AML

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Photo by Rhoda Baer

The National Comprehensive Cancer Network® (NCCN) has announced the release of the newly completed NCCN Radiation Therapy Compendium™.

This resource includes information designed to support clinical decision-making regarding the use of radiation therapy in cancer patients.

The content is based on the NCCN Clinical Practice Guidelines in Oncology and includes information from the 41 guidelines that reference radiation therapy.

“By compiling every recommendation for radiation therapy in one place, we’ve made it significantly easier for specialists . . .  to stay up-to-date on the very latest recommendations, regardless of how many different cancer types they treat,” said Robert W. Carlson, MD, chief executive officer of NCCN.

“This targeted content provides radiation oncologists with the specific, cutting-edge information they need, without forcing them to sift through any extraneous information. It’s part of our ongoing effort to always provide the most pertinent data on emerging treatment practices in the clearest, most efficient way possible.”

The NCCN Radiation Therapy Compendium includes a full complement of radiation therapy recommendations found in the current NCCN guidelines, including specific treatment modalities such as 2D/3D conformal external beam radiation therapy, intensity modulated radiation therapy, intra-operative radiation therapy, stereotactic radiosurgery/stereotactic body radiotherapy/stereotactic ablative body radiotherapy, image-guided radiation therapy, low dose-rate/high dose-rate brachytherapy, radioisotope, and particle therapy.

NCCN first announced the launch of the Radiation Therapy Compendium in March at the NCCN Annual Conference: Improving the Quality, Effectiveness, and Efficiency of Cancer Care.

At the time, the NCCN released a preliminary version of the compendium featuring 24 cancer types. The newly completed version now contains all 41 disease sites that are currently being treated using radiation therapy.

The compendium will be updated on a continual basis in conjunction with the library of clinical guidelines.

For more information and to access the NCCN Radiation Therapy Compendium, visit NCCN.org/RTCompendium. The compendium is available free-of-charge through March 2018.

Detecting hereditary MDS/AML

Unexplained cytopenias or failure to mobilize stem cells in related donors of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) – important clues for the detection of a hereditary MDS/AML syndrome – should prompt efforts to obtain germ line tissue sources for collaborative research, Jane E. Churpek, MD, of the Hereditary Hematologic Malignancies Program at The University of Chicago Medicine, wrote.

Partnering with families to obtain germ line tissue sources uncontaminated by tumor cells from large numbers of patients with MDS/AML, and international collaboration to determine the mechanisms and multi-step processes from the carrier state to overt disease, have enormous potential to improve the outcomes of patients with both familial and sporadic forms of MDS/AML. Incorporating collection of ideal germ line tissue along with family histories to the already robust international MDS/AML registries and data sharing are all essential to future progress in this field, she wrote in a recent article published onlne in Best Practice & Research Clinical Haematology.
 

Prophylactic granulocyte transfusions

Giving prophylactic granulocyte transfusions to AML patients during the induction phase of therapy is feasible and safe, but assuring an adequate donor pool and patient continuation of the transfusions are another matter.

In a phase 2 trial of 45 neutropenic patients with AML or high-risk myelodysplastic syndrome undergoing induction or first-salvage therapy, non-irradiated allogeneic granulocyte transfusions were to be given every 3-4 days until sustained ANC recovery, initiation of new therapy, or completion of 6 weeks on study. But logistical problems limited the success of the protocol: 5 patients never received a granulocyte transfusion due to donor screening failure or donor unavailability and the other 40 received a median of 3 (range 1-9) granulocyte transfusions.

“We anticipated approximately 8 GTs per patient ... only 11 received 6 or more GTs,” Fleur M. Aung, MD, and colleagues at The MD Anderson Cancer Center, Houston, wrote in the Journal of Blood Disorders and Transfusion (DOI 10.4172/2155-9864.1000376).

The authors concluded that while the process is feasible, ex vivo expanded neutrophils, produced from multiple donors and cryopreserved to provide an “off the shelf” myeloid progenitor product, will likely prove more reliable for treating patients with prolonged neutropenia.
 

From ONC201 to ONC212

Oncoceutics has expanded its research collaboration agreement with The University of Texas MD Anderson Cancer Center, Houston, to include the clinical development of a second novel imipridone called ONC212.

Oncoceutics and MD Anderson are already collaborating on the clinical development of another imipridone, ONC201. Both drugs have the same chemical core that interacts with G-Protein Coupled Receptors (GPCRs). ONC212 targets GPR132, which influences the growth of acute leukemias and has not previously been successfully targeted by a small molecule.

This alliance between MD Anderson and Oncoceutics will support Phase I and Phase II clinical trials of ONC212 in patients with refractory acute myeloid leukemia (AML), according to Oncoceutics. The alliance provides for a sharing of risk and rewards from potential commercialization of ONC212.
 

Top risk factor miRNA

The miRNA hsa-mir-425 was identified as the top risk factor miRNA of AML survival and CD44 was identified as one of the top three risk factor target-genes associated with AML survival, based on a miRNA-mRNA interaction network.

