Leukemia, Myelodysplasia, Transplantation

Image from PLOS ONE

Researchers believe they have found a way to prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT) while preserving a strong graft-versus-leukemia (GVL) effect.

In experiments with mice, the team found that temporary in vivo depletion of CD4+ T cells soon after HSCT prevented GVHD without inhibiting GVL effects.

The depletion of CD4+ cells essentially caused CD8+ cells to become exhausted in their quest to destroy normal tissue but strengthened in their fight against leukemia, which meant the CD8+ cells could eliminate leukemic cells without causing GVHD.

Defu Zeng, MD, of City of Hope in Duarte, California, and his colleagues recounted these findings in the Journal of Clinical Investigation.

The researchers were able to achieve temporary in vivo depletion of CD4+ T cells by injecting mice with an anti-CD4 monoclonal antibody (mAb).

The team found that a single injection of the mAb given immediately after HSCT prevented acute but not chronic GVHD. Three injections of the mAb—given on days 0, 14, and 28—prevented both types of GVHD.

The researchers said their results suggest GVHD is more effectively prevented by temporary in vivo depletion of donor CD4+ T cells early after HSCT than by ex vivo depletion of donor CD4+ T cells.

This is because treatment with an anti-CD4 mAb temporarily depletes both the injected mature CD4+ T cells and the CD4+ T cells generated de novo from the marrow progenitors early after HSCT.

In explaining the mechanism behind their observations, the researchers noted that the interaction between PD-L1 and CD80 has been shown to exacerbate GVHD, but costimulation of CD80 and PD-1 ameliorates GVHD.

In their experiments, the team found that depleting CD4+ T cells increased serum IFN-γ and reduced IL-2 concentrations. And this led to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells.

The researchers said that, in GVHD target tissues, the interactions of PD-L1 and PD-1 on donor CD8+ T cells caused anergy, exhaustion, and apoptosis. These effects prevented the development of GVHD.

On the other hand, in lymphoid tissues, the interactions of PD-L1 and CD80 augmented CD8+ T-cell expansion without increasing anergy, exhaustion, or apoptosis. This allowed for the preservation of GVL effects.

“If successfully translated into clinical application, this [CD4+ T-cell-depleting] regimen may represent one of the novel approaches that allow strong GVL effects without causing GVHD,” Dr Zeng said.

“This kind of regimen has the potential to promote widespread application of allogenic [HSCT] as a curative therapy for hematological malignancies.”

Image from PLOS ONE

Researchers believe they have found a way to prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT) while preserving a strong graft-versus-leukemia (GVL) effect.

In experiments with mice, the team found that temporary in vivo depletion of CD4+ T cells soon after HSCT prevented GVHD without inhibiting GVL effects.

The depletion of CD4+ cells essentially caused CD8+ cells to become exhausted in their quest to destroy normal tissue but strengthened in their fight against leukemia, which meant the CD8+ cells could eliminate leukemic cells without causing GVHD.

Defu Zeng, MD, of City of Hope in Duarte, California, and his colleagues recounted these findings in the Journal of Clinical Investigation.

The researchers were able to achieve temporary in vivo depletion of CD4+ T cells by injecting mice with an anti-CD4 monoclonal antibody (mAb).

The team found that a single injection of the mAb given immediately after HSCT prevented acute but not chronic GVHD. Three injections of the mAb—given on days 0, 14, and 28—prevented both types of GVHD.

The researchers said their results suggest GVHD is more effectively prevented by temporary in vivo depletion of donor CD4+ T cells early after HSCT than by ex vivo depletion of donor CD4+ T cells.

This is because treatment with an anti-CD4 mAb temporarily depletes both the injected mature CD4+ T cells and the CD4+ T cells generated de novo from the marrow progenitors early after HSCT.

In explaining the mechanism behind their observations, the researchers noted that the interaction between PD-L1 and CD80 has been shown to exacerbate GVHD, but costimulation of CD80 and PD-1 ameliorates GVHD.

In their experiments, the team found that depleting CD4+ T cells increased serum IFN-γ and reduced IL-2 concentrations. And this led to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells.

The researchers said that, in GVHD target tissues, the interactions of PD-L1 and PD-1 on donor CD8+ T cells caused anergy, exhaustion, and apoptosis. These effects prevented the development of GVHD.

On the other hand, in lymphoid tissues, the interactions of PD-L1 and CD80 augmented CD8+ T-cell expansion without increasing anergy, exhaustion, or apoptosis. This allowed for the preservation of GVL effects.

“If successfully translated into clinical application, this [CD4+ T-cell-depleting] regimen may represent one of the novel approaches that allow strong GVL effects without causing GVHD,” Dr Zeng said.

“This kind of regimen has the potential to promote widespread application of allogenic [HSCT] as a curative therapy for hematological malignancies.”

Image from PLOS ONE

Researchers believe they have found a way to prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplant (HSCT) while preserving a strong graft-versus-leukemia (GVL) effect.

In experiments with mice, the team found that temporary in vivo depletion of CD4+ T cells soon after HSCT prevented GVHD without inhibiting GVL effects.

The depletion of CD4+ cells essentially caused CD8+ cells to become exhausted in their quest to destroy normal tissue but strengthened in their fight against leukemia, which meant the CD8+ cells could eliminate leukemic cells without causing GVHD.

Defu Zeng, MD, of City of Hope in Duarte, California, and his colleagues recounted these findings in the Journal of Clinical Investigation.

The researchers were able to achieve temporary in vivo depletion of CD4+ T cells by injecting mice with an anti-CD4 monoclonal antibody (mAb).

The team found that a single injection of the mAb given immediately after HSCT prevented acute but not chronic GVHD. Three injections of the mAb—given on days 0, 14, and 28—prevented both types of GVHD.

The researchers said their results suggest GVHD is more effectively prevented by temporary in vivo depletion of donor CD4+ T cells early after HSCT than by ex vivo depletion of donor CD4+ T cells.

This is because treatment with an anti-CD4 mAb temporarily depletes both the injected mature CD4+ T cells and the CD4+ T cells generated de novo from the marrow progenitors early after HSCT.

In explaining the mechanism behind their observations, the researchers noted that the interaction between PD-L1 and CD80 has been shown to exacerbate GVHD, but costimulation of CD80 and PD-1 ameliorates GVHD.

In their experiments, the team found that depleting CD4+ T cells increased serum IFN-γ and reduced IL-2 concentrations. And this led to upregulation of PD-L1 expression by recipient tissues and donor CD8+ T cells.

