Leukemia, Myelodysplasia, Transplantation

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

Prescription drugs

Photo by Steven Harbour

The US Food and Drug Administration (FDA) has approved the use of imatinib mesylate, a generic version of Novartis’s Gleevec being developed by a subsidiary of Sun Pharmaceuticals Limited.

Under the terms of a settlement agreement with Novartis, the Sun Pharma subsidiary is allowed to launch its generic imatinib in the US on February 1, 2016.

The drug will be available in 100 mg and 400 mg tablets.

The Sun Pharma subsidiary was the first company to file an abbreviated new drug application for generic imatinib with a para IV certification and is therefore eligible for 180 days of marketing exclusivity in the US.

Sun Pharma’s imatinib mesylate is approved for the following indications:

• Newly diagnosed adult and pediatric patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase
• Patients with (Ph+ CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy
• Adult patients with relapsed or refractory Ph+ acute lymphoblastic leukemia
• Adult patients with myelodysplastic/myeloproliferative diseases associated with PDGFR gene re-arrangements
• Adult patients with aggressive systemic mastocytosis without the D816V c-Kit mutation or with c-Kit mutational status unknown
•  Adult patients with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1- PDGFRα fusion kinase negative or unknown
• Adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans.

The drug is not approved to treat patients with KIT (CD117)-positive unresectable and/or metastatic malignant gastrointestinal stromal tumors.

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – Cytogenetic profile and response to initial induction therapy can identify a subgroup of National Cancer Institute (NCI) high risk childhood B-lymphoblastic leukemia patients who have good outcomes, Dr. Elizabeth Raetz said, reporting results for her colleagues in the Children’s Oncology Group (COG).

Outcomes were excellent for patients with favorable cytogenetic features and rapid minimal residual disease responses during induction therapy, said Dr. Raetz, of Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City. Notably, 5-year overall survival (OS) was over 98% for those with favorable cytogenetic subsets, nearly half of all patients, in a combined analysis of standard risk and high risk patients.

Mary Jo Dales

The findings suggest that these patients would not benefit from further intensification of their chemotherapy, sparing them possible toxicity and late effects.

The COG used clinical, biologic, and early disease response measures to study 11,144 patients, aged 1-30 years, enrolled on the COG AALL03B1 classification study. Patients began either a standard risk 3-drug or high risk 4-drug induction therapy based on NCI risk group, she said at the annual meeting of the American Society of Hematology.

After induction therapy, patients were classified into low (29%), standard (33%), high (34%), or very high (4%) risk groups for treatment allocation. Variables used for risk classification included age, initial WBC, extramedullary disease status, blast cytogenetics, early treatment response based on bone marrow morphology and minimal residual disease in marrow at day 29.

Rapid early response was defined as having less than 5% blasts in bone marrow by day 15 plus flow cytometry-based minimal residual disease less than 0.1% on day 29 of induction. Those with either 5% or more blasts in their marrow at day 15 or minimal residual disease of 0.1% or more at day 29 were deemed slow early responders.

Of the 96% of patients evaluable for post-induction treatment assignment, 5104 (65%) were treated for NCI standard risk and 2791 were treated for NCI high-risk B-ALL.

Rapid early responses were seen in 84% and slow early responses in 16%. For those with rapid early responses, the 5-year event-free survival rates was 89% and the overall survival rate was 95%. For those with slow early responses, EFS was 68% and OS was 84%.

The standard risk and high risk groups were then combined and analyzed based on cytogenetic subtype. The favorable gene ETV6-RUNX1 was seen in 26% (1,928 patients) and associated with an EFS of 93% as compared to an EFS of 84% for the 5578 patients without ETV6-RUNX1. OS was 98% for positive patients and 92% for negative patients. In the 21% (1,483 patients) with the triple trisomy 4/10/17, EFS was 95% as compared to an EFS of 84% for the 5,603 patients without the trisomy. OS was 99% and 92%, respectively.

In a subsequent analysis using current COG minimum residual disease response measures – with rapid early response defined as day 8 blood minimal residual disease less than 1% and day 29 marrow minimal residual disease less than 0.01% – the 243 high risk patients who had favorable cytogenetics and no detectable leukemia cells in their CSF had 5 years EFS of 95% and OS of 98%.

Dr. Raetz had no relevant financial disclosures.

Abstract 807: Genetic and Response-Based Risk Classification Identifies a Subgroup of NCI High Risk Childhood B-Lymphoblastic Leukemia (HR B-ALL) with Outstanding Outcomes: A Report from the Children’s Oncology Group (COG).

mdales@frontlinemedcom.com

On Twitter @maryjodales

ORLANDO – A single infusion of donor-derived chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved remission in 9 of 20 patients with B-cell malignancies that progressed after allogeneic stem cell transplant, a study shows.

The seven complete remissions and two partial remissions occurred without any chemotherapy and without causing acute graft-versus-host disease (GVHD).

The experimental anti-CD 19 CAR T-cells seem particularly effective against acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), but responses also occurred in lymphoma, Dr. James Kochenderfer of the Center for Cancer Research, National Cancer Institute, in Bethesda, Md., reported at the annual meeting of the American Society of Hematology.

B-cell malignancies that persist after transplantation are often treated with unmanipulated donor lymphocytes, but these infusions are often ineffective and associated with significant morbidity and mortality from GVHD.

To improve on this approach, 20 patients were infused with T cells obtained from the original stem cell donor and transduced with a CD19-directed CAR that was encoded by a gamma-retroviral vector and included a CD28 co-stimulatory domain. The highest dose reached in the phase I study was 10⁷ total cell/kg. Production of the anti-CD19 CAR T cells took only eight days for each patient, Dr. Kochenderfer said at a press briefing.

The patients had received at least one standard donor-leukocyte infusion, had to have minimal or no GVHD, and could not be receiving systemic immunosuppressive drugs.

The highest response rates were in ALL, where four of five patients obtained complete remission (CR) with no detectable minimal residual disease by multi-color flow cytometry, Dr. Kochenderfer said. Two of these patients later relapsed, one is in ongoing CR at 18 months, and one went on to a second allogeneic transplant and continues in complete remission.