Chunmei Zhang, MD, of the department of hematology at Taian City Central Hospital, Taian, Shandong, China, and colleagues used The Cancer Genome Atlas database to obtain miRNA and mRNA expression profiles from AML patients. Of 14 miRNAs associated with AML survival, 3 were associated with risk – hsa-mir-425, hsa-mir-1201, and hsa-mir-1978. GTSF1, RTN4R, and CD44 were the top risk factor target-genes associated with AML survival. Med Sci Monit 2017; 23:4705-14 (DOI: 10.12659/MSM.903989)
 

Detecting hereditary MDS/AML

Unexplained cytopenias or failure to mobilize stem cells in related donors of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) – important clues for the detection of a hereditary MDS/AML syndrome – should prompt efforts to obtain germ line tissue sources for collaborative research, Jane E. Churpek, MD, of the Hereditary Hematologic Malignancies Program at The University of Chicago Medicine, wrote.

Partnering with families to obtain germ line tissue sources uncontaminated by tumor cells from large numbers of patients with MDS/AML, and international collaboration to determine the mechanisms and multi-step processes from the carrier state to overt disease, have enormous potential to improve the outcomes of patients with both familial and sporadic forms of MDS/AML. Incorporating collection of ideal germ line tissue along with family histories to the already robust international MDS/AML registries and data sharing are all essential to future progress in this field, she wrote in a recent article published onlne in Best Practice & Research Clinical Haematology.
 

Prophylactic granulocyte transfusions

Giving prophylactic granulocyte transfusions to AML patients during the induction phase of therapy is feasible and safe, but assuring an adequate donor pool and patient continuation of the transfusions are another matter.

In a phase 2 trial of 45 neutropenic patients with AML or high-risk myelodysplastic syndrome undergoing induction or first-salvage therapy, non-irradiated allogeneic granulocyte transfusions were to be given every 3-4 days until sustained ANC recovery, initiation of new therapy, or completion of 6 weeks on study. But logistical problems limited the success of the protocol: 5 patients never received a granulocyte transfusion due to donor screening failure or donor unavailability and the other 40 received a median of 3 (range 1-9) granulocyte transfusions.

“We anticipated approximately 8 GTs per patient ... only 11 received 6 or more GTs,” Fleur M. Aung, MD, and colleagues at The MD Anderson Cancer Center, Houston, wrote in the Journal of Blood Disorders and Transfusion (DOI 10.4172/2155-9864.1000376).

The authors concluded that while the process is feasible, ex vivo expanded neutrophils, produced from multiple donors and cryopreserved to provide an “off the shelf” myeloid progenitor product, will likely prove more reliable for treating patients with prolonged neutropenia.
 

From ONC201 to ONC212

Oncoceutics has expanded its research collaboration agreement with The University of Texas MD Anderson Cancer Center, Houston, to include the clinical development of a second novel imipridone called ONC212.

Oncoceutics and MD Anderson are already collaborating on the clinical development of another imipridone, ONC201. Both drugs have the same chemical core that interacts with G-Protein Coupled Receptors (GPCRs). ONC212 targets GPR132, which influences the growth of acute leukemias and has not previously been successfully targeted by a small molecule.

This alliance between MD Anderson and Oncoceutics will support Phase I and Phase II clinical trials of ONC212 in patients with refractory acute myeloid leukemia (AML), according to Oncoceutics. The alliance provides for a sharing of risk and rewards from potential commercialization of ONC212.
 

Top risk factor miRNA

The miRNA hsa-mir-425 was identified as the top risk factor miRNA of AML survival and CD44 was identified as one of the top three risk factor target-genes associated with AML survival, based on a miRNA-mRNA interaction network.

Chunmei Zhang, MD, of the department of hematology at Taian City Central Hospital, Taian, Shandong, China, and colleagues used The Cancer Genome Atlas database to obtain miRNA and mRNA expression profiles from AML patients. Of 14 miRNAs associated with AML survival, 3 were associated with risk – hsa-mir-425, hsa-mir-1201, and hsa-mir-1978. GTSF1, RTN4R, and CD44 were the top risk factor target-genes associated with AML survival. Med Sci Monit 2017; 23:4705-14 (DOI: 10.12659/MSM.903989)
 

Detecting hereditary MDS/AML

Unexplained cytopenias or failure to mobilize stem cells in related donors of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) – important clues for the detection of a hereditary MDS/AML syndrome – should prompt efforts to obtain germ line tissue sources for collaborative research, Jane E. Churpek, MD, of the Hereditary Hematologic Malignancies Program at The University of Chicago Medicine, wrote.

Partnering with families to obtain germ line tissue sources uncontaminated by tumor cells from large numbers of patients with MDS/AML, and international collaboration to determine the mechanisms and multi-step processes from the carrier state to overt disease, have enormous potential to improve the outcomes of patients with both familial and sporadic forms of MDS/AML. Incorporating collection of ideal germ line tissue along with family histories to the already robust international MDS/AML registries and data sharing are all essential to future progress in this field, she wrote in a recent article published onlne in Best Practice & Research Clinical Haematology.
 