The researchers said that, in GVHD target tissues, the interactions of PD-L1 and PD-1 on donor CD8+ T cells caused anergy, exhaustion, and apoptosis. These effects prevented the development of GVHD.

On the other hand, in lymphoid tissues, the interactions of PD-L1 and CD80 augmented CD8+ T-cell expansion without increasing anergy, exhaustion, or apoptosis. This allowed for the preservation of GVL effects.

“If successfully translated into clinical application, this [CD4+ T-cell-depleting] regimen may represent one of the novel approaches that allow strong GVL effects without causing GVHD,” Dr Zeng said.

“This kind of regimen has the potential to promote widespread application of allogenic [HSCT] as a curative therapy for hematological malignancies.”

AML cells

A large study of adults with acute myeloid leukemia (AML) correlates cancer-related genetic mutations with subtypes of AML defined by the presence of specific cytogenetic abnormalities.

Researchers combined the cytogenetic abnormalities that define each of 34 AML subgroups with the mutation status of 80 cancer-related genes to produce an “oncoprint,” a tabular summary of the mutations associated with each cytogenetic group.

This allowed the researchers to identify genetic differences among the 34 subgroups and unexpected associations between the AML subsets and specific genetic mutations as well as gene functional groups.

The researchers believe their findings, published in Leukemia, might help guide mutation testing and treatment decisions in the future.

The study involved 1603 newly diagnosed adult AML patients who were treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials in multiple centers across the US. Most patients (n=1080) were under age 60.

The researchers classified the patients into 34 karyotype subgroups within 5 major cytogenetic groups—cytogenetically normal (CN) AML, complex karyotype (CK) AML, core-binding factor (CBF) AML, AML with balanced translocations or inversions other than those associated with CBF-AML, and AML with unbalanced chromosomal abnormalities detected in non-complex karyotypes.

The team sequenced pretreatment bone marrow or peripheral blood samples from each patient to learn the mutational status of 80 cancer- and leukemia-related genes.

The mutations were assigned to 1 of 9 categories based on the gene’s biological function—for example, methylation-related, cohesin complex, chromatin remodeling, and tumor-suppressor genes.

The researchers identified 4390 mutations, with a median of 3 mutations per patient.

Overall, the most frequently mutated genes that contributed to AML in this cohort belonged to the methylation group.

The researchers observed a high incidence of mutations in methylation-related genes in patients with CN-AML, CK-AML, or unbalanced chromosomal abnormalities.

In contrast, mutations in methylation-related genes were almost absent in CBF-AML patients and were rather rare in patients with non-CBF-AML-related balanced translocations or inversions.

Mutations in spliceosome genes were frequent in patients with unbalanced chromosomal abnormalities, especially those with sole trisomy of chromosomes 4, 8, 11, 13, or 21.

“Our study summarizes cytogenetic and mutational information of 1603 AML patients in a single image,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“The identification of key mutational features of each subgroup may help us to better understand the pathogenesis of the different AML types and provides a wealth of information for ongoing and future research.”

AML cells

A large study of adults with acute myeloid leukemia (AML) correlates cancer-related genetic mutations with subtypes of AML defined by the presence of specific cytogenetic abnormalities.

Researchers combined the cytogenetic abnormalities that define each of 34 AML subgroups with the mutation status of 80 cancer-related genes to produce an “oncoprint,” a tabular summary of the mutations associated with each cytogenetic group.

This allowed the researchers to identify genetic differences among the 34 subgroups and unexpected associations between the AML subsets and specific genetic mutations as well as gene functional groups.

The researchers believe their findings, published in Leukemia, might help guide mutation testing and treatment decisions in the future.

The study involved 1603 newly diagnosed adult AML patients who were treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials in multiple centers across the US. Most patients (n=1080) were under age 60.

The researchers classified the patients into 34 karyotype subgroups within 5 major cytogenetic groups—cytogenetically normal (CN) AML, complex karyotype (CK) AML, core-binding factor (CBF) AML, AML with balanced translocations or inversions other than those associated with CBF-AML, and AML with unbalanced chromosomal abnormalities detected in non-complex karyotypes.

The team sequenced pretreatment bone marrow or peripheral blood samples from each patient to learn the mutational status of 80 cancer- and leukemia-related genes.

The mutations were assigned to 1 of 9 categories based on the gene’s biological function—for example, methylation-related, cohesin complex, chromatin remodeling, and tumor-suppressor genes.

The researchers identified 4390 mutations, with a median of 3 mutations per patient.

Overall, the most frequently mutated genes that contributed to AML in this cohort belonged to the methylation group.

The researchers observed a high incidence of mutations in methylation-related genes in patients with CN-AML, CK-AML, or unbalanced chromosomal abnormalities.

In contrast, mutations in methylation-related genes were almost absent in CBF-AML patients and were rather rare in patients with non-CBF-AML-related balanced translocations or inversions.

Mutations in spliceosome genes were frequent in patients with unbalanced chromosomal abnormalities, especially those with sole trisomy of chromosomes 4, 8, 11, 13, or 21.

“Our study summarizes cytogenetic and mutational information of 1603 AML patients in a single image,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“The identification of key mutational features of each subgroup may help us to better understand the pathogenesis of the different AML types and provides a wealth of information for ongoing and future research.”

AML cells

A large study of adults with acute myeloid leukemia (AML) correlates cancer-related genetic mutations with subtypes of AML defined by the presence of specific cytogenetic abnormalities.

Researchers combined the cytogenetic abnormalities that define each of 34 AML subgroups with the mutation status of 80 cancer-related genes to produce an “oncoprint,” a tabular summary of the mutations associated with each cytogenetic group.

This allowed the researchers to identify genetic differences among the 34 subgroups and unexpected associations between the AML subsets and specific genetic mutations as well as gene functional groups.

The researchers believe their findings, published in Leukemia, might help guide mutation testing and treatment decisions in the future.

The study involved 1603 newly diagnosed adult AML patients who were treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology trials in multiple centers across the US. Most patients (n=1080) were under age 60.

The researchers classified the patients into 34 karyotype subgroups within 5 major cytogenetic groups—cytogenetically normal (CN) AML, complex karyotype (CK) AML, core-binding factor (CBF) AML, AML with balanced translocations or inversions other than those associated with CBF-AML, and AML with unbalanced chromosomal abnormalities detected in non-complex karyotypes.