The longest ongoing CR at 36 months occurred in a patient treated for CLL. Another patient achieved a partial remission (PR) ongoing at 18 months, two patients progressed, and one has stable disease.

In five patients treated for Mantle cell lymphoma, there is one CR ongoing at 31 months, one PR, and three stable diseases.

Three of the five patients treated for diffuse large B-cell lymphoma experienced stable disease, one progressive disease, and one obtained a CR, but is no longer evaluable because she received other therapies for chronic GVHD. Dr. Kochenderfer went on describe an impressive response in this patient, who had large lymphoma masses at the back of her head and in her eye socket before infusion.

“Amazingly, the tumor masses completely disappeared within five days of CAR T-cell infusion,” he said.

Patients with high tumor burdens, however, experienced severe cytokine-release syndrome with fever, tachycardia, and hypertension that was treated with the interleukin-6 receptor antagonist tocilizumab (Actemra).

Only one case of mild aphasia occurred, which contrasts with other CAR T-cell therapies where neurotoxicity is common, Dr. Kochenderfer said.

One patient had continued worsening of pre-existing chronic GVHD after CAR T-cell therapy, and one patient developed very mild chronic eye GVHD more than a year after infusion.

The press corps was not fully convinced by the findings, however, asking Dr. Kochenderfer why they should be excited by the 40% remission rate when other CAR T-cell therapies have yielded remission rates as high as 90%.

Dr. Kochenderfer pointed out that four of the five ALL patients (80%) achieved a MRD-negative complete response, which compares favorably with other protocols. The remaining patients had far more advanced, treatment-resident disease of varying histologies than evaluated in other trials and, unlike most trials, all patients had received an allogeneic transplant. Further, the investigators used no chemotherapy whatsoever, whereas other CAR T-cells trials have used chemotherapy, sometimes in huge does, he said.

pwendling@frontlinemedcom.com

ORLANDO – A single infusion of donor-derived chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved remission in 9 of 20 patients with B-cell malignancies that progressed after allogeneic stem cell transplant, a study shows.

The seven complete remissions and two partial remissions occurred without any chemotherapy and without causing acute graft-versus-host disease (GVHD).

The experimental anti-CD 19 CAR T-cells seem particularly effective against acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), but responses also occurred in lymphoma, Dr. James Kochenderfer of the Center for Cancer Research, National Cancer Institute, in Bethesda, Md., reported at the annual meeting of the American Society of Hematology.

B-cell malignancies that persist after transplantation are often treated with unmanipulated donor lymphocytes, but these infusions are often ineffective and associated with significant morbidity and mortality from GVHD.

To improve on this approach, 20 patients were infused with T cells obtained from the original stem cell donor and transduced with a CD19-directed CAR that was encoded by a gamma-retroviral vector and included a CD28 co-stimulatory domain. The highest dose reached in the phase I study was 10⁷ total cell/kg. Production of the anti-CD19 CAR T cells took only eight days for each patient, Dr. Kochenderfer said at a press briefing.

The patients had received at least one standard donor-leukocyte infusion, had to have minimal or no GVHD, and could not be receiving systemic immunosuppressive drugs.

The highest response rates were in ALL, where four of five patients obtained complete remission (CR) with no detectable minimal residual disease by multi-color flow cytometry, Dr. Kochenderfer said. Two of these patients later relapsed, one is in ongoing CR at 18 months, and one went on to a second allogeneic transplant and continues in complete remission.

The longest ongoing CR at 36 months occurred in a patient treated for CLL. Another patient achieved a partial remission (PR) ongoing at 18 months, two patients progressed, and one has stable disease.

In five patients treated for Mantle cell lymphoma, there is one CR ongoing at 31 months, one PR, and three stable diseases.

Three of the five patients treated for diffuse large B-cell lymphoma experienced stable disease, one progressive disease, and one obtained a CR, but is no longer evaluable because she received other therapies for chronic GVHD. Dr. Kochenderfer went on describe an impressive response in this patient, who had large lymphoma masses at the back of her head and in her eye socket before infusion.

“Amazingly, the tumor masses completely disappeared within five days of CAR T-cell infusion,” he said.

Patients with high tumor burdens, however, experienced severe cytokine-release syndrome with fever, tachycardia, and hypertension that was treated with the interleukin-6 receptor antagonist tocilizumab (Actemra).

Only one case of mild aphasia occurred, which contrasts with other CAR T-cell therapies where neurotoxicity is common, Dr. Kochenderfer said.

One patient had continued worsening of pre-existing chronic GVHD after CAR T-cell therapy, and one patient developed very mild chronic eye GVHD more than a year after infusion.

The press corps was not fully convinced by the findings, however, asking Dr. Kochenderfer why they should be excited by the 40% remission rate when other CAR T-cell therapies have yielded remission rates as high as 90%.

Dr. Kochenderfer pointed out that four of the five ALL patients (80%) achieved a MRD-negative complete response, which compares favorably with other protocols. The remaining patients had far more advanced, treatment-resident disease of varying histologies than evaluated in other trials and, unlike most trials, all patients had received an allogeneic transplant. Further, the investigators used no chemotherapy whatsoever, whereas other CAR T-cells trials have used chemotherapy, sometimes in huge does, he said.

pwendling@frontlinemedcom.com

ORLANDO – A single infusion of donor-derived chimeric antigen receptor (CAR)-modified T cells targeting CD19 achieved remission in 9 of 20 patients with B-cell malignancies that progressed after allogeneic stem cell transplant, a study shows.

The seven complete remissions and two partial remissions occurred without any chemotherapy and without causing acute graft-versus-host disease (GVHD).

The experimental anti-CD 19 CAR T-cells seem particularly effective against acute lymphoid leukemia (ALL) and chronic lymphocytic leukemia (CLL), but responses also occurred in lymphoma, Dr. James Kochenderfer of the Center for Cancer Research, National Cancer Institute, in Bethesda, Md., reported at the annual meeting of the American Society of Hematology.