Prophylactic granulocyte transfusions

Giving prophylactic granulocyte transfusions to AML patients during the induction phase of therapy is feasible and safe, but assuring an adequate donor pool and patient continuation of the transfusions are another matter.

In a phase 2 trial of 45 neutropenic patients with AML or high-risk myelodysplastic syndrome undergoing induction or first-salvage therapy, non-irradiated allogeneic granulocyte transfusions were to be given every 3-4 days until sustained ANC recovery, initiation of new therapy, or completion of 6 weeks on study. But logistical problems limited the success of the protocol: 5 patients never received a granulocyte transfusion due to donor screening failure or donor unavailability and the other 40 received a median of 3 (range 1-9) granulocyte transfusions.

“We anticipated approximately 8 GTs per patient ... only 11 received 6 or more GTs,” Fleur M. Aung, MD, and colleagues at The MD Anderson Cancer Center, Houston, wrote in the Journal of Blood Disorders and Transfusion (DOI 10.4172/2155-9864.1000376).

The authors concluded that while the process is feasible, ex vivo expanded neutrophils, produced from multiple donors and cryopreserved to provide an “off the shelf” myeloid progenitor product, will likely prove more reliable for treating patients with prolonged neutropenia.
 

From ONC201 to ONC212

Oncoceutics has expanded its research collaboration agreement with The University of Texas MD Anderson Cancer Center, Houston, to include the clinical development of a second novel imipridone called ONC212.

Oncoceutics and MD Anderson are already collaborating on the clinical development of another imipridone, ONC201. Both drugs have the same chemical core that interacts with G-Protein Coupled Receptors (GPCRs). ONC212 targets GPR132, which influences the growth of acute leukemias and has not previously been successfully targeted by a small molecule.

This alliance between MD Anderson and Oncoceutics will support Phase I and Phase II clinical trials of ONC212 in patients with refractory acute myeloid leukemia (AML), according to Oncoceutics. The alliance provides for a sharing of risk and rewards from potential commercialization of ONC212.
 

Top risk factor miRNA

The miRNA hsa-mir-425 was identified as the top risk factor miRNA of AML survival and CD44 was identified as one of the top three risk factor target-genes associated with AML survival, based on a miRNA-mRNA interaction network.

Chunmei Zhang, MD, of the department of hematology at Taian City Central Hospital, Taian, Shandong, China, and colleagues used The Cancer Genome Atlas database to obtain miRNA and mRNA expression profiles from AML patients. Of 14 miRNAs associated with AML survival, 3 were associated with risk – hsa-mir-425, hsa-mir-1201, and hsa-mir-1978. GTSF1, RTN4R, and CD44 were the top risk factor target-genes associated with AML survival. Med Sci Monit 2017; 23:4705-14 (DOI: 10.12659/MSM.903989)
 

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.

SAN FRANCISCO – Routine testing for minimal residual disease is probably not of value in acute myeloid leukemia, as there is no evidence that changing treatment based on MRD status currently makes a difference in patient outcomes, experts said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.

“If we find minimal residual disease, we don’t always have a better therapy to offer our patients,” Jessica Altman, MD, associate professor of hematology and oncology at the Northwestern University Feinberg School of Medicine, said.

Beyond that therapeutic reality, there are no clear guidelines and standards for MRD testing. The optimal timing for MRD testing and a standard threshold for an MRD classification are not yet established, she said.

“Having MRD is bad, not having it is better,” Richard Stone, MD, PhD, clinical director of the adult leukemia program at the Dana-Farber Cancer Institute, said. The problem in AML, he said, is, “So?” There is no reliable “MRD eraser” in AML, he said. Until then, there is not much point in knowing whether a patient is MRD positive or not.

A recent survey conducted by researchers at Moffitt Cancer Center, Tampa, addressed MRD testing at 13 major cancer centers. While most centers reported that they test for MRD, many physicians said that they are unsure about what to do with the results.

A 2013 study by the HOVON group found that patients who were in complete remission but MRD positive after their first course of therapy, subsequently became MRD negative after their second course of therapy. But the second regimen would not have been different based on knowledge of MRD status, according to the HOVON/SAKK AML 42A study (J Clin Oncol. 2013; 31:3889-97).

The AML community is awaiting guidelines on MRD use from the NCCN and other groups, Dr. Altman said. An option for using NPM1 mutations to assess MRD should be available soon, and could be an improvement on existing options (N Engl J Med 2016; 374:422-33).

Given the treatment limitations, knowing about MRD status can have a negative mental toll on patients, Dr. Stone said. “I would not underplay the psychological burden.” Nevertheless, MRD should be measured in clinical trials, and it could be a valuable surrogate marker by which to compare drug efficacy.

