Leukemia, Myelodysplasia, Transplantation

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.

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.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

Fred Hutch News Service

Researchers say they have identified potential biomarkers that may be used to help identify patients at an increased risk of neurotoxicity after chimeric antigen receptor (CAR) T-cell therapy.

The team also created an algorithm intended to identify patients whose symptoms were most likely to be life-threatening.

The researchers discovered the biomarkers and developed the algorithm based on data from a trial of JCAR014, an anti-CD19 CAR T-cell therapy, in patients with B-cell malignancies.

Cameron J. Turtle, MBBS, PhD, of Fred Hutchinson Cancer Research Center in Seattle, Washington, and his colleagues described this research in Cancer Discovery.

“It’s essential that we understand the potential side effects of CAR T therapies” Dr Turtle said. “While use of these cell therapies is likely to dramatically increase because they’ve been so effective in patients with resistant or refractory B-cell malignancies, there is still much to learn.”

Dr Turtle and his colleagues sought to provide a detailed clinical, radiological, and pathological characterization of neurotoxicity arising from anti-CD19 CAR T-cell therapy.

So the team analyzed data from a phase 1/2 trial of 133 adults with relapsed and/or refractory CD19+ B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia.

The patients received lymphodepleting chemotherapy followed by an infusion of JCAR014.

Neurotoxicity

Within 28 days of treatment, 53 patients (40%) developed grade 1 or higher neurologic adverse events (AEs), 28 patients (21%) had grade 3 or higher neurotoxicity, and 4 patients (3%) developed fatal neurotoxicity.

Of the 53 patients with any neurologic AE, 48 (91%) also had cytokine release syndrome (CRS). All neurologic AEs in the 5 patients who did not have CRS were mild (grade 1) and transient.

Neurologic AEs included delirium with preserved alertness (66%), headache (55%), language disturbance (34%), decreased level of consciousness (25%), seizures (8%), and macroscopic intracranial hemorrhage (2%).

For most patients, neurotoxicity resolved by day 28 after CAR T-cell infusion. The exceptions were 1 patient in whom a grade 1 neurologic AE resolved 2 months after CAR T-cell infusion and the 4 patients who died of neurotoxicity.

The 4 neurotoxicity-related deaths were due to:

• Acute cerebral edema (n=2)
• Multifocal brainstem hemorrhage and edema associated with disseminated intravascular coagulation (n=1)
• Cortical laminar necrosis with a persistent minimally conscious state until death (n=1).

Potential biomarkers

In a univariate analysis, neurotoxicity was significantly more frequent in patients who:

• Had CRS (P<0.0001)
• Received a high CAR T-cell dose (P<0.0001)
• Had pre-existing neurologic comorbidities at baseline (P=0.0059).

In a multivariable analysis (which did not include CRS as a variable), patients had an increased risk of neurotoxicity if they:

• Had pre-existing neurologic comorbidities (P=0.0023)
• Received cyclophosphamide and fludarabine lymphodepletion (P=0.0259)
• Received a higher CAR T-cell dose (P=0.0009)
• Had a higher burden of malignant CD19+ B cells in the bone marrow (P=0.0165).

The researchers noted that patients who developed grade 3 or higher neurotoxicity had more severe CRS (P<0.0001).

“It appears that cytokine release syndrome is probably necessary for most cases of severe neurotoxicity, but, in terms of what triggers a person with cytokine release syndrome to get neurotoxicity, that’s something we need to investigate further,” said study author Kevin Hay, MD, of Fred Hutchinson Cancer Research Center.

Dr Hay and his colleagues also found that patients with severe neurotoxicity exhibited evidence of endothelial activation, which could contribute to manifestations such as capillary leak, disseminated intravascular coagulation, and disruption of the blood-brain barrier.

Algorithm

The researchers developed a predictive classification tree algorithm to identify patients who have an increased risk of severe neurotoxicity.

The algorithm suggests patients who meet the following criteria in the first 36 hours after CAR T-cell infusion have a high risk of grade 4-5 neurotoxicity:

• Fever of 38.9°C or greater
• Serum levels of IL6 at 16 pg/mL or higher
• Serum levels of MCP1 at 1343.5 pg/mL or higher.

This algorithm predicted severe neurotoxicity with 100% sensitivity and 94% specificity. Eight patients were misclassified, 1 of whom did not subsequently develop grade 2-3 neurotoxicity and/or grade 2 or higher CRS.

Funding

This research was funded by Juno Therapeutics Inc. (the company developing JCAR014), the National Cancer Institute, Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinical Investigator Program, and via institutional funds from Bloodworks Northwest.

Dr Turtle receives research funding from Juno Therapeutics, holds patents licensed by Juno, and has pending patent applications that could be licensed by nonprofit institutions and for-profit companies, including Juno.

The Fred Hutchinson Cancer Research Center has a financial interest in Juno and receives licensing and other payments from the company.

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.

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.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter saying the agency cannot approve MYL-1401H, a proposed biosimilar of pegfilgrastim (Neulasta).

Biocon and Mylan are seeking approval of MYL-1401H to reduce the duration of neutropenia and the incidence of febrile neutropenia in adults receiving chemotherapy to treat non-myeloid malignancies.

Biocon and Mylan filed the biologics license application for MYL-1401H in February.

The FDA had planned to issue a decision on the application by October 9.

Biocon and Mylan said the FDA’s complete response letter relates to a pending update to the application. The update involves chemistry manufacturing and control data from facility requalification activities after recent plant modifications.

