Leukemia, Myelodysplasia, Transplantation

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Doctor evaluating a patient

Photo courtesy of the CDC

Cancer patients have a heightened risk of injuries 16 weeks before and after their diagnosis, according to a large study.

This includes injuries arising from medical complications and treatments, such as infections or bleeding after invasive treatment, and other types of injuries, such as bruising or fractures from self-harm and accidents.

Fang Fang, MD, PhD, of Karolinska Institutet in Stockholm, Sweden, and her colleagues reported these findings in The BMJ.

The researchers analyzed all injury-related hospital admissions in Swedish patients with cancer between 1990 and 2010. The team compared a diagnostic period—16 weeks before and after diagnosis—with a control period the year before diagnosis.

Among 720,901 patients, there were 7306 injuries from medical complications and drug treatments and 8331 injuries from accidents and self-harm that resulted in hospital admission during the diagnostic period.

Patients with central nervous system cancers had the highest risk of medical-related injuries—a 14.7-fold higher risk during the diagnostic period than the control period.

Patients with lymphatic or hematopoietic cancers had a 4-fold higher risk of such injuries during the diagnostic period than during the control period.

Patients who were younger, were cohabiting, had a higher socioeconomic status or education, and had no pre-existing psychiatric disorder had a higher risk of medical-related injuries during the diagnostic period than other groups of patients.

The risk of other types of injuries from self-harm and accidents was also higher during the diagnostic period. There was a 5.3-fold increased risk during the 2 weeks before diagnosis. The researchers said this suggests that psychological stress is high when patients are expecting a diagnosis.

Patients with lymphatic or hematopoietic cancers and patients with central nervous system cancers had the highest risk of self-harm and accidental injuries—a 2.8-fold increased risk during the diagnostic period compared to the control period (for both groups).

Older patients and those with lower socioeconomic status or education had slightly greater increases in the risk of self-harm and accidental injuries compared to other groups.

The researchers said the estimates of risk in this study are conservative because the team did not account for injuries that failed to result in a hospital admission or for those that were fatal.

Furthermore, this was an observational study, so no firm conclusions about cause and effect can be made.

Still, the researchers said this study sheds light on which patients might be at an increased risk of injuries, providing evidence for clinicians and policy makers to develop targeted prevention strategies.

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

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

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

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

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has granted accelerated approval for blinatumomab (Blincyto®) to treat pediatric patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

The approval is based on results from a phase 1/2 study.

Continued approval of blinatumomab for this indication may be contingent upon verification of clinical benefit in subsequent trials.

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

In 2014, blinatumomab received accelerated approval from the FDA to treat adults with Ph- relapsed or refractory BCP-ALL. The FDA has also granted the drug priority review, breakthrough therapy designation, and orphan drug designation.

Blinatumomab is being developed by Amgen. Full prescribing information is available at www.blincyto.com.

‘205 trial

The latest accelerated approval of blinatumomab is based on results from the phase 1/2 ‘205 trial, in which researchers evaluated blinatumomab in 93 pediatric patients with relapsed or refractory BCP-ALL.

Amgen said treatment in this study has been completed, subjects are being monitored for long-term efficacy, and the data will be submitted for publication.

Initial results from this study were presented at ASH 2014. The abstract included data on 39 patients with relapsed/refractory BCP-ALL and a median age of 9 (range, 2-16).

The patients received blinatumomab at a dose of 5-15 µg/m²/day. Nineteen patients completed 1 cycle of blinatumomab, 4 completed 2 cycles, and 2 completed 3 cycles.

During the first 2 treatment cycles, 12 patients achieved a complete response, 5 of whom were negative for minimal residual disease.

Six of the complete responders went on to transplant. The median relapse-free survival for complete responders was 5.6 months.

At 6 months of follow-up, the median overall survival for all 39 patients was 4.3 months.

All of the patients experienced adverse events. The most common were pyrexia (74%), anemia (33%), nausea (31%), headache (28%), hypertension (26%), increased alanine aminotransferase (23%), and cough (21%).

The most common grade 3 or higher events were anemia (26%), pyrexia (21%), increased alanine aminotransferase (18%), increased aspartate aminotransferase (18%), and febrile neutropenia (15%).

Three patients developed cytokine release syndrome (2 grade 3).

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

Ofatumumab (Arzerra)

Photo courtesy of GSK

The US Food and Drug Administration (FDA) has approved the use of ofatumumab (Arzerra®) in combination with fludarabine and cyclophosphamide to treat patients with relapsed chronic lymphocytic leukemia (CLL).

Ofatumumab was previously approved by the FDA for use in combination with chlorambucil to treat previously untreated CLL patients who cannot receive fludarabine-based therapy, as monotherapy for CLL that is refractory to fludarabine and alemtuzumab, and as maintenance therapy for patients who are in complete or partial response after receiving at least 2 lines of therapy for recurrent or progressive CLL.

Ofatumumab is a monoclonal antibody designed to target CD20.