One of the biggest hopes is that MRD status could eventually be useful in determining the need for allogeneic stem cell transplant in patients deemed intermediate risk, Dr. Altman said. “I think we are finally on the brink of this being actionable.”

Dr. Altman reports financial relationships with Astellas, Bristol-Myers Squibb, Celgene, Janssen, Novartis, and Syros. Dr. Stone reports financial relationships with AbbVie, Actinium, Agios, Amgen and many other companies.

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.

Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

About orphan designation

Gilteritinib also has orphan drug designation for the treatment of AML.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.

Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

About orphan designation

Gilteritinib also has orphan drug designation for the treatment of AML.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

AML cells

The US Food and Drug Administration (FDA) has granted fast track designation to gilteritinib for the treatment of adults with FLT3 mutation-positive relapsed or refractory acute myeloid leukemia (AML).

Gilteritinib is a compound that has demonstrated inhibitory activity against FLT3 internal tandem duplication (ITD) and FLT3 tyrosine kinase domain, 2 mutations that are seen in approximately one-third of patients with AML.

Gilteritinib has also demonstrated inhibition of AXL, which is reported to be associated with therapeutic resistance.

Astellas Pharma Inc. is currently investigating gilteritinib in phase 3 trials of AML patients.

Results from a phase 1/2 study of gilteritinib in AML were presented at the 2017 ASCO Annual Meeting.

The goal of the study was to determine the tolerability and antileukemic activity of once-daily gilteritinib in a FLT3-ITD-enriched, relapsed/refractory AML population.

Researchers said the drug exhibited potent FLT3 inhibition at doses greater than 80 mg/day. In patients who received such doses, the greatest overall response rate was 52%, and the longest median overall survival was 31 weeks.

The maximum tolerated dose of gilteritinib was 300 mg/day. Dose-limiting toxicities included diarrhea and liver function abnormalities.

About fast track designation

The FDA’s fast track program is designed to facilitate the development and expedite the review of products intended to treat or prevent serious or life-threatening conditions and address unmet medical need.

Through the fast track program, a product may be eligible for priority review. In addition, the company developing the product may be allowed to submit sections of the new drug application or biologics license application on a rolling basis as data become available.

Fast track designation also provides the company with opportunities for more frequent meetings and written communications with the FDA.

About orphan designation

Gilteritinib also has orphan drug designation for the treatment of AML.

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE)

AG120-C-009 (NCT03173248) will evaluate the efficacy and safety of AG-120 (ivosidenib) plus azacitidine vs. placebo plus azacitidine in adult subjects with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy.

The primary endpoint of this global, phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial is overall survival. Key secondary efficacy endpoints are event-free survival, rate of complete remission, rate of complete remission with partial hematologic recovery, and overall response rate. Subjects will be randomized 1:1 to receive either oral AG-120 or matched placebo, both administered in combination with subcutaneous or intravenous azacitidine. An estimated 392 subjects will participate in the study, which is sponsored by Agios Pharmaceuticals. Estimated completion date is June 2022.

Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE)

AG120-C-009 (NCT03173248) will evaluate the efficacy and safety of AG-120 (ivosidenib) plus azacitidine vs. placebo plus azacitidine in adult subjects with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy.

The primary endpoint of this global, phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial is overall survival. Key secondary efficacy endpoints are event-free survival, rate of complete remission, rate of complete remission with partial hematologic recovery, and overall response rate. Subjects will be randomized 1:1 to receive either oral AG-120 or matched placebo, both administered in combination with subcutaneous or intravenous azacitidine. An estimated 392 subjects will participate in the study, which is sponsored by Agios Pharmaceuticals. Estimated completion date is June 2022.

Study of AG-120 (Ivosidenib) vs. Placebo in Combination With Azacitidine in Patients With Previously Untreated Acute Myeloid Leukemia With an IDH1 Mutation (AGILE)

AG120-C-009 (NCT03173248) will evaluate the efficacy and safety of AG-120 (ivosidenib) plus azacitidine vs. placebo plus azacitidine in adult subjects with previously untreated IDH1m AML who are considered appropriate candidates for non-intensive therapy.

The primary endpoint of this global, phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial is overall survival. Key secondary efficacy endpoints are event-free survival, rate of complete remission, rate of complete remission with partial hematologic recovery, and overall response rate. Subjects will be randomized 1:1 to receive either oral AG-120 or matched placebo, both administered in combination with subcutaneous or intravenous azacitidine. An estimated 392 subjects will participate in the study, which is sponsored by Agios Pharmaceuticals. Estimated completion date is June 2022.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.

The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.

Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.

As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.

The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.

A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.

The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.

The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.

Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.

As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.

The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.

A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.

The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has placed a full clinical hold on a phase 1/2 trial of SEL24, a dual PIM/FLT3 kinase inhibitor, in patients with relapsed/refractory acute myeloid leukemia (AML).

The hold is due to a fatal cerebral adverse event that is considered possibly related to SEL24.

The clinical hold means no new patients will be enrolled in the trial and enrolled patients will not receive SEL24 until the hold is lifted.