The team sequenced pretreatment bone marrow or peripheral blood samples from each patient to learn the mutational status of 80 cancer- and leukemia-related genes.

The mutations were assigned to 1 of 9 categories based on the gene’s biological function—for example, methylation-related, cohesin complex, chromatin remodeling, and tumor-suppressor genes.

The researchers identified 4390 mutations, with a median of 3 mutations per patient.

Overall, the most frequently mutated genes that contributed to AML in this cohort belonged to the methylation group.

The researchers observed a high incidence of mutations in methylation-related genes in patients with CN-AML, CK-AML, or unbalanced chromosomal abnormalities.

In contrast, mutations in methylation-related genes were almost absent in CBF-AML patients and were rather rare in patients with non-CBF-AML-related balanced translocations or inversions.

Mutations in spliceosome genes were frequent in patients with unbalanced chromosomal abnormalities, especially those with sole trisomy of chromosomes 4, 8, 11, 13, or 21.

“Our study summarizes cytogenetic and mutational information of 1603 AML patients in a single image,” said Ann-Kathrin Eisfeld, MD, of The Ohio State University Comprehensive Cancer Center in Columbus.

“The identification of key mutational features of each subgroup may help us to better understand the pathogenesis of the different AML types and provides a wealth of information for ongoing and future research.”

Image from NIAID

Researchers say they have developed biodegradable nanoparticles that can be used to genetically reprogram T cells while they are still in the body.

The nanoparticles were able to program T cells with genes encoding leukemia-specific chimeric antigen receptors (CARs).

The resulting CAR T cells were able to eliminate leukemia or slow the progression of disease in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL).

Researchers reported these results in Nature Nanotechnology.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Dr Stephan and his colleagues designed their nanoparticles to carry genes that encode for CARs intended to target and eliminate B-ALL. The nanoparticles are coated with ligands that make them seek out and bind to T cells.

When a nanoparticle binds to a T cell, the cell engulfs the particle. The nanoparticle then travels to the cell’s nucleus and dissolves.

The CAR genes integrate into chromosomes housed in the nucleus, making it possible for the T cells to begin decoding the new genes and producing CARs within 1 or 2 days.

Once they determined their CAR-carrying nanoparticles reprogrammed a noticeable percentage of T cells, the researchers tested the T cells’ efficacy in a mouse model of B-ALL.

The team infused the nanoparticles into 10 mice and found the treatment eradicated tumors in 7 of the animals. The other 3 mice “showed substantial regression” of leukemia, the researchers said.

On average, mice that received CAR-carrying nanoparticles had a 58-day improvement in survival compared to control mice.

Mice that received the nanoparticles also had “dramatically reduced” B-cell numbers in their spleens. The researchers noted that this is consistent with the reversible B-cell aplasia observed in patients who receive conventional CD19 CAR T-cell therapy.

Dr Stephan and his colleagues also tested conventional CAR T-cell therapy in the B-ALL mouse model. The mice received cyclophosphamide followed by CAR T cells created ex vivo.

These mice had significantly better survival than controls, but their survival was comparable to that of the mice that received the CAR-carrying nanoparticles.

Although these nanoparticles are several steps away from the clinic, Dr Stephan said he imagines a future in which nanoparticles transform cell-based immunotherapies into easily administered, off-the-shelf treatments that are available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis, I would want to start treatment right away,” Dr Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

Image from NIAID

Researchers say they have developed biodegradable nanoparticles that can be used to genetically reprogram T cells while they are still in the body.

The nanoparticles were able to program T cells with genes encoding leukemia-specific chimeric antigen receptors (CARs).

The resulting CAR T cells were able to eliminate leukemia or slow the progression of disease in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL).

Researchers reported these results in Nature Nanotechnology.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Dr Stephan and his colleagues designed their nanoparticles to carry genes that encode for CARs intended to target and eliminate B-ALL. The nanoparticles are coated with ligands that make them seek out and bind to T cells.

When a nanoparticle binds to a T cell, the cell engulfs the particle. The nanoparticle then travels to the cell’s nucleus and dissolves.

The CAR genes integrate into chromosomes housed in the nucleus, making it possible for the T cells to begin decoding the new genes and producing CARs within 1 or 2 days.

Once they determined their CAR-carrying nanoparticles reprogrammed a noticeable percentage of T cells, the researchers tested the T cells’ efficacy in a mouse model of B-ALL.

The team infused the nanoparticles into 10 mice and found the treatment eradicated tumors in 7 of the animals. The other 3 mice “showed substantial regression” of leukemia, the researchers said.

On average, mice that received CAR-carrying nanoparticles had a 58-day improvement in survival compared to control mice.

Mice that received the nanoparticles also had “dramatically reduced” B-cell numbers in their spleens. The researchers noted that this is consistent with the reversible B-cell aplasia observed in patients who receive conventional CD19 CAR T-cell therapy.

Dr Stephan and his colleagues also tested conventional CAR T-cell therapy in the B-ALL mouse model. The mice received cyclophosphamide followed by CAR T cells created ex vivo.

These mice had significantly better survival than controls, but their survival was comparable to that of the mice that received the CAR-carrying nanoparticles.

Although these nanoparticles are several steps away from the clinic, Dr Stephan said he imagines a future in which nanoparticles transform cell-based immunotherapies into easily administered, off-the-shelf treatments that are available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis, I would want to start treatment right away,” Dr Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

Image from NIAID

Researchers say they have developed biodegradable nanoparticles that can be used to genetically reprogram T cells while they are still in the body.

The nanoparticles were able to program T cells with genes encoding leukemia-specific chimeric antigen receptors (CARs).

The resulting CAR T cells were able to eliminate leukemia or slow the progression of disease in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL).

Researchers reported these results in Nature Nanotechnology.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Matthias Stephan, MD, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington.

“The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Dr Stephan and his colleagues designed their nanoparticles to carry genes that encode for CARs intended to target and eliminate B-ALL. The nanoparticles are coated with ligands that make them seek out and bind to T cells.

When a nanoparticle binds to a T cell, the cell engulfs the particle. The nanoparticle then travels to the cell’s nucleus and dissolves.

The CAR genes integrate into chromosomes housed in the nucleus, making it possible for the T cells to begin decoding the new genes and producing CARs within 1 or 2 days.

Once they determined their CAR-carrying nanoparticles reprogrammed a noticeable percentage of T cells, the researchers tested the T cells’ efficacy in a mouse model of B-ALL.