The drug’s prescribing information includes a boxed warning noting that hepatitis B virus reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab. In some cases, this results in fulminant hepatitis, hepatic failure, and death.

The boxed warning also states that progressive multifocal leukoencephalopathy, resulting in death, can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.

Ofatumumab is marketed under a collaboration agreement between Genmab and Novartis.

COMPLEMENT 2 trial

The FDA’s latest approval for ofatumumab is based on results of the phase 3 COMPLEMENT 2 trial. Novartis reported top-line results from this study in April.

The trial enrolled 365 patients with relapsed CLL. The patients were randomized 1:1 to receive up to 6 cycles of ofatumumab in combination with fludarabine and cyclophosphamide or up to 6 cycles of fludarabine and cyclophosphamide alone.

The primary endpoint was progression-free survival, as assessed by an independent review committee.

The median progression-free survival was 28.9 months for patients receiving ofatumumab plus fludarabine and cyclophosphamide, compared to 18.8 months for patients receiving fludarabine and cyclophosphamide alone (hazard ratio=0.67, P=0.0032).

Novartis said the safety profile observed in this study was consistent with other trials of ofatumumab, and no new safety signals were observed.

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

The combination of dasatinib and venetoclax had a synergistic effect that was associated with lower toxicity than single-agent therapy, based on responses of primary Philadelphia chromosome–positive acute lymphoblastic leukemia (PH+ALL) samples in xenografted immunodeficient mice, according to Jessica T. Leonard, MD.

Dr. Leonard and her colleagues at Oregon Health and Science University in Portland demonstrated that the combination of venetoclax – a selective inhibitor of B cell lymphoma 2 – was highly synergistic with tyrosine kinase inhibitors in vitro. In the preclinical model of PH+ALL, a stepwise reduction in median inhibitory concentration of dasatinib was observed with increasing doses of venetoclax, as was decreased cell viability and induced apoptosis. Dasatinib – a breakpoint cluster region–Abelson kinase inhibitor – has an additional advantage of potentially overcoming venetoclax resistance by blocking a common mechanism of resistance to the agent, the investigators reported Aug. 31 in Science Translational Medicine (2016; 8[354]:354ra114).

The combination boosted antitumor activity against Ph+ALL cells grown in culture. In the mouse model of Ph+ALL, all of the mice in the combination dosing group remained alive during the 4-week treatment period. The combination therapy was well tolerated, and superior to either agent alone with respect to antileukemic efficacy.

The investigators focused on combining venetoclax with dasatinib because it is “the current backbone for the treatment of adult Ph+ALL ... These results lay the foundation for the testing of this combination in patients with Ph+ALL with the goal of improving treatment,” they concluded.

This study was supported in part by the Leukemia & Lymphoma Society and the Newman’s Own Foundation. Dr. Leonard reported having no other disclosures, but various coauthors reported receiving research support from, and/or serving as a consultant or scientific advisory board member to Genentech, the maker of venetoclax, and Bristol-Myers Squibb, the maker of dasatinib, as well as numerous other drug companies.

sworcester@frontlinemedcom.com

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

The European Society of Cardiology (ESC) has launched a novel position paper, under the auspices of its Committee for Practice Guidelines, on the cardiac toxicity of anticancer therapies.

The paper is a summary and evaluation of relevant scientific evidence that is intended to assist health professionals in selecting the best strategies for preventing and managing cardiac toxicity in patients with cancer, including leukemia, lymphoma, and multiple myeloma.

The paper was published in European Heart Journal and on the ESC website.

The document reviews the potential cardiovascular complications of anticancer therapies.

The complications are divided into 9 categories: myocardial dysfunction and heart failure, coronary artery disease, valvular disease, arrhythmias, arterial hypertension, thromboembolic disease, peripheral vascular disease and stroke, pulmonary hypertension, and pericardial complications.

For each type of complication, the authors outline which patients are at risk and how to detect and prevent the possible side effects. Recommendations are given on how to treat and follow patients who develop that type of cardiotoxicity.

Cardiotoxicity is detected using electrocardiogram, cardiac imaging, and biomarkers. Prevention and treatment may involve the use of cardioprotective drugs (such as angiotensin converting enzyme inhibitors or beta-blockers) and adopting a healthy lifestyle (eating a healthy diet, not smoking, exercising regularly, and controlling body weight).

Regarding long-term surveillance for cancer survivors, the paper says patients should be informed of their increased risk of cardiovascular disease at the outset of cancer treatment and supported to make lifestyle changes. They should be told to report early signs and symptoms of cardiovascular disease promptly.

The paper also emphasizes the importance of establishing multidisciplinary teams to provide the best care for cancer patients and survivors. These should include cardiologists, oncologists, nurses, and heart failure and imaging specialists. Ultimately, cardio-oncology centers with a structured service are needed.

The authors note that under- or over-diagnosis of cardiovascular disease sometimes results in failure to prevent adverse events or inappropriate interruption of a potentially life-saving anticancer treatment.