Selvita S.A., the company developing SEL24, received a clinical hold letter from the FDA on October 6 and said it plans to work with the agency to have the hold lifted.

As part of this process, Selvita will provide the FDA with additional data and analysis on patients treated with SEL24 as well as a proposed protocol amendment.

The trial began in the first quarter of 2017. The study is designed to determine the maximum tolerated dose and recommended dose of SEL24 in patients with relapsed and refractory AML. The study began with a 25 mg daily dose, which was then escalated following cohort reviews.

One AML patient started treatment with a 150 mg dose of SEL24 as the third patient in this dose cohort and received 4 doses of the drug. This patient developed a life-threatening, grade 4 venous thrombus in the brain with subsequent intracerebral hemorrhage, which required hospitalization.

The patient died in hospice 4 days later due to the cerebral event. The patient’s death was subsequently evaluated as possibly related to SEL24.

A safety report and a review of data by the trial’s data monitoring committee were submitted to the FDA. The agency then placed a clinical hold on the trial and requested more safety data on patients who have received SEL24, as well as specific protocol changes and additional guidance to the study staff.

Selvita said it plans to comply with the requests and provide additional information to the agency and clinical trial centers, in collaboration with the Menarini Group, its global development partner for SEL24.

The FDA has 30 days from the receipt of Selvita’s response to let the company know whether the clinical hold is lifted.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Henrique Orlandi Mourao

The US Food and Drug Administration (FDA) has granted orphan drug designation to PCM-075 for the treatment of patients with acute myeloid leukemia (AML).

PCM-075 is an oral adenosine triphosphate competitive inhibitor of the serine/threonine Polo-like kinase 1 (PLK1) enzyme, which appears to be overexpressed in several hematologic and solid tumor malignancies.

PCM-075 is being developed by Trovagene, Inc.

The company is initiating a phase 1b/2 trial of PCM-075 in combination with standard care (low-dose cytarabine or decitabine) in patients with AML (NCT03303339).

Trovagene has already completed a phase 1 dose-escalation study of PCM-075 in patients with advanced metastatic solid tumor malignancies. This study was recently published in Investigational New Drugs.

According to Trovagene, preclinical studies have shown that PCM-075 synergizes with more than 10 drugs used to treat hematologic and solid tumor malignancies, including FLT3 and HDAC inhibitors, taxanes, and cytotoxins.

Trovagene believes the combination of PCM-075 with other compounds has the potential for improved clinical efficacy in AML, non-Hodgkin lymphoma, castration-resistant prostate cancer, triple-negative breast cancer, and adrenocortical carcinoma.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo by Bill Branson

A study of cancer drugs approved by the European Commission from 2009 to 2013 showed that few hematology drugs were known to provide a benefit in overall survival (OS) or quality of life (QOL) over existing treatments.

Of 12 drugs approved for 17 hematology indications, 3 drugs had been shown to provide a benefit in OS (for 3 indications) at the time of approval.

None of the other hematology drugs were known to provide an OS benefit even after a median follow-up of 5.4 years.

Two hematology drugs were shown to provide a benefit in QOL (for 2 indications) after approval, but none of the drugs were known to provide a QOL benefit at the time of approval.

These findings were published in The BMJ alongside a related editorial, feature article, and patient commentary.

All cancer drugs

Researchers analyzed reports on all cancer drug approvals by the European Commission from 2009 to 2013.

There were 48 drugs approved for 68 cancer indications during this period. Fifty-one of the indications were for solid tumor malignancies, and 17 were for hematologic malignancies.

For 24 indications (35%), research had demonstrated a significant improvement in OS at the time of the drugs’ approval. For 3 indications, an improvement in OS was demonstrated after approval.

There was a known improvement in QOL for 7 of the indications (10%) at the time of approval and for 5 indications after approval.

The median follow-up was 5.4 years (range, 3.3 years to 8.1 years).

Overall, there was a significant improvement in OS or QOL during the study period for 51% of the indications (35/68). For the other half (49%, n=33), it wasn’t clear if the drugs provide any benefits in OS or QOL.

All cancer trials

The 68 approvals of cancer drugs were supported by 72 clinical trials.

Sixty approvals (88%) were supported by at least 1 randomized, controlled trial. Eight approvals (12%) were based on a single-arm study. This included 6 of 10 conditional marketing authorizations and 2 of 58 regular marketing authorizations.

Eighteen of the approvals (26%) were supported by a pivotal study powered to evaluate OS as the primary endpoint. And 37 of the approvals (54%) had a supporting pivotal trial evaluating QOL, but results were not reported for 2 of these trials.

Hematology trials and drugs

Of the 12 drugs approved for 17 hematology indications, 4 were regular approvals, 5 were conditional approvals, and 8 had orphan drug designation.

The approvals were supported by data from 18 trials—13 randomized and 5 single-arm trials.