B-cell malignancies that persist after transplantation are often treated with unmanipulated donor lymphocytes, but these infusions are often ineffective and associated with significant morbidity and mortality from GVHD.

To improve on this approach, 20 patients were infused with T cells obtained from the original stem cell donor and transduced with a CD19-directed CAR that was encoded by a gamma-retroviral vector and included a CD28 co-stimulatory domain. The highest dose reached in the phase I study was 10⁷ total cell/kg. Production of the anti-CD19 CAR T cells took only eight days for each patient, Dr. Kochenderfer said at a press briefing.

The patients had received at least one standard donor-leukocyte infusion, had to have minimal or no GVHD, and could not be receiving systemic immunosuppressive drugs.

The highest response rates were in ALL, where four of five patients obtained complete remission (CR) with no detectable minimal residual disease by multi-color flow cytometry, Dr. Kochenderfer said. Two of these patients later relapsed, one is in ongoing CR at 18 months, and one went on to a second allogeneic transplant and continues in complete remission.

The longest ongoing CR at 36 months occurred in a patient treated for CLL. Another patient achieved a partial remission (PR) ongoing at 18 months, two patients progressed, and one has stable disease.

In five patients treated for Mantle cell lymphoma, there is one CR ongoing at 31 months, one PR, and three stable diseases.

Three of the five patients treated for diffuse large B-cell lymphoma experienced stable disease, one progressive disease, and one obtained a CR, but is no longer evaluable because she received other therapies for chronic GVHD. Dr. Kochenderfer went on describe an impressive response in this patient, who had large lymphoma masses at the back of her head and in her eye socket before infusion.

“Amazingly, the tumor masses completely disappeared within five days of CAR T-cell infusion,” he said.

Patients with high tumor burdens, however, experienced severe cytokine-release syndrome with fever, tachycardia, and hypertension that was treated with the interleukin-6 receptor antagonist tocilizumab (Actemra).

Only one case of mild aphasia occurred, which contrasts with other CAR T-cell therapies where neurotoxicity is common, Dr. Kochenderfer said.

One patient had continued worsening of pre-existing chronic GVHD after CAR T-cell therapy, and one patient developed very mild chronic eye GVHD more than a year after infusion.

The press corps was not fully convinced by the findings, however, asking Dr. Kochenderfer why they should be excited by the 40% remission rate when other CAR T-cell therapies have yielded remission rates as high as 90%.

Dr. Kochenderfer pointed out that four of the five ALL patients (80%) achieved a MRD-negative complete response, which compares favorably with other protocols. The remaining patients had far more advanced, treatment-resident disease of varying histologies than evaluated in other trials and, unlike most trials, all patients had received an allogeneic transplant. Further, the investigators used no chemotherapy whatsoever, whereas other CAR T-cells trials have used chemotherapy, sometimes in huge does, he said.

pwendling@frontlinemedcom.com

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

CML cells

Image by Difu Wu

Researchers say they have identified a mechanism governing malignant reprogramming of progenitors into self-renewing leukemia stem cells (LSCs).

And their discovery has revealed a potential new therapeutic approach for chronic myeloid leukemia (CML).

Experiments in mice showed that a targeted monoclonal antibody could impair LSCs’ ability to regenerate and made them easier to eradicate with a tyrosine kinase inhibitor.

Catriona Jamieson, MD, PhD, of the University of California, San Diego, and her colleagues described this research in PNAS.

The researchers found that downregulation of Muscleblind-like 3 (MBNL3) RNA binding proteins resulted in re-expression of a human embryonic stem cell-specific alternative splicing gene regulatory network—a mechanism that controls embryonic stem cell pluripotency and fate. One effect of this was reprogramming of progenitor cells into LSCs in blast crisis CML.

“This is the first description of cancer stem cell generation through decreased expression of a transcriptional repressor of an embryonic pattern of alternative splicing that enhances stem cell self-renewal and survival,” Dr Jamieson said.

“Rather than acquiring multiple DNA mutations, as was previously thought, cancer stem cells in chronic myeloid leukemia switch to embryonic RNA splicing, which enhances their capacity to self-renew or clone themselves.”

“If we can detect and turn off embryonic splicing, we may be able to prevent cancer stem cells from propagating themselves. Also, if we target embryonic versions of proteins that are re-expressed by cancer, like CD44 variant 3, with specific antibodies together with tyrosine kinase inhibitors, we may be able to circumvent cancer relapse—a leading cause of cancer-related mortality.”

The researchers tested this theory in mice. They found that treatment with a humanized pan-CD44 monoclonal antibody and a targeted tyrosine kinase antagonist disrupted the development of LSCs in their protected microenvironment.

This forced the cells to enter the bloodstream, where dasatinib could effectively target them.

Monica Guzman, PhD

Photo by Kristin Gladney

New research published in Cell Reports has revealed biomarkers that may help predict which acute myeloid leukemia (AML) patients will respond to treatment with PU-H71.

This drug targets a tumor-enriched form of the protein Hsp90 called teHSP90, which is critical to the growth of cancer cells.

However, previous preclinical experiments showed that PU-H71 only kills some AML cells.

“We observed that only a subset of leukemia patient samples were sensitive to the drug,” said study author Monica Guzman, PhD, of Weill Cornell Medical College in New York, New York.

“We wanted to be able to identify which patients with leukemia would respond to this drug.”

So Dr Guzman and her colleagues focused on groups of proteins that function within signaling networks in leukemia cells.

The researchers found that 2 of these networks, JAK-STAT and PI3K-AKT, were important for leukemia cells to function. These signaling pathways are critical for the survival of AML cells, and they, in turn, are dependent on teHsp90.

The team treated AML cells with PU-H71 and found that cells with greater JAK-STAT and PI3K-AKT activity were killed by the drug. Cells with less active signaling networks did not respond to PU-H71.