The team infused the nanoparticles into 10 mice and found the treatment eradicated tumors in 7 of the animals. The other 3 mice “showed substantial regression” of leukemia, the researchers said.

On average, mice that received CAR-carrying nanoparticles had a 58-day improvement in survival compared to control mice.

Mice that received the nanoparticles also had “dramatically reduced” B-cell numbers in their spleens. The researchers noted that this is consistent with the reversible B-cell aplasia observed in patients who receive conventional CD19 CAR T-cell therapy.

Dr Stephan and his colleagues also tested conventional CAR T-cell therapy in the B-ALL mouse model. The mice received cyclophosphamide followed by CAR T cells created ex vivo.

These mice had significantly better survival than controls, but their survival was comparable to that of the mice that received the CAR-carrying nanoparticles.

Although these nanoparticles are several steps away from the clinic, Dr Stephan said he imagines a future in which nanoparticles transform cell-based immunotherapies into easily administered, off-the-shelf treatments that are available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis, I would want to start treatment right away,” Dr Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

Photo by Rhoda Baer

A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.

Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.

ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).

The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).

The work was conducted by employees of Asana BioSciences, the company developing ASN002.

The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:

• Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
• Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
• Myeloma—H929, JJN3, OPM2, and U266.

In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.

In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.

The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).

The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.

The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.

Photo by Rhoda Baer

A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.

Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.

ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).

The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).

The work was conducted by employees of Asana BioSciences, the company developing ASN002.

The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:

• Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
• Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
• Myeloma—H929, JJN3, OPM2, and U266.

In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.

In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.

The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).

The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.

The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.

Photo by Rhoda Baer

A dual kinase inhibitor is active against a range of hematologic malignancies, according to preclinical research.

Investigators found that ASN002, a SYK/JAK inhibitor, exhibited “potent” antiproliferative activity in leukemia, lymphoma, and myeloma cell lines.

ASN002 also inhibited tumor growth in mouse models of these malignancies and proved active against ibrutinib-resistant diffuse large B-cell lymphoma (DLBCL).

The investigators presented these results at the AACR Annual Meeting 2017 (abstract 4204).

The work was conducted by employees of Asana BioSciences, the company developing ASN002.

The investigators tested ASN002 in 178 cell lines and found the drug exhibited “strong antiproliferative activity” in a range of hematologic cancer cell lines, including:

• Leukemia—HEL31, HL60, Jurkat, MOLM-13, and MOLM-16
• Lymphoma—KARPAS-299, OCI-LY10, OCI-LY-19, Pfeiffer, Raji, Ramos, SU-DHL-1, SU-DHL-6, and SU-DHL-10
• Myeloma—H929, JJN3, OPM2, and U266.

In addition, ASN002 was active against ibrutinib-resistant clones derived from the DLBCL cell line SU-DHL-6.

In a SU-DHL-6 xenograft model, the combination of ASN002 and ibrutinib was more effective than either compound alone.

The investigators also found that ASN002 alone demonstrated “strong tumor growth inhibition” in mouse models of DLBCL (Pfeiffer and SU-DHL-6), myeloma (H929), and erythroleukemia (HEL).

The team pointed out that ASN002 is currently under investigation in a phase 1/2 study of patients with B-cell lymphomas (DLBCL, mantle cell lymphoma, and follicular lymphoma) as well as solid tumors.

The investigators said that, to date, ASN002 has been well tolerated and has shown encouraging early evidence of clinical activity and symptomatic benefit in the lymphoma patients.

Photo by Sally McCay

Researchers say they have discovered an imbalance that drives the development of B-cell acute lymphoblastic leukemia (B-ALL).

The group’s study suggests that activation of STAT5 causes competition among other transcription factors that leads to B-ALL.

Therefore, the researchers believe that inhibiting the activation of STAT5 and restoring the natural balance of proteins could mean more effective treatment for B-ALL.

Seth Frietze, PhD, of the University of Vermont in Burlington, Vermont, and his colleagues conducted this research and reported the results in Nature Immunology.

The researchers first studied the role of STAT5 in B-ALL using mouse models.

The experiments revealed that STAT5 activation and defects in a signaling pathway worked together to promote B-ALL. The defects were in signaling components of the B-cell antigen receptor precursor—IKAROS, NF-κB, BLNK, BTK, and PKCβ.

With further investigation, the researchers found that STAT5 “antagonized NF-κB and IKAROS by opposing the regulation of shared target genes.”

The team also studied samples from patients with B-ALL and found that patients with a high ratio of active STAT5 to NF-κB or IKAROS had more aggressive disease.

Specifically, the ratio of active STAT5 to IKAROS was negatively cor­related with patient survival and the duration of remission. The ratio of active STAT5 to the NF-κB subunit RELA correlated with remission duration but not survival.

“The major outcome of this story is that a signature emerged from looking at the level of activated proteins compared to other proteins that’s very predictive of how a patient will respond to therapy,” Dr Frietze said.

“That’s a novel finding. If we could find drugs to target that activation, that could be an incredibly effective way to treat leukemia.”

Photo by Sally McCay

Researchers say they have discovered an imbalance that drives the development of B-cell acute lymphoblastic leukemia (B-ALL).

The group’s study suggests that activation of STAT5 causes competition among other transcription factors that leads to B-ALL.

Therefore, the researchers believe that inhibiting the activation of STAT5 and restoring the natural balance of proteins could mean more effective treatment for B-ALL.

Seth Frietze, PhD, of the University of Vermont in Burlington, Vermont, and his colleagues conducted this research and reported the results in Nature Immunology.

The researchers first studied the role of STAT5 in B-ALL using mouse models.

The experiments revealed that STAT5 activation and defects in a signaling pathway worked together to promote B-ALL. The defects were in signaling components of the B-cell antigen receptor precursor—IKAROS, NF-κB, BLNK, BTK, and PKCβ.

With further investigation, the researchers found that STAT5 “antagonized NF-κB and IKAROS by opposing the regulation of shared target genes.”

The team also studied samples from patients with B-ALL and found that patients with a high ratio of active STAT5 to NF-κB or IKAROS had more aggressive disease.

Specifically, the ratio of active STAT5 to IKAROS was negatively cor­related with patient survival and the duration of remission. The ratio of active STAT5 to the NF-κB subunit RELA correlated with remission duration but not survival.

“The major outcome of this story is that a signature emerged from looking at the level of activated proteins compared to other proteins that’s very predictive of how a patient will respond to therapy,” Dr Frietze said.