The study drug was compared to an active comparator in 9 of the trials. The drug was evaluated as an add-on treatment in 4 trials. And the drug was not compared to anything in 5 trials (the single-arm trials).

OS was the primary endpoint in 1 of the trials, and 17 trials had OS or QOL as a secondary endpoint.

There were 3 drugs that had demonstrated an OS benefit at the time of approval but no QOL benefit at any time:

• Decitabine used for first-line treatment of acute myeloid leukemia in adults 65 and older who are ineligible for chemotherapy
• Pomalidomide in combination with dexamethasone as third-line therapy for relapsed/refractory multiple myeloma (MM)
• Rituximab plus chemotherapy for first-line treatment of chronic lymphocytic leukemia (CLL).

There were 2 drugs that had demonstrated a QOL benefit, only after approval, but they were not known to provide an OS benefit at any time:

• Nilotinib as a treatment for adults with newly diagnosed, chronic phase, Ph+ chronic myeloid leukemia (CML)
• Ofatumumab for CLL that is refractory to fludarabine and alemtuzumab

For the remaining drugs, there was no evidence of an OS or QOL benefit at any time during the period studied. The drugs included:

• Bortezomib given alone or in combination with doxorubicin or dexamethasone as second-line therapy for MM patients ineligible for hematopoietic stem cell transplant (HSCT)
• Bortezomib plus dexamethasone with or without thalidomide as first-line therapy in MM patients eligible for HSCT
• Bosutinib as second- or third-line treatment of Ph+ CML (any phase)
• Brentuximab vedotin for relapsed or refractory systemic anaplastic large-cell lymphoma
• Brentuximab vedotin for relapsed or refractory, CD30+ Hodgkin lymphoma after autologous HSCT or as third-line treatment for patients ineligible for autologous HSCT
• Dasatinib for first-line treatment of chronic phase, Ph+ CML
• Pixantrone for multiply relapsed or refractory B-cell non-Hodgkin lymphoma
• Ponatinib for patients with Ph+ acute lymphoblastic leukemia who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib or characterized by T315I mutation
• Ponatinib for patients with any phase of CML who are ineligible for imatinib or have disease that is resistant or intolerant to dasatinib/nilotinib or characterized by T315I mutation
• Rituximab as maintenance after induction for patients with follicular lymphoma
• Rituximab plus chemotherapy for relapsed or refractory CLL
• Temsirolimus for relapsed or refractory mantle cell lymphoma.
  

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Photo from Business Wire

Researchers say they have identified genetic mutations that can significantly affect treatment outcomes in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

The findings come from a clinical trial in which the team examined whether combining vorinostat with azacitidine could improve survival in patients with AML and MDS.

The results showed no additional benefit with the combination, when compared to azacitidine alone.

However, researchers did find that patients had significantly shorter survival times if they had mutations in CDKN2A, IDH1, or TP53.

“This important trial . . . has rapidly answered the important question of whether combining azacitidine with vorinostat improves outcomes for people with AML and MDS and emphasizes the need for further studies with new drug partners for azacitidine,” said Charles Craddock, DPhil, of the Queen Elizabeth Hospital in Birmingham, UK.

“Importantly, the linked molecular studies have shed new light on which people will benefit most from azacitidine. Furthermore, discovering that the CDKN2A gene mutation affects treatment response may be hugely valuable in helping doctors to design new treatment combinations in the future.”

Dr Craddock and his colleagues reported their discoveries in Clinical Cancer Research.

Previous, smaller trials had suggested that adding vorinostat to treatment with azacitidine could improve outcomes for patients with AML and MDS.

To test this idea, Dr Craddock and his colleagues enrolled 259 patients in the current trial. Most of these patients (n=217) had AML—111 were newly diagnosed, 73 had relapsed AML, and 33 had refractory disease.

The remaining 42 patients had MDS—36 were newly diagnosed, 5 had relapsed MDS, and 1 had refractory disease.

Half of patients (n=130) received azacitidine and vorinostat, and the other half received azacitidine alone (n=129).

In both arms, azacitidine was given at 75 mg/m² on a 5-2-2 schedule, beginning on day 1 of a 28-day cycle for up to 6 cycles. In the combination arm, patients also received vorinostat at 300 mg twice daily for 7 consecutive days, beginning on day 3 of each cycle.

Results

The combination did not significantly improve response rates or survival times.

The overall response rate was 41% in the azacitidine arm and 42% in the combination arm (odds ratio [OR]=1.05, P=0.84).

The rate of compete response (CR)/CR with incomplete count recovery/marrow CR was 22% in the azacitidine arm and 26% in the combination arm (OR=0.82, P=0.49).

The median overall survival (OS) was 9.6 months in the azacitidine arm and 11.0 months in the combination arm (hazard ratio[HR]=1.15, P=0.32).

Impact of mutations

In a multivariable analysis adjusted for all clinical variables, mutations in NPM1 were associated with reduced overall response (OR=8.6, P=0.012).