“Higher activation of these networks makes the leukemia cells more dependent on Hsp90,” Dr Guzman said. “Since PU-H71 targets teHsp90, leukemia samples with these features are good targets for treatment with the drug.”

The next step for Dr Guzman’s team is to test their findings in patients. Ideally, the JAK-STAT and PI3K-AKT signaling pathways will serve as biomarkers for identifying patients whose leukemias will be sensitive to PU-H71.

“We are working on a tool that will quickly and easily identify patients whose cancers will respond to PU-H71,” Dr Guzman said. “We are really looking forward to seeing this in leukemic patients and being able to offer them a new treatment.”

Monica Guzman, PhD

Photo by Kristin Gladney

New research published in Cell Reports has revealed biomarkers that may help predict which acute myeloid leukemia (AML) patients will respond to treatment with PU-H71.

This drug targets a tumor-enriched form of the protein Hsp90 called teHSP90, which is critical to the growth of cancer cells.

However, previous preclinical experiments showed that PU-H71 only kills some AML cells.

“We observed that only a subset of leukemia patient samples were sensitive to the drug,” said study author Monica Guzman, PhD, of Weill Cornell Medical College in New York, New York.

“We wanted to be able to identify which patients with leukemia would respond to this drug.”

So Dr Guzman and her colleagues focused on groups of proteins that function within signaling networks in leukemia cells.

The researchers found that 2 of these networks, JAK-STAT and PI3K-AKT, were important for leukemia cells to function. These signaling pathways are critical for the survival of AML cells, and they, in turn, are dependent on teHsp90.

The team treated AML cells with PU-H71 and found that cells with greater JAK-STAT and PI3K-AKT activity were killed by the drug. Cells with less active signaling networks did not respond to PU-H71.

“Higher activation of these networks makes the leukemia cells more dependent on Hsp90,” Dr Guzman said. “Since PU-H71 targets teHsp90, leukemia samples with these features are good targets for treatment with the drug.”

The next step for Dr Guzman’s team is to test their findings in patients. Ideally, the JAK-STAT and PI3K-AKT signaling pathways will serve as biomarkers for identifying patients whose leukemias will be sensitive to PU-H71.

“We are working on a tool that will quickly and easily identify patients whose cancers will respond to PU-H71,” Dr Guzman said. “We are really looking forward to seeing this in leukemic patients and being able to offer them a new treatment.”

Monica Guzman, PhD

Photo by Kristin Gladney

New research published in Cell Reports has revealed biomarkers that may help predict which acute myeloid leukemia (AML) patients will respond to treatment with PU-H71.

This drug targets a tumor-enriched form of the protein Hsp90 called teHSP90, which is critical to the growth of cancer cells.

However, previous preclinical experiments showed that PU-H71 only kills some AML cells.

“We observed that only a subset of leukemia patient samples were sensitive to the drug,” said study author Monica Guzman, PhD, of Weill Cornell Medical College in New York, New York.

“We wanted to be able to identify which patients with leukemia would respond to this drug.”

So Dr Guzman and her colleagues focused on groups of proteins that function within signaling networks in leukemia cells.

The researchers found that 2 of these networks, JAK-STAT and PI3K-AKT, were important for leukemia cells to function. These signaling pathways are critical for the survival of AML cells, and they, in turn, are dependent on teHsp90.

The team treated AML cells with PU-H71 and found that cells with greater JAK-STAT and PI3K-AKT activity were killed by the drug. Cells with less active signaling networks did not respond to PU-H71.

“Higher activation of these networks makes the leukemia cells more dependent on Hsp90,” Dr Guzman said. “Since PU-H71 targets teHsp90, leukemia samples with these features are good targets for treatment with the drug.”

The next step for Dr Guzman’s team is to test their findings in patients. Ideally, the JAK-STAT and PI3K-AKT signaling pathways will serve as biomarkers for identifying patients whose leukemias will be sensitive to PU-H71.

“We are working on a tool that will quickly and easily identify patients whose cancers will respond to PU-H71,” Dr Guzman said. “We are really looking forward to seeing this in leukemic patients and being able to offer them a new treatment.”

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

mdales@frontlinemedcom.com

On Twitter @maryjodales

Consensus guidelines for the perinatal management of hematologic malignancies detected during pregnancy have been issued by a panel of international experts.

The guidelines, published online in the Journal of Clinical Oncology, aim to ensure that timely treatment of the cancers is not delayed in pregnant women (doi: 10.1200/JCO.2015.62.4445).

While rare, hematologic malignancies in pregnancy introduce clinical, social, ethical, and moral dilemmas. Evidence-based data are scarce, according to the researchers, who note the International Network on Cancer, Infertility and Pregnancy registers all cancers occurring during gestation.

“Patient accrual is ongoing and essential, because registration of new cases and long-term follow-up will improve clinical knowledge and increase the level of evidence,” Dr. Michael Lishner of Tel Aviv University and Meir Medical Center, Kfar Saba, Israel, and his fellow panelists wrote.

Hodgkin lymphoma

The researchers note that Hodgkin lymphoma is the most common hematologic cancer in pregnancy, and the prognosis for these patients is excellent. When diagnosed during the first trimester, a regimen based on vinblastine monotherapy has been used. ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) therapy can be used postpartum and has been used in cases of progression during pregnancy, the panelists wrote.

“The limited data available suggest that ABVD may be administered safely and effectively during the latter phases of pregnancy,” the panel wrote. “Although it may be associated with prematurity and lower birth weights, studies have not reported significant disadvantages.”

Non-Hodgkin lymphoma

The second most common cancer in pregnancy is non-Hodgkin lymphoma. In the case of indolent disease, watchful waiting is possible, with the intent to treat with monoclonal antibodies – with or without chemotherapy – if symptoms or evidence of disease progression are noted. Steroids can be administered during the first trimester as a bridge to the second trimester, when chemotherapy can be used with relatively greater safety, the panelists noted.

Aggressive lymphomas diagnosed before 20 weeks’ gestation warrant pregnancy termination and treatment, they recommend. When diagnosed after 20 weeks, therapy should be comparable to that given a nonpregnant woman, including monoclonal antibodies (R-CHOP).