“That’s a novel finding. If we could find drugs to target that activation, that could be an incredibly effective way to treat leukemia.”

Photo by Sally McCay

Researchers say they have discovered an imbalance that drives the development of B-cell acute lymphoblastic leukemia (B-ALL).

The group’s study suggests that activation of STAT5 causes competition among other transcription factors that leads to B-ALL.

Therefore, the researchers believe that inhibiting the activation of STAT5 and restoring the natural balance of proteins could mean more effective treatment for B-ALL.

Seth Frietze, PhD, of the University of Vermont in Burlington, Vermont, and his colleagues conducted this research and reported the results in Nature Immunology.

The researchers first studied the role of STAT5 in B-ALL using mouse models.

The experiments revealed that STAT5 activation and defects in a signaling pathway worked together to promote B-ALL. The defects were in signaling components of the B-cell antigen receptor precursor—IKAROS, NF-κB, BLNK, BTK, and PKCβ.

With further investigation, the researchers found that STAT5 “antagonized NF-κB and IKAROS by opposing the regulation of shared target genes.”

The team also studied samples from patients with B-ALL and found that patients with a high ratio of active STAT5 to NF-κB or IKAROS had more aggressive disease.

Specifically, the ratio of active STAT5 to IKAROS was negatively cor­related with patient survival and the duration of remission. The ratio of active STAT5 to the NF-κB subunit RELA correlated with remission duration but not survival.

“The major outcome of this story is that a signature emerged from looking at the level of activated proteins compared to other proteins that’s very predictive of how a patient will respond to therapy,” Dr Frietze said.

“That’s a novel finding. If we could find drugs to target that activation, that could be an incredibly effective way to treat leukemia.”

Image by Lance Liotta

WASHINGTON, DC—Preclinical data suggest a novel tyrosine kinase inhibitor (TKI) may be an effective treatment for patients with NTRK-rearranged acute myeloid leukemia (AML).

Entrectinib is a TKI targeting tumors that harbor TRK, ROS1, or ALK fusions.

Researchers found that entrectinib inhibited cell proliferation in NTRK-rearranged AML cell lines.

In mouse models of NTRK-rearranged AML, entrectinib induced tumor regression and eliminated residual AML cells from the bone marrow.

These results were presented at the AACR Annual Meeting 2017 (abstract 5158). The research was conducted by employees of Ignyta, Inc., the company developing entrectinib.

The researchers first tested entrectinib in AML cell lines. They observed “potent” anti-proliferative activity in a pair of NTRK-fusion-positive AML cell lines, IMS-M2 and M0-91.

Entrectinib inhibited TRK signaling and induced cell-cycle arrest in these cell lines. The TKI also induced both caspase 3-dependent apoptosis and PARP cleavage in a dose- and time-dependent manner.

However, entrectinib showed minimal activity against an NTRK-fusion-negative AML cell line, Kasumi-1.

The researchers also tested entrectinib in mouse models of NTRK-fusion-driven AML.

The TKI induced tumor regression in both IMS-M2 and M0-91 models, and the drug eliminated leukemic cells in the bone marrow.

The researchers said these results provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

Entrectinib is currently being studied in a phase 2 trial of solid tumor malignancies.

Image by Lance Liotta

WASHINGTON, DC—Preclinical data suggest a novel tyrosine kinase inhibitor (TKI) may be an effective treatment for patients with NTRK-rearranged acute myeloid leukemia (AML).

Entrectinib is a TKI targeting tumors that harbor TRK, ROS1, or ALK fusions.

Researchers found that entrectinib inhibited cell proliferation in NTRK-rearranged AML cell lines.

In mouse models of NTRK-rearranged AML, entrectinib induced tumor regression and eliminated residual AML cells from the bone marrow.

These results were presented at the AACR Annual Meeting 2017 (abstract 5158). The research was conducted by employees of Ignyta, Inc., the company developing entrectinib.

The researchers first tested entrectinib in AML cell lines. They observed “potent” anti-proliferative activity in a pair of NTRK-fusion-positive AML cell lines, IMS-M2 and M0-91.

Entrectinib inhibited TRK signaling and induced cell-cycle arrest in these cell lines. The TKI also induced both caspase 3-dependent apoptosis and PARP cleavage in a dose- and time-dependent manner.

However, entrectinib showed minimal activity against an NTRK-fusion-negative AML cell line, Kasumi-1.

The researchers also tested entrectinib in mouse models of NTRK-fusion-driven AML.

The TKI induced tumor regression in both IMS-M2 and M0-91 models, and the drug eliminated leukemic cells in the bone marrow.

The researchers said these results provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

Entrectinib is currently being studied in a phase 2 trial of solid tumor malignancies.

Image by Lance Liotta

WASHINGTON, DC—Preclinical data suggest a novel tyrosine kinase inhibitor (TKI) may be an effective treatment for patients with NTRK-rearranged acute myeloid leukemia (AML).

Entrectinib is a TKI targeting tumors that harbor TRK, ROS1, or ALK fusions.

Researchers found that entrectinib inhibited cell proliferation in NTRK-rearranged AML cell lines.

In mouse models of NTRK-rearranged AML, entrectinib induced tumor regression and eliminated residual AML cells from the bone marrow.

These results were presented at the AACR Annual Meeting 2017 (abstract 5158). The research was conducted by employees of Ignyta, Inc., the company developing entrectinib.

The researchers first tested entrectinib in AML cell lines. They observed “potent” anti-proliferative activity in a pair of NTRK-fusion-positive AML cell lines, IMS-M2 and M0-91.

Entrectinib inhibited TRK signaling and induced cell-cycle arrest in these cell lines. The TKI also induced both caspase 3-dependent apoptosis and PARP cleavage in a dose- and time-dependent manner.

However, entrectinib showed minimal activity against an NTRK-fusion-negative AML cell line, Kasumi-1.

The researchers also tested entrectinib in mouse models of NTRK-fusion-driven AML.

The TKI induced tumor regression in both IMS-M2 and M0-91 models, and the drug eliminated leukemic cells in the bone marrow.

The researchers said these results provide rationale for the clinical development of entrectinib in molecularly defined hematologic malignancies.

Entrectinib is currently being studied in a phase 2 trial of solid tumor malignancies.

NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.

He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.

He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

NEW YORK – Optimal induction therapy for patients with multiple myeloma requires all the therapeutic tools currently available for combination therapy, which means using four agents followed by autologous stem cell transplantation, Paul G. Richardson, MD, said at a conference held by Imedex.