In another multivariate analysis, mutations in CDKN2A, IDH1, and TP53 were associated with decreased OS. The HRs were 10.0 (P<0.001), 3.6 (P=0.001), and 4.7 (P<0.001), respectively.

The median OS was 4.5 months in patients with CDKN2A mutations and 11.0 months in patients without them.

The median OS was 7.6 months in patients with TP53 mutations and 11.3 months in patients without them.

And the median OS was 5.6 months in patients with IDH1 mutations and 11.1 months in patients without them.

The researchers believe that testing patients newly diagnosed with AML and MDS for CDKN2A, IDH1, and TP53 mutations could help doctors tailor treatment for patients who are less likely to do well.

The team also said the information gleaned from this trial will guide the choice of new drug partners with the potential to increase azacitidine’s clinical activity.

Institute of Pathology

New research has revealed a way in which acute promyelocytic leukemia (APL) cells evade destruction by the immune system.

The study showed how group 2 innate lymphoid cells (ILC2s) are recruited by leukemic cells to suppress an essential anticancer immune response.

Researchers believe this newly discovered immunosuppressive axis likely holds sway in other cancers, and it might be disrupted by therapies already in use to treat other diseases.

Camilla Jandus, MD, PhD, of the Ludwig Institute for Cancer Research in Lausanne, Switzerland, and her colleagues described this research in Nature Communications.

“ILCs are not very abundant in the body, but, when activated, they secrete large amounts of immune factors,” Dr Jandus said. “In this way, they can dictate whether a response will be pro-inflammatory or anti-inflammatory.”

ILC1, 2, and 3 have been shown to play a role in inflammation and autoimmune diseases. However, their role in cancer has remained unclear.

To address that question, Dr Jandus and her colleagues began with the observation that one subtype of the cells, ILC2s, are abnormally abundant and hyperactivated in patients with APL.

The researchers examined ILC2 immunology in patients with active APL and compared it to that of APL patients in remission.

“Our analyses suggest that, in patients with this leukemia, ILC2s are at the beginning of a novel immunosuppressive axis, one that is likely to be active in other types of cancer as well,” Dr Jandus said.

She and her colleagues found that APL cells secrete large quantities of PGD2 and express high levels of B7H6 on their surface. Both of these molecules bind to receptors on ILC2s—CRTH2 and NKp30, respectively—activating the ILC2s and prompting them to secrete interleukin-13 (IL-13).

The IL-13 switches on and expands the population of monocytic myeloid-derived immune cells (M-MDSCs). These cells suppress immune responses and allow leukemic cells to evade immune system attack.

The researchers tested these findings in a mouse model of APL. Like patients, mice with APL displayed abnormal activation of ILC2s and M-MDSCs.

However, interfering with all the signals of the immunosuppressive axis restored anti-cancer immunity and prolonged survival in the mice.

Treating mice with a PGD2 inhibitor, an NKp30-blocking antibody, and an anti-IL-13 antibody resulted in reduced APL cell engraftment and a decrease in PGD2, ILC2s, and M-MDSCs. These mice also had significantly longer survival than untreated control mice (P<0.05).

Dr Jandus and her colleagues noted that antibodies against IL-13 and inhibitors of PGD2 are already in clinical use for other diseases, and antibodies that interfere with NKp30-B7H6 binding are in clinical development.

“We also found that this immunosuppressive axis may be operating in other types of cancer; in particular, prostate cancer,” Dr Jandus said. “We believe that some ILCs, like ILC2s, might suppress immune responses, while others might stimulate them. That’s what we are investigating in other types of tumors now.”

This research was supported by the Novartis Foundation for Medical-Biological Research, Ludwig Cancer Research, the Swiss National Science Foundation, Fondazione San Salvatore, ProFemmes UNIL, Fondation Pierre Mercier pour la Science, the Swiss Cancer League, and the Foundation for the Fight against Cancer.

Institute of Pathology

New research has revealed a way in which acute promyelocytic leukemia (APL) cells evade destruction by the immune system.

The study showed how group 2 innate lymphoid cells (ILC2s) are recruited by leukemic cells to suppress an essential anticancer immune response.

Researchers believe this newly discovered immunosuppressive axis likely holds sway in other cancers, and it might be disrupted by therapies already in use to treat other diseases.

Camilla Jandus, MD, PhD, of the Ludwig Institute for Cancer Research in Lausanne, Switzerland, and her colleagues described this research in Nature Communications.

“ILCs are not very abundant in the body, but, when activated, they secrete large amounts of immune factors,” Dr Jandus said. “In this way, they can dictate whether a response will be pro-inflammatory or anti-inflammatory.”

ILC1, 2, and 3 have been shown to play a role in inflammation and autoimmune diseases. However, their role in cancer has remained unclear.

To address that question, Dr Jandus and her colleagues began with the observation that one subtype of the cells, ILC2s, are abnormally abundant and hyperactivated in patients with APL.

The researchers examined ILC2 immunology in patients with active APL and compared it to that of APL patients in remission.

