with B-cell acute lymphocytic leukemia (ALL) who received CD19 chimeric antigen receptor (CAR) T cells, results of a retrospective study showed.

Allogeneic hematopoietic stem cell transplant (HSCT) appeared to improve both disease-free and overall survival in those patients who had achieved MRD-negative complete remission, according to results of the study, which were presented at the annual meeting of the American Society of Clinical Oncology.

“Based upon our interaction testing, the potential benefit [of transplant] appears to exist in both good-risk and bad-risk patients as identified through multivariate modeling,” said study investigator Kevin Anthony Hay, MD, of Fred Hutchinson Cancer Research Center, Seattle.

In a comment on the results, Sarah Cooley, MD, noted that the benefits of allogeneic transplant were apparent regardless of whether the patients met criteria for the good-risk subgroup, which was defined by levels of lactate dehydrogenase (LDH) and platelets along with exposure to fludarabine as part of the conditioning regimen.

“I think this suggests that the goal at this point is to get patients to an MRD-negative state and to potentially curative transplant,” said Dr. Cooley, director of investigator-initiated research at Masonic Medical Center at the University of Minnesota, Minneapolis.

The retrospective analysis by Dr. Hay and his colleagues included 53 adults with relapsed or refractory ALL who had bone marrow or extramedullary disease at baseline and had received CD19 CAR T cells at or under the maximum tolerated dose at least 1 year prior to this analysis. Of that group, 45 (85%) achieved MRD-negative complete remission.

Those patients who did achieve MRD-negative complete remission had an improved median disease-free survival at 7.6 months versus 0.8 months (P less than .0001) and improved overall survival at 20.0 months versus 5.0 months (P = 0.014).

SOURCE: Hay KA. ASCO 2018, Abstract 7005.

Credit: Anatomography

A 6-year prospective study from the Canadian STOPP investigators revealed that following treatment for acute lymphoblastic leukemia (ALL), approximately 1 out of 3 children experiences vertebral fractures (VF) and 1 out of 5 children shows non-VF.

Glucocorticoid use and vertebral fractures at diagnosis emerged as significant predictive factors.

Investigators reported a cumulative incidence of 32.5% for vertebral fractures (VF) following treatment and 23.0% for non-VF after 6 years.

Thirty-nine percent of children with VF were asymptomatic.

“The osteotoxicity of leukemia and its treatment are underscored by the observation that the non-VF incidence was more than 2.5 times higher than the general pediatric population,” the study authors wrote, “whereas the VF incidence was increased more than 2000 times.”

The STOPP investigators—the Steroid-Associated Osteoporosis in the Pediatric Population Consortium—published their findings in the Journal of Bone and Mineral Research.

To document the incidence and predictors of fractures and profile who is at greatest risk, the STOPP investigators enrolled 186 children who were diagnosed and treated at 10 children’s hospitals across Canada between 2005 and 2007.

Median age at diagnosis was 5.3 years, median duration of follow-up was 6 years, and 38.1% were boys.

Approximately 4 out of 5 children were treated with Children’s Oncology Group protocols and 1 out of 5 was treated with the Dana-Farber protocols.

In girls, glucocorticoid exposure was 7.0 g/m² and in boys it was 8.9 g/m².

The entire cohort received 54.3% of the total cumulative glucocorticoid dose in the first year and 83.1% in the second year.

For VF, incidence at baseline was 15.1%. Skeletal fractures at any site were reported in 36% of the children over the 6-year period, 71% occurring during the first 2 years. No VF was reported in the sixth year.

Of 38 children with VF, 32 sustained at least 1 VF in the first 2 years and 77% occurred while on therapy or within 6 months of the last glucocorticoid dose. None of the children had disease relapse.

Non-VF were reported in 1.6% of children at baseline; incidence peaked at years 2 (5.4%) and 5 (4.8%) and none occurred in the sixth year.

Thirty-one non-VFs were reported in 26 children; 18 occurred in the first 2 years and 23 occurred on therapy or within 6 months of the last glucocorticoid dose.

The STOPP investigators showed that glucocorticoid exposure, VF, and low spine bone mineral density Z-scores at baseline were significant predictors for risk of VF.

“[This] observation suggests the importance of baseline spine phenotype (both VF and low lumbar spine bone mineral density) in signaling the potential for future bone morbidity,” the STOPP investigators note.