“We need to be clear when it’s a must to stop the treatment, when we should reduce the dose, or when we can continue with the therapy,” said author Jose Luis Zamorano, MD, of University Hospital Ramón in Madrid, Spain. “This position paper provides guidance in this area.”

“We hope the paper will increase awareness about heart disease in cancer patients and survivors and stimulate more research in this area,” added author Patrizio Lancellotti, MD, PhD, of University of Liège Hospital in Liège, Belgium.

“More information is needed on when to screen and monitor patients and on the cardiovascular effects of new anticancer therapies.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

The European Society of Cardiology (ESC) has launched a novel position paper, under the auspices of its Committee for Practice Guidelines, on the cardiac toxicity of anticancer therapies.

The paper is a summary and evaluation of relevant scientific evidence that is intended to assist health professionals in selecting the best strategies for preventing and managing cardiac toxicity in patients with cancer, including leukemia, lymphoma, and multiple myeloma.

The paper was published in European Heart Journal and on the ESC website.

The document reviews the potential cardiovascular complications of anticancer therapies.

The complications are divided into 9 categories: myocardial dysfunction and heart failure, coronary artery disease, valvular disease, arrhythmias, arterial hypertension, thromboembolic disease, peripheral vascular disease and stroke, pulmonary hypertension, and pericardial complications.

For each type of complication, the authors outline which patients are at risk and how to detect and prevent the possible side effects. Recommendations are given on how to treat and follow patients who develop that type of cardiotoxicity.

Cardiotoxicity is detected using electrocardiogram, cardiac imaging, and biomarkers. Prevention and treatment may involve the use of cardioprotective drugs (such as angiotensin converting enzyme inhibitors or beta-blockers) and adopting a healthy lifestyle (eating a healthy diet, not smoking, exercising regularly, and controlling body weight).

Regarding long-term surveillance for cancer survivors, the paper says patients should be informed of their increased risk of cardiovascular disease at the outset of cancer treatment and supported to make lifestyle changes. They should be told to report early signs and symptoms of cardiovascular disease promptly.

The paper also emphasizes the importance of establishing multidisciplinary teams to provide the best care for cancer patients and survivors. These should include cardiologists, oncologists, nurses, and heart failure and imaging specialists. Ultimately, cardio-oncology centers with a structured service are needed.

The authors note that under- or over-diagnosis of cardiovascular disease sometimes results in failure to prevent adverse events or inappropriate interruption of a potentially life-saving anticancer treatment.

“We need to be clear when it’s a must to stop the treatment, when we should reduce the dose, or when we can continue with the therapy,” said author Jose Luis Zamorano, MD, of University Hospital Ramón in Madrid, Spain. “This position paper provides guidance in this area.”

“We hope the paper will increase awareness about heart disease in cancer patients and survivors and stimulate more research in this area,” added author Patrizio Lancellotti, MD, PhD, of University of Liège Hospital in Liège, Belgium.

“More information is needed on when to screen and monitor patients and on the cardiovascular effects of new anticancer therapies.”

Cancer patient receiving

chemotherapy

Photo by Rhoda Baer

The European Society of Cardiology (ESC) has launched a novel position paper, under the auspices of its Committee for Practice Guidelines, on the cardiac toxicity of anticancer therapies.

The paper is a summary and evaluation of relevant scientific evidence that is intended to assist health professionals in selecting the best strategies for preventing and managing cardiac toxicity in patients with cancer, including leukemia, lymphoma, and multiple myeloma.

The paper was published in European Heart Journal and on the ESC website.

The document reviews the potential cardiovascular complications of anticancer therapies.

The complications are divided into 9 categories: myocardial dysfunction and heart failure, coronary artery disease, valvular disease, arrhythmias, arterial hypertension, thromboembolic disease, peripheral vascular disease and stroke, pulmonary hypertension, and pericardial complications.

For each type of complication, the authors outline which patients are at risk and how to detect and prevent the possible side effects. Recommendations are given on how to treat and follow patients who develop that type of cardiotoxicity.

Cardiotoxicity is detected using electrocardiogram, cardiac imaging, and biomarkers. Prevention and treatment may involve the use of cardioprotective drugs (such as angiotensin converting enzyme inhibitors or beta-blockers) and adopting a healthy lifestyle (eating a healthy diet, not smoking, exercising regularly, and controlling body weight).

Regarding long-term surveillance for cancer survivors, the paper says patients should be informed of their increased risk of cardiovascular disease at the outset of cancer treatment and supported to make lifestyle changes. They should be told to report early signs and symptoms of cardiovascular disease promptly.

The paper also emphasizes the importance of establishing multidisciplinary teams to provide the best care for cancer patients and survivors. These should include cardiologists, oncologists, nurses, and heart failure and imaging specialists. Ultimately, cardio-oncology centers with a structured service are needed.

The authors note that under- or over-diagnosis of cardiovascular disease sometimes results in failure to prevent adverse events or inappropriate interruption of a potentially life-saving anticancer treatment.

“We need to be clear when it’s a must to stop the treatment, when we should reduce the dose, or when we can continue with the therapy,” said author Jose Luis Zamorano, MD, of University Hospital Ramón in Madrid, Spain. “This position paper provides guidance in this area.”