Chronic myeloid leukemia

Chronic myeloid leukemia occurs in approximately 1 in 100,000 pregnancies and is typically diagnosed during routine blood testing in an asymptomatic patient. As a result, treatment may not be needed until the patient’s white count or platelet count have risen to levels associated with the onset of symptoms. An approximate guideline is a white cell count greater than 100 X 10⁹/L and a platelet count greater than 500 X 10⁹/L.

Therapeutic approaches in pregnancy include interferon-a (INF-a), which does not inhibit DNA synthesis or readily cross the placenta, and leukapheresis, which is frequently required two to three times per week during the first and second trimesters. Counts tend to drop during the third trimester, allowing less frequent intervention.

Consideration should be given to adding aspirin or low-molecular-weight heparin (LMWH) when the platelet count exceeds 1,000 X 10⁹/L.

Myeloproliferative neoplasms

The most common myeloproliferative neoplasm seen in women of childbearing age is essential thrombocytosis.

“A large meta-analysis of pregnant women with essential thrombocytosis reported a live birth rate of 50%-70%, first trimester loss in 25%-40%, late pregnancy loss in 10%, placental abruption in 3.6%, and intrauterine growth restriction in 4.5%. Maternal morbidity is rare, but stroke has been reported,” according to the panelists.

Limited literature suggests similar outcomes for pregnant women with polycythemia vera and primary myelofibrosis.

In low-risk pregnancies, aspirin (75 mg/day) should be offered unless clearly contraindicated. For women with polycythemia vera, venesection may be continued when tolerated to maintain the hematocrit within the gestation-appropriate range.

Fetal ultrasound scans should be performed at 20, 26, and 34 weeks of gestation and uterine artery Doppler should be performed at 20 weeks’ gestation. If the mean pulsatility index exceeds 1.4, the pregnancy may be considered high risk, and treatment and monitoring should be increased.

In high-risk pregnancies, additional treatment includes cytoreductive therapy with or without LMWH. If cytoreductive therapy is required, INF-a should be titrated to maintain a platelet count of less than 400 X 10⁹/L and hematocrit within appropriate range.

Local protocols regarding interruption of LMWH should be adhered to during labor, and dehydration should be avoided. Platelet count and hematocrit may increase postpartum, requiring cytoreductive therapy. Thromboprophylaxis should be considered at 6 weeks’ postpartum because of the increased risk of thrombosis, the guidelines note.

Acute leukemia

“The remarkable anemia, thrombocytopenia, and neutropenia that characterize acute myeloid and lymphoblastic leukemia” require prompt treatment. Leukapheresis in the presence of clinically significant evidence of leukostasis can be considered, regardless of gestational stage. When patients are diagnosed with acute myeloid leukemia during the first trimester, pregnancy termination followed by conventional induction therapy (cytarabine/anthracycline) is recommended.

Those diagnosed later in pregnancy can receive conventional induction therapy, although this seems to be associated with increased risk of fetal growth restriction and even fetal loss. “Notably, neonates rarely experience neutropenia and cardiac impairment unless exposed to lipophilic idarubicin, which should not be used,” the panelists wrote.

When acute promyelocytic leukemia is diagnosed in the first trimester, pregnancy termination is recommended before initiating conventional ATRA-anthracycline therapy. Later in pregnancy, the regimen demonstrates low teratogenicity and can be used in women diagnosed after that stage. Arsenic treatment is highly teratogenic and is prohibited throughout gestation.

Acute lymphocytic leukemia (ALL) requires prophylactic CNS therapy, including methotrexate and L-asparaginase, which are fetotoxic. Methotrexate interferes with organogenesis and is prohibited before week 20 of gestation. L-asparaginase may increase the high risk for thromboembolic events attributed to the combination of pregnancy and malignancy.

Notably, tyrosine kinase inhibitors, essential for patients with Philadelphia chromosome–positive ALL, are teratogenic. Given these limitations, women diagnosed with ALL before 20 weeks’ gestation should undergo termination of the pregnancy and start conventional treatment. After week 20, conventional chemotherapy can be administered during pregnancy. Tyrosine kinase inhibitors can be initiated postpartum.

The guidelines also contain recommendations on diagnostic testing and radiotherapy, maternal supportive care, and perinatal and pediatric aspects of hematologic malignancies in pregnancy. An online appendix offers recommendations on the treatment of rare hematologic malignancies, including hairy cell leukemia, multiple myeloma, and myelodysplastic syndromes.

Dr. Lishner and nine of his coauthors had no financial relationships to disclose. Three coauthors received honoraria and research funding or are consultants to a wide variety of drug makers.

mdales@frontlinemedcom.com

On Twitter @maryjodales

DNA repair

Image by Tom Ellenberger

PARP inhibitors could prove useful for treating aggressive acute myeloid leukemia (AML), according to preclinical research published in Nature Medicine.

Experiments showed that AML driven by leukemia-associated transcription factors, including AML1-ETO and PML-RARα, was “extremely sensitive” to PARP inhibition.

Mixed-lineage leukemia (MLL) was initially resistant to treatment with PARP inhibitors, but inhibiting Hoxa9 changed that.

“PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of acute myeloid leukemia,” said study author Chi Wai Eric So, PhD, of King’s College London in the UK.

He and his colleagues first tested the PARP inhibitor olaparib on primary mouse hematopoietic cells transformed by the leukemia-associated transcription factors AML1-ETO, PML-RARα, MLL-AF9, and E2A-PBX.

The drug suppressed the colony-forming ability of cells transformed by AML1-ETO or PML-RARα by about 90% but had little impact on MLL-AF9- or E2A-PBX-transformed cells. Olaparib also had minimal effects on normal bone marrow.

The investigators observed similar results in experiments with the PARP inhibitor veliparib.

They then tested PARP inhibitors in patient-derived leukemic cell lines carrying AML1-ETO (Kasumi), mutated PML-RARα that is resistant to standard all-trans retinoic acid treatment (NB4-LR2), or MLL-AF9 (THP1).