“In revealing that vertebral fractures are frequent in children with ALL on chemotherapy, and that older children and those with more severe collapse are at risk for residual vertebral deformities, strategies to prevent vertebral fractures in those at greatest risk for permanent sequelae now merit further study,” said lead author Leanne Ward, MD, of the University of Ottawa, Canada, in a statement.

The study was primarily supported by an operating grant from the Canadian Institutes for Health Research (CIHR) with additional funding from a CIHR New Investigator Award, a Canadian Child Health Clinician Scientist Career Enhancement Award, a University of Ottawa Research Chair Award, a Children’s Hospital of Eastern Ontario (CHEO) Research Institute Capacity Building Award, and the CHEO Departments of Pediatrics and Surgery. This work was also supported by the University of Alberta Women and Children’s Health Research Institute. 

Credit: Anatomography

A 6-year prospective study from the Canadian STOPP investigators revealed that following treatment for acute lymphoblastic leukemia (ALL), approximately 1 out of 3 children experiences vertebral fractures (VF) and 1 out of 5 children shows non-VF.

Glucocorticoid use and vertebral fractures at diagnosis emerged as significant predictive factors.

Investigators reported a cumulative incidence of 32.5% for vertebral fractures (VF) following treatment and 23.0% for non-VF after 6 years.

Thirty-nine percent of children with VF were asymptomatic.

“The osteotoxicity of leukemia and its treatment are underscored by the observation that the non-VF incidence was more than 2.5 times higher than the general pediatric population,” the study authors wrote, “whereas the VF incidence was increased more than 2000 times.”

The STOPP investigators—the Steroid-Associated Osteoporosis in the Pediatric Population Consortium—published their findings in the Journal of Bone and Mineral Research.

To document the incidence and predictors of fractures and profile who is at greatest risk, the STOPP investigators enrolled 186 children who were diagnosed and treated at 10 children’s hospitals across Canada between 2005 and 2007.

Median age at diagnosis was 5.3 years, median duration of follow-up was 6 years, and 38.1% were boys.

Approximately 4 out of 5 children were treated with Children’s Oncology Group protocols and 1 out of 5 was treated with the Dana-Farber protocols.

In girls, glucocorticoid exposure was 7.0 g/m² and in boys it was 8.9 g/m².

The entire cohort received 54.3% of the total cumulative glucocorticoid dose in the first year and 83.1% in the second year.

For VF, incidence at baseline was 15.1%. Skeletal fractures at any site were reported in 36% of the children over the 6-year period, 71% occurring during the first 2 years. No VF was reported in the sixth year.

Of 38 children with VF, 32 sustained at least 1 VF in the first 2 years and 77% occurred while on therapy or within 6 months of the last glucocorticoid dose. None of the children had disease relapse.

Non-VF were reported in 1.6% of children at baseline; incidence peaked at years 2 (5.4%) and 5 (4.8%) and none occurred in the sixth year.

Thirty-one non-VFs were reported in 26 children; 18 occurred in the first 2 years and 23 occurred on therapy or within 6 months of the last glucocorticoid dose.

The STOPP investigators showed that glucocorticoid exposure, VF, and low spine bone mineral density Z-scores at baseline were significant predictors for risk of VF.

“[This] observation suggests the importance of baseline spine phenotype (both VF and low lumbar spine bone mineral density) in signaling the potential for future bone morbidity,” the STOPP investigators note.

“In revealing that vertebral fractures are frequent in children with ALL on chemotherapy, and that older children and those with more severe collapse are at risk for residual vertebral deformities, strategies to prevent vertebral fractures in those at greatest risk for permanent sequelae now merit further study,” said lead author Leanne Ward, MD, of the University of Ottawa, Canada, in a statement.

The study was primarily supported by an operating grant from the Canadian Institutes for Health Research (CIHR) with additional funding from a CIHR New Investigator Award, a Canadian Child Health Clinician Scientist Career Enhancement Award, a University of Ottawa Research Chair Award, a Children’s Hospital of Eastern Ontario (CHEO) Research Institute Capacity Building Award, and the CHEO Departments of Pediatrics and Surgery. This work was also supported by the University of Alberta Women and Children’s Health Research Institute. 

Credit: Anatomography

A 6-year prospective study from the Canadian STOPP investigators revealed that following treatment for acute lymphoblastic leukemia (ALL), approximately 1 out of 3 children experiences vertebral fractures (VF) and 1 out of 5 children shows non-VF.

Glucocorticoid use and vertebral fractures at diagnosis emerged as significant predictive factors.