“We hope the paper will increase awareness about heart disease in cancer patients and survivors and stimulate more research in this area,” added author Patrizio Lancellotti, MD, PhD, of University of Liège Hospital in Liège, Belgium.

“More information is needed on when to screen and monitor patients and on the cardiovascular effects of new anticancer therapies.”

Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.

“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.

Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).

Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.

The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.

Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.

The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.

Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.

“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.

Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).

Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.

The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.

Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.

The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.

Extramedullary disease is common in newly diagnosed acute myeloid leukemia, and frequently occurs in at least two sites, but is not an independent prognostic factor for overall survival, according to an analysis of 11 clinical trials.

“Importantly, the presence of extramedullary disease should not affect the choice of post-remission therapy,” concluded Dr. Chezi Ganzel of Shaare Zedek Medical Center, Jerusalem, Israel, together with his associates on behalf of the ECOG-ACRIN Cancer Research Group.

Extramedullary disease was found in anywhere from 2% to 30% of AML patients in past studies, and its prognostic impact was “unfavorable in some reports, but not in others,” the investigators noted. To help clarify the issue, they studied patients aged 15 years and up with newly diagnosed AML from 11 clinical trials conducted between 1980 and 2008. The initial study population included 3,522 patients, of which 282 were excluded for having promyelocytic leukemia (168 patients), leukemia that was not AML (29 patieints), no baseline assessment of extramedullary disease (41 patients), no survival data (20 patients), or no eligibility for retrospective central review (24 patients). That left 3,240 patients, of whom 769 (24%) had extramedullary disease. The most commonly involved sites included the lymph nodes (about 12% of patients), spleen (7%), liver (5%), skin (5%), and gingiva (4%). Only 1% of patients had detectable central nervous system involvement. Most (65%) of patients had one site of extramedullary disease, while 21% had two sites, and the rest had more extensive involvement (J Clin Oncol. 2016 Aug 29. doi: 10.1200/JCO.2016.67.1305).

Rates of complete remission were 59.7% overall, 59% among patients with extramedullary disease, and 60% among patients without extramedullary disease, the investigators said. Just as the presence of extramedullary disease did not significantly affect the likelihood of complete remission, nor did any specific site of extramedullary disease, although there was a non-significant trend toward lower rates of complete remission among patients with splenic or gingival involvement.

The median overall survival for the cohort was 1 year. Univariate analyses linked the presence of any extramedullary disease (P = .005) and involvement of the skin (P = .002), spleen (P less than .001), and liver (P less than .001) with shorter overall survival. However, none of these relationships held up in a multivariable analysis that accounted for other significant prognostic factors, including earlier year of registration, older age, high white blood cell count, low platelet count, poor performance status, high cytogenetic risk status, and not achieving a complete remission, said the researchers.“It is possible that individual sites of extramedullary disease are, in fact, associated with poorer prognosis [but that] these patients also have other unfavorable prognostic factors, such as high white blood cell count and unfavorable cytogenetics,” the researchers commented.

Based on this large study, treatment decisions “should be made on the basis of recognized AML prognostic factors, irrespective of the presence of extramedullary disease,” they concluded.

The National Institutes of Health supported the work. Dr. Ganzel had no disclosures.

The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.

These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.

The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10^-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).

The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).

Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).

Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).

In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.

They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.

The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.

The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.

These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.

The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10^-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).

The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).

Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).

Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).

In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.

They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.

The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.

The presence or absence of minimal residual disease predicted progression-free and, to a lesser degree, overall survival among chronic lymphocytic leukemia (CLL) patients who achieved complete or partial remission with six courses of chemoimmunotherapy, based on two randomized phase III trials.

These findings underscore the value of measuring minimal residual disease (MRD) in patients who respond to a defined period of CLL therapy, Dr. Gabor Kovacs of the University of Cologne (Germany) and his associates wrote Aug. 29 in the Journal of Clinical Oncology.

The investigators examined the predictive value of measuring MRD in peripheral blood by using four-color flow cytometry at a threshold of 10^-4 by analyzing data from 554 adult CLL patients who achieved complete or partial remission during two phase III trials – one (CLL8) comparing fludarabine and cyclophosphamide with fludarabine, cyclophosphamide, and rituximab (FCR) and a second (CLL10) comparing FCR with bendamustine plus rituximab (J Clin Oncol. 2016 Aug 29. doi:10.1200/JCO.2016.67.1305).

The median progression-free survival (PFS) after the end of treatment was 61 months for the 34% (186 patients) who attained MRD-negative complete remission (CR), 54 months for the 29% of patients who attained MRD-negative partial remission (PR), 35 months for the 7% of patients who attained MRD-positive CR, and 21 months for the 30% of patients who attained MRD-positive PR. Progression-free survival did not differ significantly between MRD-negative CR and MRD-negative PR patients, but was significantly longer for MRD-negative PR patients than for MRD-positive CR patients (P = .048).