“Our analyses suggest that, in patients with this leukemia, ILC2s are at the beginning of a novel immunosuppressive axis, one that is likely to be active in other types of cancer as well,” Dr Jandus said.

She and her colleagues found that APL cells secrete large quantities of PGD2 and express high levels of B7H6 on their surface. Both of these molecules bind to receptors on ILC2s—CRTH2 and NKp30, respectively—activating the ILC2s and prompting them to secrete interleukin-13 (IL-13).

The IL-13 switches on and expands the population of monocytic myeloid-derived immune cells (M-MDSCs). These cells suppress immune responses and allow leukemic cells to evade immune system attack.

The researchers tested these findings in a mouse model of APL. Like patients, mice with APL displayed abnormal activation of ILC2s and M-MDSCs.

However, interfering with all the signals of the immunosuppressive axis restored anti-cancer immunity and prolonged survival in the mice.

Treating mice with a PGD2 inhibitor, an NKp30-blocking antibody, and an anti-IL-13 antibody resulted in reduced APL cell engraftment and a decrease in PGD2, ILC2s, and M-MDSCs. These mice also had significantly longer survival than untreated control mice (P<0.05).

Dr Jandus and her colleagues noted that antibodies against IL-13 and inhibitors of PGD2 are already in clinical use for other diseases, and antibodies that interfere with NKp30-B7H6 binding are in clinical development.

“We also found that this immunosuppressive axis may be operating in other types of cancer; in particular, prostate cancer,” Dr Jandus said. “We believe that some ILCs, like ILC2s, might suppress immune responses, while others might stimulate them. That’s what we are investigating in other types of tumors now.”

This research was supported by the Novartis Foundation for Medical-Biological Research, Ludwig Cancer Research, the Swiss National Science Foundation, Fondazione San Salvatore, ProFemmes UNIL, Fondation Pierre Mercier pour la Science, the Swiss Cancer League, and the Foundation for the Fight against Cancer.

Institute of Pathology

New research has revealed a way in which acute promyelocytic leukemia (APL) cells evade destruction by the immune system.

The study showed how group 2 innate lymphoid cells (ILC2s) are recruited by leukemic cells to suppress an essential anticancer immune response.

Researchers believe this newly discovered immunosuppressive axis likely holds sway in other cancers, and it might be disrupted by therapies already in use to treat other diseases.

Camilla Jandus, MD, PhD, of the Ludwig Institute for Cancer Research in Lausanne, Switzerland, and her colleagues described this research in Nature Communications.

“ILCs are not very abundant in the body, but, when activated, they secrete large amounts of immune factors,” Dr Jandus said. “In this way, they can dictate whether a response will be pro-inflammatory or anti-inflammatory.”

ILC1, 2, and 3 have been shown to play a role in inflammation and autoimmune diseases. However, their role in cancer has remained unclear.

To address that question, Dr Jandus and her colleagues began with the observation that one subtype of the cells, ILC2s, are abnormally abundant and hyperactivated in patients with APL.

The researchers examined ILC2 immunology in patients with active APL and compared it to that of APL patients in remission.

“Our analyses suggest that, in patients with this leukemia, ILC2s are at the beginning of a novel immunosuppressive axis, one that is likely to be active in other types of cancer as well,” Dr Jandus said.

She and her colleagues found that APL cells secrete large quantities of PGD2 and express high levels of B7H6 on their surface. Both of these molecules bind to receptors on ILC2s—CRTH2 and NKp30, respectively—activating the ILC2s and prompting them to secrete interleukin-13 (IL-13).

The IL-13 switches on and expands the population of monocytic myeloid-derived immune cells (M-MDSCs). These cells suppress immune responses and allow leukemic cells to evade immune system attack.

The researchers tested these findings in a mouse model of APL. Like patients, mice with APL displayed abnormal activation of ILC2s and M-MDSCs.

However, interfering with all the signals of the immunosuppressive axis restored anti-cancer immunity and prolonged survival in the mice.

Treating mice with a PGD2 inhibitor, an NKp30-blocking antibody, and an anti-IL-13 antibody resulted in reduced APL cell engraftment and a decrease in PGD2, ILC2s, and M-MDSCs. These mice also had significantly longer survival than untreated control mice (P<0.05).

Dr Jandus and her colleagues noted that antibodies against IL-13 and inhibitors of PGD2 are already in clinical use for other diseases, and antibodies that interfere with NKp30-B7H6 binding are in clinical development.

“We also found that this immunosuppressive axis may be operating in other types of cancer; in particular, prostate cancer,” Dr Jandus said. “We believe that some ILCs, like ILC2s, might suppress immune responses, while others might stimulate them. That’s what we are investigating in other types of tumors now.”

This research was supported by the Novartis Foundation for Medical-Biological Research, Ludwig Cancer Research, the Swiss National Science Foundation, Fondazione San Salvatore, ProFemmes UNIL, Fondation Pierre Mercier pour la Science, the Swiss Cancer League, and the Foundation for the Fight against Cancer.