Similar to the previous experiments, PARP inhibition reduced the colony-forming ability of Kasumi and NB4-LR2 cells but not THP1 cells.

Next, the investigators transplanted the 3 cell lines into immunocompromised mice and treated the mice with olaparib. The drug delayed disease onset and prolonged survival in both the Kasumi and NB4-LR2 models but had no effect on disease onset or survival in the THP1 model.

Dr So and his colleagues said PARP inhibition was likely effective in AML driven by AML1-ETO and PML-RARα because of the suppressed expression of key homologous recombination-associated genes and the compromised DNA-damage response observed in these malignancies.

The team noted that PARP has proven critical in a variety of DNA repair processes, including as a sensor of single-strand breaks in base-excision repair, as a mediator for restarting stalled replication forks of homologous recombination-mediated double-strand break repair, and as a means of preventing the binding of Ku proteins to DNA ends in non-homologous end-joining pathways.

It therefore follows that MLL-driven AML was resistant to treatment with PARP inhibitors because DNA repair is not suppressed in this malignancy. The Hoxa9 protein activates other DNA damage repair pathways in these leukemia cells, keeping them alive.

So the investigators tested drugs that could (indirectly) inhibit Hoxa9—the GSK3 inhibitors LiCl and Li2CO3—in combination with olaparib. Both in vitro and in vivo, treatment with a GSK3 inhibitor and olaparib proved effective against MLL-driven AML.

“While this approach seems promising from these laboratory studies, it is still very early days,” said Matt Kaiser, PhD, head of research at Bloodwise, a charity that helped fund this study.

“We need to see how real patients respond to these drugs and how effective they are. PARP inhibitors such as olaparib are already being used to treat patients with other cancers and have been shown to be safe. This should speed up the time it takes for this potentially effective new treatment to enter clinical trials.”

DNA repair

Image by Tom Ellenberger

PARP inhibitors could prove useful for treating aggressive acute myeloid leukemia (AML), according to preclinical research published in Nature Medicine.

Experiments showed that AML driven by leukemia-associated transcription factors, including AML1-ETO and PML-RARα, was “extremely sensitive” to PARP inhibition.

Mixed-lineage leukemia (MLL) was initially resistant to treatment with PARP inhibitors, but inhibiting Hoxa9 changed that.

“PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of acute myeloid leukemia,” said study author Chi Wai Eric So, PhD, of King’s College London in the UK.

He and his colleagues first tested the PARP inhibitor olaparib on primary mouse hematopoietic cells transformed by the leukemia-associated transcription factors AML1-ETO, PML-RARα, MLL-AF9, and E2A-PBX.

The drug suppressed the colony-forming ability of cells transformed by AML1-ETO or PML-RARα by about 90% but had little impact on MLL-AF9- or E2A-PBX-transformed cells. Olaparib also had minimal effects on normal bone marrow.

The investigators observed similar results in experiments with the PARP inhibitor veliparib.

They then tested PARP inhibitors in patient-derived leukemic cell lines carrying AML1-ETO (Kasumi), mutated PML-RARα that is resistant to standard all-trans retinoic acid treatment (NB4-LR2), or MLL-AF9 (THP1).

Similar to the previous experiments, PARP inhibition reduced the colony-forming ability of Kasumi and NB4-LR2 cells but not THP1 cells.

Next, the investigators transplanted the 3 cell lines into immunocompromised mice and treated the mice with olaparib. The drug delayed disease onset and prolonged survival in both the Kasumi and NB4-LR2 models but had no effect on disease onset or survival in the THP1 model.

Dr So and his colleagues said PARP inhibition was likely effective in AML driven by AML1-ETO and PML-RARα because of the suppressed expression of key homologous recombination-associated genes and the compromised DNA-damage response observed in these malignancies.

The team noted that PARP has proven critical in a variety of DNA repair processes, including as a sensor of single-strand breaks in base-excision repair, as a mediator for restarting stalled replication forks of homologous recombination-mediated double-strand break repair, and as a means of preventing the binding of Ku proteins to DNA ends in non-homologous end-joining pathways.

It therefore follows that MLL-driven AML was resistant to treatment with PARP inhibitors because DNA repair is not suppressed in this malignancy. The Hoxa9 protein activates other DNA damage repair pathways in these leukemia cells, keeping them alive.

So the investigators tested drugs that could (indirectly) inhibit Hoxa9—the GSK3 inhibitors LiCl and Li2CO3—in combination with olaparib. Both in vitro and in vivo, treatment with a GSK3 inhibitor and olaparib proved effective against MLL-driven AML.

“While this approach seems promising from these laboratory studies, it is still very early days,” said Matt Kaiser, PhD, head of research at Bloodwise, a charity that helped fund this study.

“We need to see how real patients respond to these drugs and how effective they are. PARP inhibitors such as olaparib are already being used to treat patients with other cancers and have been shown to be safe. This should speed up the time it takes for this potentially effective new treatment to enter clinical trials.”

DNA repair

Image by Tom Ellenberger

PARP inhibitors could prove useful for treating aggressive acute myeloid leukemia (AML), according to preclinical research published in Nature Medicine.

Experiments showed that AML driven by leukemia-associated transcription factors, including AML1-ETO and PML-RARα, was “extremely sensitive” to PARP inhibition.

Mixed-lineage leukemia (MLL) was initially resistant to treatment with PARP inhibitors, but inhibiting Hoxa9 changed that.

“PARP inhibitors could potentially offer a completely different approach to specifically target certain subtypes of acute myeloid leukemia,” said study author Chi Wai Eric So, PhD, of King’s College London in the UK.

He and his colleagues first tested the PARP inhibitor olaparib on primary mouse hematopoietic cells transformed by the leukemia-associated transcription factors AML1-ETO, PML-RARα, MLL-AF9, and E2A-PBX.

The drug suppressed the colony-forming ability of cells transformed by AML1-ETO or PML-RARα by about 90% but had little impact on MLL-AF9- or E2A-PBX-transformed cells. Olaparib also had minimal effects on normal bone marrow.