Progression-free survival was even more distinct for MRD-positive CR patients, compared with those who attained MRD-positive PR (P = .002). Overall survival was significantly shorter only when patients had MRD-positive PR rather than MRD-negative CR (72 months vs. not reached, P = .001).

Among the MRD-negative PR patients, 16% had only residual lymphadenopathy, 11% had only bone marrow involvement, 48% had only splenomegaly, and 25% had more than one organ system affected, the researchers noted. Importantly, PFS for MRD-negative PR with residual splenomegaly (63 months) was similar to that for MRD-negative CR (61 months, P = .354).

In contrast, patients with MRD-negative PR and residual lymphadenopathy had shorter PFS than did MRD-negative CR patients (31 months, P = .001). “We hypothesize that residual splenomegaly after chemoimmunotherapy often represents tissue that does not contribute to a subsequent clinical progression,” the researchers commented.

They also noted an important caveat – their findings are only valid for patients who received a defined period of CLL treatment followed by observation (without maintenance), not for patients who are treated indefinitely until progression.

The CLL8 and CLL10 trials were funded by Roche, Mundipharma, and the German Federal Ministry of Education and Research. Dr. Kavocs disclosed support for travel, accommodations, and expenses from Roche and Celgene.

DURBAN, SOUTH AFRICA – The 15 HIV-infected patients who have undergone allogeneic stem-cell transplant for life-threatening hematologic cancers under the auspices of the European EpiStem Consortium have uniformly demonstrated a profound and durable reduction in viral reservoir to a degree that hasn’t been approached by any other investigational cure strategy, Annemarie Wensing, MD, said at the 21st International AIDS Conference.

“We see an enormous reduction in the viral reservoir, and in two patients we cannot find any viable HIV in the blood using ultrasensitive tests. But we don’t know whether these patients are cured because they are still on antiretroviral therapy,” said Dr. Wensing of Utrecht (The Netherlands) University.

Bruce Jancin/Frontline Medical News

Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma are 7-9 times more frequent in HIV-positive patients than in the general population. But allogeneic stem cell transplantation is an even higher-risk treatment in HIV-positive patients with life-threatening leukemia or lymphoma than in the HIV-negative population. Only 6 of the 15 EuroStem patients remain alive. Eight died within 4 months of the procedure and another died 2.5 years post-transplant, all from progression of their cancer or as a result of opportunistic infections arising during the immunosuppressive chemoablation that’s central to stem-cell transplantation. However, 3 of the 15 patients have survived longer than 3 years. In two of them, no HIV can be detected in blood or intestinal tissue using ultrasensitive tests, while in the third there is “only a slight trace,” according to Dr. Wensing, a clinical virologist.

EpiStem (the European Project to Guide and Investigate the Potential for HIV Cure by Stem-Cell Transplantation) is a multinational collaboration of European oncologists, infectious disease physicians, and other specialists. It was formed in response to the successful outcome of allogeneic stem cell transplantation for acute myeloid leukemia in HIV-positive Timothy Brown, more famously known as “the Berlin patient” (N Engl J Med. 2009 Feb 12;360(7):692-8). He has thus far survived 7 years off antiretroviral therapy.

Much has been made of the fact that Mr. Brown’s donor cells were homozygous for the CCR5 delta32 mutation, which confers natural resistance to HIV infection because it prevents the virus from infecting T cells. Only 1% or less of the population is homozygous for this mutation. But Dr. Wensing isn’t convinced that using donor cells with the mutation is a prerequisite for success. Indeed, while 4 of the 15 EpiStem patients received stem cells from donors homozygous for the mutation and another got donor cells heterozygous for the CCR5 delta32 mutation, the other 10 received stem cells capable of being infected by HIV – yet all 15 experienced an enormous reduction in their viral reservoir. And two of the three patients who have survived longer than 3 years got stem cells without the CCR5 delta32 mutation.

Dr. Wensing observed that a common denominator shared by Timothy Brown and the two EpiStem patients who have trace or undetectable HIV in blood or tissue samples more than 3 years post-transplant is that all three developed severe graft-versus-host disease in conjunction with their stem cell transplantation. She suspects this may have helped them to clear the infection, a hypothesis she intends to pursue further as EpiStem gathers more patients.

Eventually, if patients continue to test negative for HIV using ultrasensitive tests, it will be time to have a discussion with patients and their treating physicians as to whether they should continue on antiretroviral therapy.

“In the end it’s the patients’ decision, but they should be very well counseled because it can have medical and also psychological consequences if HIV returns,” she said.

EpiStem is funded by the American Foundation for AIDS Research Conssortium on HIV Eradication. Dr. Wensing reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – The 15 HIV-infected patients who have undergone allogeneic stem-cell transplant for life-threatening hematologic cancers under the auspices of the European EpiStem Consortium have uniformly demonstrated a profound and durable reduction in viral reservoir to a degree that hasn’t been approached by any other investigational cure strategy, Annemarie Wensing, MD, said at the 21st International AIDS Conference.