Investigators reported a cumulative incidence of 32.5% for vertebral fractures (VF) following treatment and 23.0% for non-VF after 6 years.

Thirty-nine percent of children with VF were asymptomatic.

“The osteotoxicity of leukemia and its treatment are underscored by the observation that the non-VF incidence was more than 2.5 times higher than the general pediatric population,” the study authors wrote, “whereas the VF incidence was increased more than 2000 times.”

The STOPP investigators—the Steroid-Associated Osteoporosis in the Pediatric Population Consortium—published their findings in the Journal of Bone and Mineral Research.

To document the incidence and predictors of fractures and profile who is at greatest risk, the STOPP investigators enrolled 186 children who were diagnosed and treated at 10 children’s hospitals across Canada between 2005 and 2007.

Median age at diagnosis was 5.3 years, median duration of follow-up was 6 years, and 38.1% were boys.

Approximately 4 out of 5 children were treated with Children’s Oncology Group protocols and 1 out of 5 was treated with the Dana-Farber protocols.

In girls, glucocorticoid exposure was 7.0 g/m² and in boys it was 8.9 g/m².

The entire cohort received 54.3% of the total cumulative glucocorticoid dose in the first year and 83.1% in the second year.

For VF, incidence at baseline was 15.1%. Skeletal fractures at any site were reported in 36% of the children over the 6-year period, 71% occurring during the first 2 years. No VF was reported in the sixth year.

Of 38 children with VF, 32 sustained at least 1 VF in the first 2 years and 77% occurred while on therapy or within 6 months of the last glucocorticoid dose. None of the children had disease relapse.

Non-VF were reported in 1.6% of children at baseline; incidence peaked at years 2 (5.4%) and 5 (4.8%) and none occurred in the sixth year.

Thirty-one non-VFs were reported in 26 children; 18 occurred in the first 2 years and 23 occurred on therapy or within 6 months of the last glucocorticoid dose.

The STOPP investigators showed that glucocorticoid exposure, VF, and low spine bone mineral density Z-scores at baseline were significant predictors for risk of VF.

“[This] observation suggests the importance of baseline spine phenotype (both VF and low lumbar spine bone mineral density) in signaling the potential for future bone morbidity,” the STOPP investigators note.

“In revealing that vertebral fractures are frequent in children with ALL on chemotherapy, and that older children and those with more severe collapse are at risk for residual vertebral deformities, strategies to prevent vertebral fractures in those at greatest risk for permanent sequelae now merit further study,” said lead author Leanne Ward, MD, of the University of Ottawa, Canada, in a statement.

The study was primarily supported by an operating grant from the Canadian Institutes for Health Research (CIHR) with additional funding from a CIHR New Investigator Award, a Canadian Child Health Clinician Scientist Career Enhancement Award, a University of Ottawa Research Chair Award, a Children’s Hospital of Eastern Ontario (CHEO) Research Institute Capacity Building Award, and the CHEO Departments of Pediatrics and Surgery. This work was also supported by the University of Alberta Women and Children’s Health Research Institute. 

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

Photo by Petr Kratochvil

Childhood acute lymphoblastic leukemia (ALL) may be preventable, according to a researcher.

Mel Greaves, PhD, of The Institute of Cancer Research in London, UK, reviewed more than 30 years of research and concluded that ALL develops in 2 steps—genetic mutation before birth and further genetic change after birth triggered by infection.

The evidence suggests that infection early in life is beneficial to prime the immune system, but later infection without earlier priming can trigger ALL.

So priming the immune system in the first year of life could potentially prevent childhood ALL, according to Dr Greaves.

He outlined this theory in Nature Reviews Cancer.

Dr Greaves compiled more than 30 years of research into genetics, cell biology, immunology, epidemiology, and animal modelling of ALL.

The evidence led him to conclude that ALL begins with a genetic mutation that occurs before birth and predisposes a child to leukemia.

The disease is triggered later, in childhood, by exposure to one or more common infections. This primarily occurs in children who experienced “clean” childhoods in their first year of life, without much interaction with other infants or older children.

Dr Greaves challenged previous reports of possible environmental causes for ALL, such as ionizing radiation, electromagnetic waves, or man-made chemicals. He argued that none of these reports are supported by robust evidence.

Instead, he believes there is strong evidence suggesting that infection later in childhood, in the absence of earlier priming, can trigger ALL.

Dr Greaves’ studies of identical twins with ALL showed that 2 mutations were required for ALL development. The first arises in one twin in the womb but produces a population of pre-malignant cells that spread to the other twin via their shared blood supply. The second mutation arises after birth and is different in the twins.