The investigators observed similar results in experiments with the PARP inhibitor veliparib.

They then tested PARP inhibitors in patient-derived leukemic cell lines carrying AML1-ETO (Kasumi), mutated PML-RARα that is resistant to standard all-trans retinoic acid treatment (NB4-LR2), or MLL-AF9 (THP1).

Similar to the previous experiments, PARP inhibition reduced the colony-forming ability of Kasumi and NB4-LR2 cells but not THP1 cells.

Next, the investigators transplanted the 3 cell lines into immunocompromised mice and treated the mice with olaparib. The drug delayed disease onset and prolonged survival in both the Kasumi and NB4-LR2 models but had no effect on disease onset or survival in the THP1 model.

Dr So and his colleagues said PARP inhibition was likely effective in AML driven by AML1-ETO and PML-RARα because of the suppressed expression of key homologous recombination-associated genes and the compromised DNA-damage response observed in these malignancies.

The team noted that PARP has proven critical in a variety of DNA repair processes, including as a sensor of single-strand breaks in base-excision repair, as a mediator for restarting stalled replication forks of homologous recombination-mediated double-strand break repair, and as a means of preventing the binding of Ku proteins to DNA ends in non-homologous end-joining pathways.

It therefore follows that MLL-driven AML was resistant to treatment with PARP inhibitors because DNA repair is not suppressed in this malignancy. The Hoxa9 protein activates other DNA damage repair pathways in these leukemia cells, keeping them alive.

So the investigators tested drugs that could (indirectly) inhibit Hoxa9—the GSK3 inhibitors LiCl and Li2CO3—in combination with olaparib. Both in vitro and in vivo, treatment with a GSK3 inhibitor and olaparib proved effective against MLL-driven AML.

“While this approach seems promising from these laboratory studies, it is still very early days,” said Matt Kaiser, PhD, head of research at Bloodwise, a charity that helped fund this study.

“We need to see how real patients respond to these drugs and how effective they are. PARP inhibitors such as olaparib are already being used to treat patients with other cancers and have been shown to be safe. This should speed up the time it takes for this potentially effective new treatment to enter clinical trials.”

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The European Commission (EC) has granted conditional marketing authorization for blinatumomab (Blincyto) to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

This applies to the 28 member countries of the European Union as well as Iceland, Lichtenstein, and Norway.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.

Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.

The EC granted conditional marketing authorization for blinatumomab based on a pair of phase 2 trials—Study ‘211 and Study ‘206.

Study ‘211

Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.

The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.

According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).

Study ‘206

Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.

In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).

The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).

However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.

About blinatumomab

Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.

BiTE antibody constructs are intended to help the immune system detect and target malignant cells. The modified antibodies are designed to engage 2 different targets simultaneously, thereby juxtaposing T cells to cancer cells.

BiTE antibody constructs help place the T cells within reach of the targeted cells, with the intent of allowing T cells to inject toxins and trigger apoptosis in the cancer cells.

Blinatumomab was granted orphan drug designation by the European Medicines Agency in 2009 for the treatment of ALL.

The drug was granted breakthrough therapy designation and priority review by the US Food and Drug Administration.

Blinatumomab has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is being developed by Amgen.

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The European Commission (EC) has granted conditional marketing authorization for blinatumomab (Blincyto) to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

This applies to the 28 member countries of the European Union as well as Iceland, Lichtenstein, and Norway.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.

Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.

The EC granted conditional marketing authorization for blinatumomab based on a pair of phase 2 trials—Study ‘211 and Study ‘206.

Study ‘211

Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.

The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.

According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).

Study ‘206

Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.

In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).

The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).

However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.

About blinatumomab

Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.

BiTE antibody constructs are intended to help the immune system detect and target malignant cells. The modified antibodies are designed to engage 2 different targets simultaneously, thereby juxtaposing T cells to cancer cells.

BiTE antibody constructs help place the T cells within reach of the targeted cells, with the intent of allowing T cells to inject toxins and trigger apoptosis in the cancer cells.

Blinatumomab was granted orphan drug designation by the European Medicines Agency in 2009 for the treatment of ALL.

The drug was granted breakthrough therapy designation and priority review by the US Food and Drug Administration.

Blinatumomab has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is being developed by Amgen.

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The European Commission (EC) has granted conditional marketing authorization for blinatumomab (Blincyto) to treat adults with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL).

This applies to the 28 member countries of the European Union as well as Iceland, Lichtenstein, and Norway.

Conditional marketing authorizations are valid for 1 year, on a renewable basis. The holder is required to complete ongoing studies or conduct new studies with the goal of confirming that a drug’s benefit-risk balance is positive.

Conditional marketing authorization is converted to a full authorization once these commitments have been fulfilled.

The EC granted conditional marketing authorization for blinatumomab based on a pair of phase 2 trials—Study ‘211 and Study ‘206.

Study ‘211

Results of Study ‘211 were presented at EHA 2014. The trial included 189 patients with Ph- relapsed or refractory B-precursor ALL.

The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh). About 43% of patients achieved this endpoint within 2 cycles of therapy.

According to researchers, the most serious adverse events in this study were infection (31.7%), neurologic events (16.4%), neutropenia/febrile neutropenia (15.3%), cytokine release syndrome (CRS, 0.5%), and tumor lysis syndrome (0.5%).

Study ‘206

Results of Study ‘206 were presented at ASCO 2012. The trial included 36 patients with relapsed or refractory B-precursor ALL.

In this trial, the CR/CRh rate was 69.4% (25/36), with 15 patients achieving a CR (41.7%), and 10 patients achieving CRh (27.8%).

The “medically important” adverse events in this study, according to researchers, were CRS (n=3), central nervous system (CNS) events (3 seizures and 3 cases of encephalopathy), and fungal infection resulting in death (n=1).

However, the researchers found they could prevent CRS with dexamethasone. In addition, the CNS events were reversible, and blinatumomab could be reintroduced in 4 of the 6 patients with CNS events.