“We see an enormous reduction in the viral reservoir, and in two patients we cannot find any viable HIV in the blood using ultrasensitive tests. But we don’t know whether these patients are cured because they are still on antiretroviral therapy,” said Dr. Wensing of Utrecht (The Netherlands) University.

Bruce Jancin/Frontline Medical News

Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma are 7-9 times more frequent in HIV-positive patients than in the general population. But allogeneic stem cell transplantation is an even higher-risk treatment in HIV-positive patients with life-threatening leukemia or lymphoma than in the HIV-negative population. Only 6 of the 15 EuroStem patients remain alive. Eight died within 4 months of the procedure and another died 2.5 years post-transplant, all from progression of their cancer or as a result of opportunistic infections arising during the immunosuppressive chemoablation that’s central to stem-cell transplantation. However, 3 of the 15 patients have survived longer than 3 years. In two of them, no HIV can be detected in blood or intestinal tissue using ultrasensitive tests, while in the third there is “only a slight trace,” according to Dr. Wensing, a clinical virologist.

EpiStem (the European Project to Guide and Investigate the Potential for HIV Cure by Stem-Cell Transplantation) is a multinational collaboration of European oncologists, infectious disease physicians, and other specialists. It was formed in response to the successful outcome of allogeneic stem cell transplantation for acute myeloid leukemia in HIV-positive Timothy Brown, more famously known as “the Berlin patient” (N Engl J Med. 2009 Feb 12;360(7):692-8). He has thus far survived 7 years off antiretroviral therapy.

Much has been made of the fact that Mr. Brown’s donor cells were homozygous for the CCR5 delta32 mutation, which confers natural resistance to HIV infection because it prevents the virus from infecting T cells. Only 1% or less of the population is homozygous for this mutation. But Dr. Wensing isn’t convinced that using donor cells with the mutation is a prerequisite for success. Indeed, while 4 of the 15 EpiStem patients received stem cells from donors homozygous for the mutation and another got donor cells heterozygous for the CCR5 delta32 mutation, the other 10 received stem cells capable of being infected by HIV – yet all 15 experienced an enormous reduction in their viral reservoir. And two of the three patients who have survived longer than 3 years got stem cells without the CCR5 delta32 mutation.

Dr. Wensing observed that a common denominator shared by Timothy Brown and the two EpiStem patients who have trace or undetectable HIV in blood or tissue samples more than 3 years post-transplant is that all three developed severe graft-versus-host disease in conjunction with their stem cell transplantation. She suspects this may have helped them to clear the infection, a hypothesis she intends to pursue further as EpiStem gathers more patients.

Eventually, if patients continue to test negative for HIV using ultrasensitive tests, it will be time to have a discussion with patients and their treating physicians as to whether they should continue on antiretroviral therapy.

“In the end it’s the patients’ decision, but they should be very well counseled because it can have medical and also psychological consequences if HIV returns,” she said.

EpiStem is funded by the American Foundation for AIDS Research Conssortium on HIV Eradication. Dr. Wensing reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com

DURBAN, SOUTH AFRICA – The 15 HIV-infected patients who have undergone allogeneic stem-cell transplant for life-threatening hematologic cancers under the auspices of the European EpiStem Consortium have uniformly demonstrated a profound and durable reduction in viral reservoir to a degree that hasn’t been approached by any other investigational cure strategy, Annemarie Wensing, MD, said at the 21st International AIDS Conference.

“We see an enormous reduction in the viral reservoir, and in two patients we cannot find any viable HIV in the blood using ultrasensitive tests. But we don’t know whether these patients are cured because they are still on antiretroviral therapy,” said Dr. Wensing of Utrecht (The Netherlands) University.

Bruce Jancin/Frontline Medical News

Non-Hodgkin’s lymphoma and Hodgkin’s lymphoma are 7-9 times more frequent in HIV-positive patients than in the general population. But allogeneic stem cell transplantation is an even higher-risk treatment in HIV-positive patients with life-threatening leukemia or lymphoma than in the HIV-negative population. Only 6 of the 15 EuroStem patients remain alive. Eight died within 4 months of the procedure and another died 2.5 years post-transplant, all from progression of their cancer or as a result of opportunistic infections arising during the immunosuppressive chemoablation that’s central to stem-cell transplantation. However, 3 of the 15 patients have survived longer than 3 years. In two of them, no HIV can be detected in blood or intestinal tissue using ultrasensitive tests, while in the third there is “only a slight trace,” according to Dr. Wensing, a clinical virologist.

EpiStem (the European Project to Guide and Investigate the Potential for HIV Cure by Stem-Cell Transplantation) is a multinational collaboration of European oncologists, infectious disease physicians, and other specialists. It was formed in response to the successful outcome of allogeneic stem cell transplantation for acute myeloid leukemia in HIV-positive Timothy Brown, more famously known as “the Berlin patient” (N Engl J Med. 2009 Feb 12;360(7):692-8). He has thus far survived 7 years off antiretroviral therapy.