He suggested that a rational combination regimen for induction therapy of multiple myeloma would include a second- or third-generation immunomodulator such as lenalidomide (Revlimid) or pomalidomide (Pomalyst); a proteasome inhibitor such as bortezomib (Velcade), carfilzomib (Kyprolis), or ixazomib (Ninlaro); plus standard dexamethasone to form a contemporary backbone regimen for inducing remission in patients with multiple myeloma.

Mitchel L. Zoler/Frontline Medical News

[email protected]

On Twitter @mitchelzoler

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Photo by Rod Waddington

The cancer profile of black US immigrants born in sub-Saharan Africa (ABs) differs from that of US-born black individuals (USBs) and varies by region of birth, according to a new study.

For instance, the data showed that ABs who immigrated to the US had a higher incidence of leukemia and non-Hodgkin lymphoma (NHL) than USBs.

And there was a higher incidence of NHL among ABs born in Eastern Africa than among those born in Western Africa.

“Typically, cancer occurrence among blacks in the United States is presented as one homogeneous group, with no breakdown by country or region of birth,” said Ahemdin Jemal, DVM, PhD, of the American Cancer Society in Atlanta, Georgia.

“Our study shows that approach masks important potential differences that may be key to guiding cancer prevention programs for African-born black immigrants.”

Dr Jemal and his colleagues described this study in the journal Cancer.

The team reviewed cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER 17) program covering the period from 2000 through 2012.

They calculated age-standardized proportional incidence ratios (PIRs), comparing the frequency of the top 15 cancers in ABs with that of USBs, by sex and region of birth.

ABs had a significantly higher proportion of hematologic malignancies (leukemia and NHL), infection-related cancers (liver, stomach, and Kaposi sarcoma), prostate cancer, and thyroid cancers (in females only), when compared to USBs.

In females, the incidence of NHL was 3.4% in ABs and 2.5% in USBs, with a PIR of 1.19. The incidence of leukemia was 3.0% in ABs and 1.9% in USBs, with a PIR of 1.62.

In males, the incidence of NHL was 5.9% in ABs and 3.0% in USBs, with a PIR of 1.34. The incidence of leukemia was 3.0% in ABs and 2.2% in USBs, with a PIR of 1.40.

The investigators also calculated the PIRs of the 5 most frequent cancers in ABs compared to USBs by region of origin (Western Africa vs Eastern Africa).

For both sexes, the incidence of NHL was 4.0% in ABs born in Western Africa (PIR=1.17) and 5.5% in ABs born in Eastern Africa (PIR=1.44).

Leukemia was not included in this analysis because it was not among the top 5 cancers.

Photo by Bill Branson

New research has revealed global inequalities in survival rates for pediatric patients with leukemia.

Investigators analyzed data on nearly 90,000 pediatric leukemia patients treated in 53 countries.

In most countries, patients with lymphoid leukemias or acute myeloid leukemia (AML) saw an increase in 5-year survival between 1995 and 2009.

However, there were wide variations in survival between the countries.

The investigators reported these findings in The Lancet Haematology.

They evaluated data from 89,828 leukemia patients (ages 0 to 14) included in 198 cancer registries in 53 countries.

The team estimated 5-year net survival for patients with AML or lymphoid leukemias (controlling for non-leukemia-related deaths) by calendar period of diagnosis—1995–1999, 2000–2004, and 2005–2009—in each country.

For children diagnosed with lymphoid leukemias between 1995 and 1999, 5-year survival rates ranged from 10.6% (in China) to 86.8% (in Austria). For children diagnosed between 2005 and 2009, the rates ranged from 52.4% (Colombia) to 91.6% (Germany).

For AML, 5-year survival rates ranged from 4.2% (China) to 72.2% (Sweden) in patients diagnosed between 1995 and 1999. For children diagnosed between 2005 and 2009, 5-year survival rates ranged from 33.3% (Bulgaria) to 78.2% (Germany).

The investigators noted that, in some countries, survival for both groups of leukemia patients was consistently high.

In Austria, for example, 5-year survival rates for lymphoid leukemias were 86.8% in 1995-1999 and 91.1% in 2005-2009. For AML, rates were 60.1% and 72.6%, respectively.

Other countries saw substantial increases in survival over time.

In China, the 5-year survival rate for patients with lymphoid leukemias increased from 10.6% in 1995-1999 to 69.2% in 2005-2009. For patients with AML, the rate increased from 4.2% to 41.1%.

“These findings show the extent of worldwide inequalities in access to optimal healthcare for children with cancer,” said study author Audrey Bonaventure, MD, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“Providing additional resources, alongside evidence-based initiatives such as international collaborations and treatment guidelines, could improve access to efficient treatment and care for all children with leukemia. This would contribute substantially to reducing worldwide inequalities in survival.”

Photo by Bill Branson

New research has revealed global inequalities in survival rates for pediatric patients with leukemia.

Investigators analyzed data on nearly 90,000 pediatric leukemia patients treated in 53 countries.

In most countries, patients with lymphoid leukemias or acute myeloid leukemia (AML) saw an increase in 5-year survival between 1995 and 2009.

However, there were wide variations in survival between the countries.

The investigators reported these findings in The Lancet Haematology.

They evaluated data from 89,828 leukemia patients (ages 0 to 14) included in 198 cancer registries in 53 countries.

The team estimated 5-year net survival for patients with AML or lymphoid leukemias (controlling for non-leukemia-related deaths) by calendar period of diagnosis—1995–1999, 2000–2004, and 2005–2009—in each country.

For children diagnosed with lymphoid leukemias between 1995 and 1999, 5-year survival rates ranged from 10.6% (in China) to 86.8% (in Austria). For children diagnosed between 2005 and 2009, the rates ranged from 52.4% (Colombia) to 91.6% (Germany).

For AML, 5-year survival rates ranged from 4.2% (China) to 72.2% (Sweden) in patients diagnosed between 1995 and 1999. For children diagnosed between 2005 and 2009, 5-year survival rates ranged from 33.3% (Bulgaria) to 78.2% (Germany).

The investigators noted that, in some countries, survival for both groups of leukemia patients was consistently high.

In Austria, for example, 5-year survival rates for lymphoid leukemias were 86.8% in 1995-1999 and 91.1% in 2005-2009. For AML, rates were 60.1% and 72.6%, respectively.

Other countries saw substantial increases in survival over time.