The complete response letter did not raise any questions on the biosimilarity of MYL-1401H, pharmacokinetic/pharmacodynamic data, clinical data, or immunogenicity. (Results of a phase 3 study presented at ESMO 2016 Congress suggested MYL-1401H is equivalent to Neulasta.)

Biocon and Mylan said they do not expect the complete response letter for MYL-1401H to impact the commercial launch timing of the drug in the US. The companies said they are committed to working with the FDA to resolve the issues outlined in the letter.

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.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

SAN FRANCISCO – A growing number of immunotherapy options for adults with acute lymphocytic leukemia (ALL) – rituximab, inotuzumab ozogamicin, blinatumomab and chimeric antigen receptor (CAR) T-cell therapy – have improved remission rates, but their collective effects on patient outcomes remain to be seen, David Maloney, MD, PhD, said at the National Comprehensive Cancer Network Annual Congress: Hematologic Malignancies.

The main challenge for the field is deciding when and how to use a variety of therapies, he said. “How are we going to put these together? What’s the order?” he asked. “Are we going to be able to decrease the need for allogeneic stem cell transplant? And, obviously, that’s the goal.”

About 30%-50% of adults with ALL exhibit CD20-positive cells, making them potentially treatable with rituximab. Data show a better event-free survival rate and a reduced relapse rate when rituximab is added to standard chemotherapy as compared with standard chemotherapy alone, Dr. Maloney of the clinical research division at the Fred Hutchinson Cancer Research Center, Seattle, noted (N Engl J Med. 2016 Sep 15;375[11]:1044-53). But the improvement was only “modest,” he said.

The anti-CD22 antibody inotuzumab ozogamicin has produced complete remission in 81% of relapsed or refractory ALL patients, compared with those getting standard therapy (N Engl J Med. 2016 Aug 25;375:740-53). Dr. Maloney said it seems well tolerated, but there is concern about an increase in veno-occlusive disease in patients who have undergone or will undergo an allogeneic stem cell transplant.

Blinatumomab produces moderate response rates and minimal residual disease–negative remissions, but delivery of the drug is “cumbersome,” requiring a 4-week continuous infusion, he said. The drug seems to be more effective in those with a lower burden of disease, he noted.

CAR T-cell therapy has produced MRD-negative complete responses in 94% of patients, based on results from a clinical trial at Fred Hutchinson. And using the chemotherapy drug fludarabine in combination with this therapy “dramatically” boosts the peak number of the CAR T cells and how long they persist, Dr. Maloney said. Still, CAR T-cell therapy is a work-intensive treatment requiring cells harvested from the patient, and the procedure often brings on cytokine-release syndrome and neurotoxicity, though both adverse events are typically reversible, he said.

It may be that using fewer CAR T cells can reduce toxicity without compromising treatment response, he said.

Questions remain over whether to transplant patients who are in remission after CAR T-cell therapy. “This is a hot debate,” he said. The decision will likely depend on their prior therapy, whether they’ve had a prior transplant, and the how robust the CAR T-cell expansion has been, he said.

Dr. Maloney reports financial relationships with Celgene, Gilead Sciences, Kite Pharma, and Roche.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

Photo courtesy of NIH

Primary care may not meet the healthcare needs of cancer survivors in the US, according to research published in JAMA Internal Medicine.

Researchers examined 12 advanced primary care practices selected from a national registry of “workforce innovators” and found that none of these practices had a comprehensive survivorship care program in place.

In addition, there were 3 main barriers to survivorship care—not treating cancer survivors as a distinct population, limitations of electronic health records, and a lack of information and guidance for clinicians.

“This is troubling because these are highly innovative practices that have a national reputation,” said study author Benjamin Crabtree, PhD, of Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

Dr Crabtree and his colleagues evaluated survivorship care* at the 12 practices, which were based in Colorado, Illinois, Maine, New York, Pennsylvania, and Washington.

Over nearly 2 years, the team spent 10 to 12 days observing each of the practices and interviewing clinicians and administrators.

In this way, the researchers identified 3 main barriers to integrating survivorship care into primary medicine.

Barrier 1

The first barrier was that clinicians did not treat cancer survivors as a distinct population or clinical category.

“There is no diagnosis code for ‘cancer survivor’ that can be entered into the medical record, which is important if you want physicians to pay attention,” Dr Crabtree said.

Some of the clinicians interviewed said their care was comprehensive enough to address the needs of all patients. Other clinicians did not understand what survivorship care entails.

Barrier 2

The second barrier was that electronic health record systems didn’t support survivorship care.

Clinicians reported an inability to identify patients with a history of cancer. Even if a patient’s cancer history was included in his or her record, it might take searching through multiple screens to find the information.

In addition, medical records were sometimes lost as patients changed clinicians over the years, which left it up to patients to report their cancer histories.

Barrier 3

The third barrier was that clinicians did not receive adequate information or guidance for follow-up care of cancer survivors.

Although some of the practices received cancer-related information about their patients, it was considered “inadequate” or “not actionable.”

Clinicians expressed concerns about their knowledge gaps in cancer care and the need to monitor changing information in oncology.

“There is nothing in the residency curriculum about cancer survivorship,” Dr Crabtree said. “There is also nothing in Continuing Medical Education courses. It’s just not there.”

Dr Crabtree and his colleagues believe these barriers must be addressed so that comprehensive cancer survivorship services can move to the forefront of primary care.

* Survivorship care includes checking for cancer recurrence, monitoring long-term effects of radiation and chemotherapy, and assessing a patient’s psychological well-being.

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.