Much has been made of the fact that Mr. Brown’s donor cells were homozygous for the CCR5 delta32 mutation, which confers natural resistance to HIV infection because it prevents the virus from infecting T cells. Only 1% or less of the population is homozygous for this mutation. But Dr. Wensing isn’t convinced that using donor cells with the mutation is a prerequisite for success. Indeed, while 4 of the 15 EpiStem patients received stem cells from donors homozygous for the mutation and another got donor cells heterozygous for the CCR5 delta32 mutation, the other 10 received stem cells capable of being infected by HIV – yet all 15 experienced an enormous reduction in their viral reservoir. And two of the three patients who have survived longer than 3 years got stem cells without the CCR5 delta32 mutation.

Dr. Wensing observed that a common denominator shared by Timothy Brown and the two EpiStem patients who have trace or undetectable HIV in blood or tissue samples more than 3 years post-transplant is that all three developed severe graft-versus-host disease in conjunction with their stem cell transplantation. She suspects this may have helped them to clear the infection, a hypothesis she intends to pursue further as EpiStem gathers more patients.

Eventually, if patients continue to test negative for HIV using ultrasensitive tests, it will be time to have a discussion with patients and their treating physicians as to whether they should continue on antiretroviral therapy.

“In the end it’s the patients’ decision, but they should be very well counseled because it can have medical and also psychological consequences if HIV returns,” she said.

EpiStem is funded by the American Foundation for AIDS Research Conssortium on HIV Eradication. Dr. Wensing reported having no financial conflicts regarding her presentation.

bjancin@frontlinemedcom.com

Catriona Jamieson, MD, PhD

Photo courtesy of the University

of California San Diego

Researchers say they have identified RNA-based biomarkers that distinguish normal, aged hematopoietic stem and progenitor cells (HSPCs) from leukemia stem cells (LSCs) associated with secondary acute myeloid leukemia (sAML).

The team believes their discovery may provide a new way to predict leukemic relapse and identify targets for drug development.

Catriona Jamieson, MD, PhD, of the University of California San Diego in La Jolla, and her colleagues described the discovery in Cell Stem Cell.

The researchers noted that age-related hematopoietic stem cell exhaustion and myeloid-lineage skewing promote the transformation of hematopoietic progenitors into therapy-resistant LSCs in sAML. However, the contribution of RNA processing alterations to HSPC aging and LSC generation remains unclear.

With this study, Dr Jamieson and her colleagues discovered RNA splice isoform expression patterns that distinguished normal, aged HSPCs from sAML LSCs.

The team said the aged HSPCs displayed pro-apoptotic BCL2 splice isoform switching, while sAML LSCs favored pro-survival expression of BCL2L1 (BCL-XL).

“These splicing signatures could potentially be used as clinical biomarkers to detect blood stem cells that show signs of early aging or leukemia and to monitor patient responses to treatment,” said study author Leslie Crews, PhD, of the University of California San Diego.

“By being able to distinguish benign from malignant aging based on distinctive RNA splicing patterns, we can develop therapeutic strategies that selectively target leukemia stem cells while sparing normal hematopoietic stem cells,” Dr Jamieson added.

In fact, she and her colleagues were able to show that treatment with a pharmacologic splicing modulator known as 17S-FD-895 could eradicate sAML LSCs while sparing normal HSPCs. The compound reversed pro-survival splice isoform switching and impaired LSC maintenance.

“Our findings show that RNA splicing is a unique therapeutic vulnerability for secondary AML,” Dr Jamieson said. “RNA-splicing-targeted therapies may be a potent and selective way to clear leukemia stem cells and prevent relapse.”

Catriona Jamieson, MD, PhD

Photo courtesy of the University

of California San Diego

Researchers say they have identified RNA-based biomarkers that distinguish normal, aged hematopoietic stem and progenitor cells (HSPCs) from leukemia stem cells (LSCs) associated with secondary acute myeloid leukemia (sAML).

The team believes their discovery may provide a new way to predict leukemic relapse and identify targets for drug development.

Catriona Jamieson, MD, PhD, of the University of California San Diego in La Jolla, and her colleagues described the discovery in Cell Stem Cell.

The researchers noted that age-related hematopoietic stem cell exhaustion and myeloid-lineage skewing promote the transformation of hematopoietic progenitors into therapy-resistant LSCs in sAML. However, the contribution of RNA processing alterations to HSPC aging and LSC generation remains unclear.

With this study, Dr Jamieson and her colleagues discovered RNA splice isoform expression patterns that distinguished normal, aged HSPCs from sAML LSCs.

The team said the aged HSPCs displayed pro-apoptotic BCL2 splice isoform switching, while sAML LSCs favored pro-survival expression of BCL2L1 (BCL-XL).

“These splicing signatures could potentially be used as clinical biomarkers to detect blood stem cells that show signs of early aging or leukemia and to monitor patient responses to treatment,” said study author Leslie Crews, PhD, of the University of California San Diego.

“By being able to distinguish benign from malignant aging based on distinctive RNA splicing patterns, we can develop therapeutic strategies that selectively target leukemia stem cells while sparing normal hematopoietic stem cells,” Dr Jamieson added.