About blinatumomab

Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that binds to CD19 on the surface of B cells and CD3 on the surface of T cells.

BiTE antibody constructs are intended to help the immune system detect and target malignant cells. The modified antibodies are designed to engage 2 different targets simultaneously, thereby juxtaposing T cells to cancer cells.

BiTE antibody constructs help place the T cells within reach of the targeted cells, with the intent of allowing T cells to inject toxins and trigger apoptosis in the cancer cells.

Blinatumomab was granted orphan drug designation by the European Medicines Agency in 2009 for the treatment of ALL.

The drug was granted breakthrough therapy designation and priority review by the US Food and Drug Administration.

Blinatumomab has conditional approval in the US to treat patients with relapsed or refractory Ph- B-precursor ALL. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is being developed by Amgen.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for pegaspargase (Oncaspar) as part of combination antineoplastic therapy for pediatric and adult patients with acute lymphoblastic leukemia (ALL).

The CHMP’s opinion has been referred to the European Commission, which grants marketing authorization for drugs in the European Union.

If approved, pegaspargase will be marketed for the aforementioned indication in the 28 member countries of the European Union, as well as Iceland, Liechtenstein, and Norway.

Baxalta Incorporated, the company developing pegaspargase, expects a decision from the European Commission early next year.

First-line ALL

Researchers have evaluated the safety and effectiveness of pegaspargase in a study of 118 pediatric patients (ages 1 to 9) with newly diagnosed ALL. The patients were randomized 1:1 to pegaspargase or native E coli L-asparaginase, both as part of combination therapy.

Asparagine depletion (magnitude and duration) was similar between the 2 treatment arms. Event-free survival rates were also similar (about 80% in both arms), but the study was not designed to evaluate differences in event-free survival.

Grade 3/4 adverse events occurring in the pegaspargase and native E coli L-asparaginase arms, respectively, were abnormal liver tests (5% and 8%), elevated transaminases (3% and 7%), hyperbilirubinemia (2% and 2%), hyperglycemia (5% and 3%), central nervous system thrombosis (3% and 3%), coagulopathy (2% and 5%), pancreatitis (2% and 2%), and clinical allergic reactions to asparaginase (2% and 0%).

Previously treated ALL

Researchers have evaluated the effectiveness of pegaspargase in 4 open-label studies of patients with a history of prior clinical allergic reaction to asparaginase. The studies enrolled a total of 42 patients with multiply relapsed acute leukemia (39 with ALL).

Patients received pegaspargase as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50%—36% complete responses and 14% partial responses.

These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E coli L-asparaginase-containing re-induction chemotherapy. However, antitumor activity was observed with single-agent pegaspargase as well (3 responses).

Adverse event information on pegaspargase in relapsed ALL has been compiled from 5 clinical trials. The studies enrolled a total of 174 patients with relapsed ALL who received pegaspargase as a single agent or in combination with multi-agent chemotherapy.

Sixty-two of the patients had prior hypersensitivity reactions to asparaginase, and 112 did not. Allergic reactions to pegaspargase occurred in 32% of previously hypersensitive patients and 10% of non-hypersensitive patients.

The most common adverse events observed in patients who received pegaspargase were clinical allergic reactions, elevated transaminases, hyperbilirubinemia, and coagulopathies. The most common serious adverse events due to pegaspargase were thrombosis (4%), hyperglycemia requiring insulin therapy (3%), and pancreatitis (1%).

For more details on these trials and pegaspargase, see the product information.

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”

Preparing a patient

for radiation therapy

Photo by Rhoda Baer

A new template can help standardize plans for long-term care of cancer survivors who have undergone radiation therapy (RT), according to the American Society for Radiation Oncology (ASTRO).

An ASTRO advisory committee created the template to coordinate post-treatment care for cancer survivors among primary care providers (PCPs) and oncology

specialists (radiation, medical, and surgical), as well as patients themselves.

Details on the template appear in Practical Radiation Oncology.

“Factors such as earlier detection of cancer, increasingly effective treatment options, and an aging population lead to a growing number of cancer survivors and, ultimately, a need to educate and empower these individuals for their ongoing care,” said ASTRO chair Bruce D. Minsky, MD.

“The ASTRO template is designed to foster better coordination of post-treatment care for cancer survivors, including greater clarity in the dialogue between radiation oncologists and PCPs for issues such as less common side effects that may appear well after treatment is complete.”

Many radiation oncologists may already provide their patients with post-treatment materials such as diagnosis and treatment summaries, contacts for ancillary services such as financial or nutritional counselling, and information on potential late treatment effects.

But the ASTRO template coordinates these components in a central, plain-language document.

It also enables practices to meet new accreditation requirements set by the American College of Surgeons Commission on Cancer (CoC).

In response to a 2006 recommendation from the Institutes of Medicine that cancer patients be provided with a survivorship care plan (SCP) following treatment, CoC issued a mandate that cancer programs provide SCPs for all curative cancer patients by 2019 to maintain accreditation.

ASTRO’s template includes both elements required by the CoC in SCPs—namely, a summary of past treatment and directions for future care.

The treatment summary outlines the survivor’s diagnosis and stage information; treatment details such as the site, dosage, and schedule of RT; and contact information for providers who delivered the treatment.

The plan for follow-up care covers anticipated toxicities from RT, expected course of recovery from treatment-related toxicities, possible functional and/or social limitations, recommendations for preventative measures and behaviors, cancer information resources, and referrals to supportive care providers.

“This 2-page template facilitates consistency in SCPs across the discipline and also reduces the time and effort required by providers to complete each individual plan,” said Ronald Chen, MD, of the University of North Carolina at Chapel Hill.

“The field of radiation oncology has a long tradition of creating treatment summaries for each patient, even before the Institute of Medicine recommended survivorship care plans in 2006. This radiation-oncology-specific template will serve a dual purpose as both a traditional radiation oncology treatment summary and a plan for survivorship care that meets CoC requirements, thus reducing the burden on radiation oncologists from having to create 2 documents for each patient.”