Population studies and animal experiments suggest this second genetic hit can be triggered by infection, probably by a range of common viruses and bacteria. In one unique cluster of cases investigated by Dr Greaves and his colleagues, all cases were infected with flu virus.

In other work, researchers engineered mice with an active leukemia-initiating gene. When the team moved the mice from an ultra-clean, germ-free environment to one that had common microbes, the mice developed ALL.

Population studies have indicated that early exposure to infection in infancy, such as via day care attendance and breast feeding, can protect against ALL, probably by priming the immune system. This suggests childhood ALL may be preventable.

Dr Greaves is now investigating whether earlier exposure to harmless microbes could prevent leukemia in mice.

“I have spent more than 40 years researching childhood leukemia, and, over that time, there has been huge progress in our understanding of its biology and its treatment . . . ,” Dr Greaves said. “But it has always struck me that something big was missing, a gap in our knowledge [that failed to explain] why or how otherwise healthy children develop leukemia and whether this cancer is preventable.”

“This body of research is a culmination of decades of work and at last provides a credible explanation for how the major type of childhood leukemia develops. The research strongly suggests that ALL has a clear biological cause and is triggered by a variety of infections in predisposed children whose immune systems have not been properly primed. It also busts some persistent myths about the causes of leukemia, such as the damaging but unsubstantiated claims that the disease is commonly caused by exposure to electro-magnetic waves or pollution.”

“I hope this research will have a real impact on the lives of children. The most important implication is that most cases of childhood leukemia are likely to be preventable. It might be done in the same way that is currently under consideration for autoimmune disease or allergies, perhaps with simple and safe interventions to expose infants to a variety of common and harmless ‘bugs.’”

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.

A set of novel chemotherapy regimens yield excellent outcomes—the best yet—among pediatric and young adult patients with T-cell malignancies, finds a phase 3 randomized controlled trial conducted by the Children’s Oncology Group (ALL0434).

“Despite very intense and complex chemotherapy, 20% of children and adolescents enrolled in Children’s Oncology Group T-cell leukemia trials between 2000 and 2005 did not survive. New drugs were needed to improve survival rates for T-cell malignancies,” lead study author Kimberly P. Dunsmore, MD, a professor at Virginia Tech, Roanoke, said in a press briefing leading up to the annual meeting of the American Society of Clinical Oncology.

The ALL0434 trial tested the addition of methotrexate (Trexall) and/or nelarabine (Arranon), a T cell–specific drug known to be efficacious in relapsed disease, to standard chemotherapy, with tailoring of the regimen to recurrence risk. Analyses were based on 1,545 patients with T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LL).

Results for all patients with T-ALL showed that, with addition of either or both drugs, more than 90% were alive at 4 years and more than 80% were leukemia free. Adding nelarabine to standard chemotherapy improved disease-free survival among the subset having intermediate- or high-risk disease, and the best outcomes were seen with addition of both nelarabine and an escalating dose of methotrexate.

Although patients with T-LL did not see benefit from addition of nelarabine, they still had an 85% rate of overall survival at 4 years.

“ALL0434 is the largest trial for children and young adults with T-cell malignancy ever conducted. It has the best-ever survival data,” Dr. Dunsmore commented.

“Our next steps will be to examine what implications and benefits may accrue when using nelarabine in protocols without cranial irradiation. This is to decrease long-term neurologic side effects, and we think it may be possible since nelarabine also reduces CNS relapses,” she said.

Study details

The ALL0434 trial enrolled patients aged 1-30 years with newly diagnosed T-ALL or T-LL. After induction chemotherapy, all patients received standard chemotherapy, the Children’s Oncology Group augmented Berlin-Frankfurt-Munster regimen (N Engl J Med. 1998;338:1663-71), and depending on recurrence risk, cranial irradiation.

In addition to that regimen, they were randomly assigned to four arms, according to methotrexate dosing (high dose with leucovorin rescue in the inpatient setting vs. escalating dose in the outpatient setting) and nelarabine therapy (receipt vs. nonreceipt).

Among patients with T-ALL, those with low-risk disease were ineligible for nelarabine and did not receive cranial irradiation, whereas those with intermediate- and high-risk disease were randomized to all four arms, Dr. Dunsmore explained. In addition, those who did not achieve remission on induction chemotherapy were nonrandomly assigned to the high-dose methotrexate plus nelarabine arm.