In fact, she and her colleagues were able to show that treatment with a pharmacologic splicing modulator known as 17S-FD-895 could eradicate sAML LSCs while sparing normal HSPCs. The compound reversed pro-survival splice isoform switching and impaired LSC maintenance.

“Our findings show that RNA splicing is a unique therapeutic vulnerability for secondary AML,” Dr Jamieson said. “RNA-splicing-targeted therapies may be a potent and selective way to clear leukemia stem cells and prevent relapse.”

Catriona Jamieson, MD, PhD

Photo courtesy of the University

of California San Diego

Researchers say they have identified RNA-based biomarkers that distinguish normal, aged hematopoietic stem and progenitor cells (HSPCs) from leukemia stem cells (LSCs) associated with secondary acute myeloid leukemia (sAML).

The team believes their discovery may provide a new way to predict leukemic relapse and identify targets for drug development.

Catriona Jamieson, MD, PhD, of the University of California San Diego in La Jolla, and her colleagues described the discovery in Cell Stem Cell.

The researchers noted that age-related hematopoietic stem cell exhaustion and myeloid-lineage skewing promote the transformation of hematopoietic progenitors into therapy-resistant LSCs in sAML. However, the contribution of RNA processing alterations to HSPC aging and LSC generation remains unclear.

With this study, Dr Jamieson and her colleagues discovered RNA splice isoform expression patterns that distinguished normal, aged HSPCs from sAML LSCs.

The team said the aged HSPCs displayed pro-apoptotic BCL2 splice isoform switching, while sAML LSCs favored pro-survival expression of BCL2L1 (BCL-XL).

“These splicing signatures could potentially be used as clinical biomarkers to detect blood stem cells that show signs of early aging or leukemia and to monitor patient responses to treatment,” said study author Leslie Crews, PhD, of the University of California San Diego.

“By being able to distinguish benign from malignant aging based on distinctive RNA splicing patterns, we can develop therapeutic strategies that selectively target leukemia stem cells while sparing normal hematopoietic stem cells,” Dr Jamieson added.

In fact, she and her colleagues were able to show that treatment with a pharmacologic splicing modulator known as 17S-FD-895 could eradicate sAML LSCs while sparing normal HSPCs. The compound reversed pro-survival splice isoform switching and impaired LSC maintenance.

“Our findings show that RNA splicing is a unique therapeutic vulnerability for secondary AML,” Dr Jamieson said. “RNA-splicing-targeted therapies may be a potent and selective way to clear leukemia stem cells and prevent relapse.”

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.

A new therapy combining an anti-c-Kit monoclonal antibody with a CD47 blocker allowed hematopoietic stem cell engraftment in immunocompetent mice without the need for toxic preconditioning using radiation or chemotherapy, according to a report published in Science Translational Medicine.

Until now, hematopoietic stem cell transplantation has required rigorous conditioning regimens to clear out the host’s bone marrow, which can cause lifelong complications. So the procedure has been reserved for patients whose life-threatening disorders justified such toxicity. “Safer and more targeted conditioning protocols could both improve the safety of transplantation and extend the existing clinical utility of this powerful form of cell therapy,” said Akanksha Chhabra, PhD, of the department of blood and marrow transplantation, Stanford (Calif.) University, and her associates.

They assessed the new combined treatment in a series of laboratory and mouse studies. The opsonizing anti-c-Kit monoclonal antibodies induced robust depletion of functional hematopoietic stem cells in immunocompetent mice, which allowed donor stem cells to engraft in these hosts. Adding the T-cell–depleting CD47-antagonists further facilitated immune ablation of host stem cells and progenitor cells. Combined, the two agents eliminated more than 99% of host hematopoietic stem cells in the bone marrow and enabled strong engraftment of the donor stem cells, while avoiding radiation- and chemotherapy-related adverse effects.

The main toxicities that occurred in treated mice were, as expected, reductions in hematologic parameters, especially red blood cell indices. This may be related to a factor in mouse physiology that is not present in humans. But if such toxicities do develop in human subjects, they can be mitigated by careful monitoring and occasional supportive transfusions, Dr. Chhabra and her associates said (Sci Transl Med. 2016;8:351ra105).

These two types of antibodies are already being investigated separately in early-phase clinical trials. If the combined treatment proves effective and safe in humans – a question that awaits further clinical studies – hematopoietic stem cell transplantation might be extended to nonmalignant conditions such as inherited immunodeficiency, inborn errors of metabolism, and hemoglobinopathies. It might also be adapted for use in solid-organ transplants, the researchers added.

This work was supported by the Virginia and D.K. Ludwig Fund for Cancer Research and several other nonprofit organizations, the California Institute for Regenerative Medicine, and the National Institutes of Health. Dr. Chhabra is a coinventor on a patent described in this article, and her associates are cofounders of Forty Seven, the company that licensed the technology for radiation- and chemotherapy-free stem-cell transplantation. Two associates also serve as advisors for Alexo Therapeutics, which develops CD47-based treatments.