In China, the 5-year survival rate for patients with lymphoid leukemias increased from 10.6% in 1995-1999 to 69.2% in 2005-2009. For patients with AML, the rate increased from 4.2% to 41.1%.

“These findings show the extent of worldwide inequalities in access to optimal healthcare for children with cancer,” said study author Audrey Bonaventure, MD, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“Providing additional resources, alongside evidence-based initiatives such as international collaborations and treatment guidelines, could improve access to efficient treatment and care for all children with leukemia. This would contribute substantially to reducing worldwide inequalities in survival.”

Photo by Bill Branson

New research has revealed global inequalities in survival rates for pediatric patients with leukemia.

Investigators analyzed data on nearly 90,000 pediatric leukemia patients treated in 53 countries.

In most countries, patients with lymphoid leukemias or acute myeloid leukemia (AML) saw an increase in 5-year survival between 1995 and 2009.

However, there were wide variations in survival between the countries.

The investigators reported these findings in The Lancet Haematology.

They evaluated data from 89,828 leukemia patients (ages 0 to 14) included in 198 cancer registries in 53 countries.

The team estimated 5-year net survival for patients with AML or lymphoid leukemias (controlling for non-leukemia-related deaths) by calendar period of diagnosis—1995–1999, 2000–2004, and 2005–2009—in each country.

For children diagnosed with lymphoid leukemias between 1995 and 1999, 5-year survival rates ranged from 10.6% (in China) to 86.8% (in Austria). For children diagnosed between 2005 and 2009, the rates ranged from 52.4% (Colombia) to 91.6% (Germany).

For AML, 5-year survival rates ranged from 4.2% (China) to 72.2% (Sweden) in patients diagnosed between 1995 and 1999. For children diagnosed between 2005 and 2009, 5-year survival rates ranged from 33.3% (Bulgaria) to 78.2% (Germany).

The investigators noted that, in some countries, survival for both groups of leukemia patients was consistently high.

In Austria, for example, 5-year survival rates for lymphoid leukemias were 86.8% in 1995-1999 and 91.1% in 2005-2009. For AML, rates were 60.1% and 72.6%, respectively.

Other countries saw substantial increases in survival over time.

In China, the 5-year survival rate for patients with lymphoid leukemias increased from 10.6% in 1995-1999 to 69.2% in 2005-2009. For patients with AML, the rate increased from 4.2% to 41.1%.

“These findings show the extent of worldwide inequalities in access to optimal healthcare for children with cancer,” said study author Audrey Bonaventure, MD, PhD, of the London School of Hygiene & Tropical Medicine in the UK.

“Providing additional resources, alongside evidence-based initiatives such as international collaborations and treatment guidelines, could improve access to efficient treatment and care for all children with leukemia. This would contribute substantially to reducing worldwide inequalities in survival.”

NEW YORK – A pair of new monoclonal antibodies have dramatically changed treatment for patients with acute lymphoblastic leukemia to prepare them for a stem cell transplant, Daniel J. DeAngelo, MD, said at a conference held by Imedex.

“We don’t use standard chemotherapy for reinduction anymore; we use blinatumomab or inotuzumab,” said Dr. DeAngelo, a hematologist oncologist at Dana-Farber Cancer Institute in Boston.

Blinatumomab (Blincyto), approved by the Food and Drug Administration in 2014, has produced “exceptional” response rates, becoming “standard of care” for patients with relapsed acute lymphoblastic leukemia (ALL) that does not have a Philadelphia chromosome, Dr. DeAngelo said in a video interview.

Approved based on results from a phase II study, blinatumomab’s efficacy and safety were recently further delineated in results from the first phase III trial (N Engl J Med. 2017 Mar 2;376[9]:836-74), with 376 treated patients. In that trial, blinatumomab more than doubled the complete remission rate, compared with control patients (34% vs. 16%), and nearly doubled median overall survival – 7.7 months with blinatumomab, compared with 4.0 months for control patients treated with standard chemotherapy.

These findings “further substantiated” blinatumomab’s role, he said.

Blinatumomab’s big limitations are certain adverse effects and the logistics of its dosing. The major adverse effect is “cytokine release syndrome,” which manifests as fever, low blood pressure, and neurologic toxicities that can range from tremors to encephalopathy and seizure. These are manageable by close observation of patients by experienced nurses, Dr. DeAngelo said.

Dosing involves 4 weeks of continuous infusion, starting with 10 days done entirely in the hospital, with the remaining 18 days with patients going home but needing to return every 48 hours to have their infusion bag changed. “Depending on how far the patient lives from the clinic, it can be a logistical challenge,” he said.

A second new antibody he has used on many patients is inotuzumab, which was accepted for review for approval by the FDA in February 2017, with action expected by August.

Dr. DeAngelo served as a coinvestigator in a phase III trial reported in 2016 with 218 evaluable patients. In that trial, investigators reported an 81% complete remission rate with inotuzumab treatment, compared with a 29% among control patients on chemotherapy (N Engl J Med. 2016 Aug 25;375[8]:740-53).

Inotuzumab was effective against patients with Philadelphia chromosome positive ALL, but it will not work for the roughly 5%-10% of ALL patients who lack CD-22 expression in their B-cell ALL.

Inotuzumab is easier to administer than blinatumomab, requiring a once a week infusion, and causes little immediate toxicity – although thrombocytopenia and liver-function abnormalities can occur with continued use, and the risk of veno-occlusive disease is increased when patients later receive a stem cell transplant, Dr. DeAngelo said.

“It’s nice to have options” when choosing antibody-based treatment, he said. Blinatumomab is a good choice for patients with a lower tumor burden – either patients with early relapse or with minimal residual disease – while inotuzumab works better for patients with more bulky disease, as well as those who are not able to accommodate the logistic demands of blinatumomab infusions.

Dr. DeAngelo also highlighted several trials now underway that are testing the efficacy of both antibodies when used as part of first-line treatment.

Dr. DeAngelo has been a consultant to Amgen, the company that markets blinatumomab (Blincyto); to Pfizer, the company developing inotuzumab; and to Ariad, InCyte, and Novartis.

[email protected]

On Twitter @mitchelzoler

NEW YORK – A pair of new monoclonal antibodies have dramatically changed treatment for patients with acute lymphoblastic leukemia to prepare them for a stem cell transplant, Daniel J. DeAngelo, MD, said at a conference held by Imedex.

“We don’t use standard chemotherapy for reinduction anymore; we use blinatumomab or inotuzumab,” said Dr. DeAngelo, a hematologist oncologist at Dana-Farber Cancer Institute in Boston.

Blinatumomab (Blincyto), approved by the Food and Drug Administration in 2014, has produced “exceptional” response rates, becoming “standard of care” for patients with relapsed acute lymphoblastic leukemia (ALL) that does not have a Philadelphia chromosome, Dr. DeAngelo said in a video interview.

Approved based on results from a phase II study, blinatumomab’s efficacy and safety were recently further delineated in results from the first phase III trial (N Engl J Med. 2017 Mar 2;376[9]:836-74), with 376 treated patients. In that trial, blinatumomab more than doubled the complete remission rate, compared with control patients (34% vs. 16%), and nearly doubled median overall survival – 7.7 months with blinatumomab, compared with 4.0 months for control patients treated with standard chemotherapy.

These findings “further substantiated” blinatumomab’s role, he said.

Blinatumomab’s big limitations are certain adverse effects and the logistics of its dosing. The major adverse effect is “cytokine release syndrome,” which manifests as fever, low blood pressure, and neurologic toxicities that can range from tremors to encephalopathy and seizure. These are manageable by close observation of patients by experienced nurses, Dr. DeAngelo said.

Dosing involves 4 weeks of continuous infusion, starting with 10 days done entirely in the hospital, with the remaining 18 days with patients going home but needing to return every 48 hours to have their infusion bag changed. “Depending on how far the patient lives from the clinic, it can be a logistical challenge,” he said.

A second new antibody he has used on many patients is inotuzumab, which was accepted for review for approval by the FDA in February 2017, with action expected by August.

Dr. DeAngelo served as a coinvestigator in a phase III trial reported in 2016 with 218 evaluable patients. In that trial, investigators reported an 81% complete remission rate with inotuzumab treatment, compared with a 29% among control patients on chemotherapy (N Engl J Med. 2016 Aug 25;375[8]:740-53).

Inotuzumab was effective against patients with Philadelphia chromosome positive ALL, but it will not work for the roughly 5%-10% of ALL patients who lack CD-22 expression in their B-cell ALL.

Inotuzumab is easier to administer than blinatumomab, requiring a once a week infusion, and causes little immediate toxicity – although thrombocytopenia and liver-function abnormalities can occur with continued use, and the risk of veno-occlusive disease is increased when patients later receive a stem cell transplant, Dr. DeAngelo said.

“It’s nice to have options” when choosing antibody-based treatment, he said. Blinatumomab is a good choice for patients with a lower tumor burden – either patients with early relapse or with minimal residual disease – while inotuzumab works better for patients with more bulky disease, as well as those who are not able to accommodate the logistic demands of blinatumomab infusions.

Dr. DeAngelo also highlighted several trials now underway that are testing the efficacy of both antibodies when used as part of first-line treatment.

Dr. DeAngelo has been a consultant to Amgen, the company that markets blinatumomab (Blincyto); to Pfizer, the company developing inotuzumab; and to Ariad, InCyte, and Novartis.

[email protected]

On Twitter @mitchelzoler

NEW YORK – A pair of new monoclonal antibodies have dramatically changed treatment for patients with acute lymphoblastic leukemia to prepare them for a stem cell transplant, Daniel J. DeAngelo, MD, said at a conference held by Imedex.

“We don’t use standard chemotherapy for reinduction anymore; we use blinatumomab or inotuzumab,” said Dr. DeAngelo, a hematologist oncologist at Dana-Farber Cancer Institute in Boston.

Blinatumomab (Blincyto), approved by the Food and Drug Administration in 2014, has produced “exceptional” response rates, becoming “standard of care” for patients with relapsed acute lymphoblastic leukemia (ALL) that does not have a Philadelphia chromosome, Dr. DeAngelo said in a video interview.

Approved based on results from a phase II study, blinatumomab’s efficacy and safety were recently further delineated in results from the first phase III trial (N Engl J Med. 2017 Mar 2;376[9]:836-74), with 376 treated patients. In that trial, blinatumomab more than doubled the complete remission rate, compared with control patients (34% vs. 16%), and nearly doubled median overall survival – 7.7 months with blinatumomab, compared with 4.0 months for control patients treated with standard chemotherapy.

These findings “further substantiated” blinatumomab’s role, he said.

Blinatumomab’s big limitations are certain adverse effects and the logistics of its dosing. The major adverse effect is “cytokine release syndrome,” which manifests as fever, low blood pressure, and neurologic toxicities that can range from tremors to encephalopathy and seizure. These are manageable by close observation of patients by experienced nurses, Dr. DeAngelo said.

Dosing involves 4 weeks of continuous infusion, starting with 10 days done entirely in the hospital, with the remaining 18 days with patients going home but needing to return every 48 hours to have their infusion bag changed. “Depending on how far the patient lives from the clinic, it can be a logistical challenge,” he said.

A second new antibody he has used on many patients is inotuzumab, which was accepted for review for approval by the FDA in February 2017, with action expected by August.

Dr. DeAngelo served as a coinvestigator in a phase III trial reported in 2016 with 218 evaluable patients. In that trial, investigators reported an 81% complete remission rate with inotuzumab treatment, compared with a 29% among control patients on chemotherapy (N Engl J Med. 2016 Aug 25;375[8]:740-53).

Inotuzumab was effective against patients with Philadelphia chromosome positive ALL, but it will not work for the roughly 5%-10% of ALL patients who lack CD-22 expression in their B-cell ALL.

Inotuzumab is easier to administer than blinatumomab, requiring a once a week infusion, and causes little immediate toxicity – although thrombocytopenia and liver-function abnormalities can occur with continued use, and the risk of veno-occlusive disease is increased when patients later receive a stem cell transplant, Dr. DeAngelo said.

“It’s nice to have options” when choosing antibody-based treatment, he said. Blinatumomab is a good choice for patients with a lower tumor burden – either patients with early relapse or with minimal residual disease – while inotuzumab works better for patients with more bulky disease, as well as those who are not able to accommodate the logistic demands of blinatumomab infusions.

Dr. DeAngelo also highlighted several trials now underway that are testing the efficacy of both antibodies when used as part of first-line treatment.

Dr. DeAngelo has been a consultant to Amgen, the company that markets blinatumomab (Blincyto); to Pfizer, the company developing inotuzumab; and to Ariad, InCyte, and Novartis.

[email protected]

On Twitter @mitchelzoler