Myelodysplastic Syndrome

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

Peripheral blood stem cell (PBSC) grafts with high doses of CD8 cells were associated with significantly lower relapse risk and improved survival in patients who were treated for hematologic malignancies with reduced-intensity conditioning (RIC) hematopoietic allogeneic stem cell transplantation (allo-HSCT), according to a report online in the Journal of Clinical Oncology.

A multivariate analysis showed that CD8 cell dose was an independent predictor of relapse (adjusted hazard ratio [aHR], 0.43; P = .009), relapse-free survival (aHR, 0.50; P = .006), and overall survival (aHR, 0.57; P = .04). The data showed a linear association between CD8 cell dose and outcomes, and further analysis identified an optimum cutoff of CD8 cell dose (0.72 x 10⁸ CD8 cells per kg) to segregate survival outcomes. Patients who received grafts with CD8 cell doses above the cutoff had significantly improved regression-free and overall survival (P = .005 and P = .007, respectively).

“These findings indicate that improved survival after RIC transplantations could be achieved by optimizing donor selection and PBSC collection to increase the likelihood of mobilizing grafts containing high CD8 cell doses,” wrote Dr. Ran Reshef of the department of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues (Journ. Clin. Onc. 2015 June 8 [doi:10.1200/JCO.2014.60.1203]).

Younger donors were more likely to have CD8 cell doses above the cutoff (CD8^hi), however, only 53% of donors younger than 30 years had CD8^hi grafts. To find methods to predict graft composition during donor screening, the investigators studied 21 randomly selected allo-HSCT donors. They found no correlations between CD8 graft content and clinical variables such as weight, sex, viral serologies, or apheresis parameters. Donors with a higher proportion of CD8 cells donated grafts with higher CD8 cell dose, but the presence of higher CD4 counts negated this. Screening for the relative proportions of CD8 and CD4 cells identifies donors most likely to mobilize CD8^hi grafts.

“This is also a practical consideration because the assay is rapid, is routinely performed in clinical laboratories, and can easily be done at the time of confirmatory HLA [human leukocyte antigen] typing,” the authors noted. Since the relationship between CD8 dose and survival is linear, the higher the dose the better, even if it is below the cutoff.

Previous studies showed conflicting results regarding the outcome of RIC transplantation with younger unrelated donors versus older sibling donors. Donor age inversely correlates with CD8 cell dose, and the results of this study showed that overall survival was significantly better with younger unrelated donors with a CD8^hi graft, compared with older sibling donors (P = .03). No such benefit was observed with younger unrelated donors with CD8^lo grafts (P = .28), indicating the benefit may rely on CD8 cell dose.

The study evaluated 200 patients with hematologic malignancy who underwent allo-HSCT with fludarabine plus busulfan conditioning from 2007 to 2014 at the Abramson Cancer Center, University of Pennsylvania in Philadelphia. The cumulative relapse incidence was 42% at 1 year and 47% at 5 years. The most common diseases in the cohort were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma.

High CD8 dose was associated with an increased, but nonsignificant risk of chronic graft-versus-host disease (GVHD); the risk for nonrelapse mortality was not associated with cell doses.

CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

CHICAGO – Pacritinib, an investigational oral inhibitor of Janus kinase 2 (JAK2), reduced splenomegaly and alleviated other symptoms in patients with myelofibrosis, in a randomized phase III trial reported at the annual meeting of the American Society of Clinical Oncology.

After 24 weeks of treatment, patients in the pacritinib arm were about four times more likely to have a sizable reduction in spleen volume than peers in the best available therapy arm, reported lead study author Dr. Ruben A. Mesa, deputy director of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

Of special note, the drug was not associated with increased anemia or thrombocytopenia. In fact, it was safe in the subset of patients who had thrombocytopenia at baseline, a group currently having an unmet need for treatments because they cannot receive ruxolitinib (Jakafi), a dual JAK1 and JAK2 inhibitor that is associated with thrombocytopenia.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have impact on the disease course,” Dr. Mesa commented. Additionally, the findings warrant studies of combination therapy with other potentially disease-modifying agents in myeloproliferative neoplasms.

“I think pacritinib for myelofibrosis represents an advance in our field,” commented invited discussant Dr. Lloyd E. Damon, a professor of medicine and director of hematologic malignancies and bone marrow transplant at the University of California, San Francisco.

The trial’s findings have a number of implications going forward, he said. “There are several avenues yet to explore with these types of agents; for instance, what is the role of JAK inhibitors in those who are actually JAK2 mutated, and for that matter, those who are actually calreticulin mutated, and for that matter, those for whom there is no known mutation? The JAK inhibitors so far are directed against wild type,” he noted. “And should we be seeking to develop agents which are very specific against JAK gene products that are mutated or calreticulin gene products that are mutated vis-a-vis what we are seeing in the FLT3 inhibitors?”

Session attendee Dr. Harry Erba, a professor of medicine and director of the hematologic malignancy program, University of Alabama at Birmingham, commented, “With ruxolitinib, I’d always assumed that the improvement in quality of life was due to the JAK1 inhibition and decreasing of inflammatory cytokine signaling. In this study, the benefit in terms of the total symptom score was maybe a little bit less robust, comparing two very different studies – only 20% or 25%.”

“I think when it comes to the mechanism of symptom improvement, JAK2 probably still remains a key piece. As we look at the entire portfolio of JAK inhibitors that have been tested, we see improvement in symptoms whether they hit JAK1 or not,” Dr. Mesa replied.

“Was there a difference in the responses between the spleen-related and the more inflammatory-related symptoms?” Dr. Erba further asked. “Also, the other thing I was struck by, with ruxolitinib, it seems to be such a quick response in terms of quality of life and symptoms, and here there just seemed to be a more gradual improvement in time.”

“We did not see a strong difference between spleen- and non–spleen-related improvements,” Dr. Mesa replied, and the majority of responses seen with pacritinib were still “fairly rapid,” occurring within 4-8 weeks.

The CTI-funded trial – known as PERSIST-1 (A Randomized Controlled Phase 3 Study of Oral Pacritinib Versus Best Available Therapy in Patients with Primary Myelofibrosis, Post-Polycythemia Vera Myelofibrosis, or Post–Essential Thrombocythemia Myelofibrosis) – was unique in allowing patients to enroll regardless of platelet count, Dr. Mesa noted.

The patients were randomized in 2:1 ratio to receive pacritinib or best available therapy. The latter typically consisted of off-label agents such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea; ruxolitinib was not permitted. Crossover was allowed, and 79% of patients in the best available therapy arm eventually did go on to receive pacritinib.

Median follow-up was 8.4 months. In intention-to-treat analyses, at 24 weeks, 19.1% of patients in the pacritinib arm had a reduction of at least 35% in spleen volume, compared with only 4.7% in the best available therapy arm (P = .0003). The findings were similar in the subsets with a platelet count of less than 50,000 per microliter (22.9% vs. 0%) and less than 100,000 per microliter (16.7% vs. 0%).

Patients in the pacritinib arm were less likely to die if they had a spleen volume reduction of at least 20%, but longer follow-up is needed to determine if the drug improves survival, according to Dr. Mesa, who disclosed that he receives honoraria from and has a consulting or advisory role with Novartis, and receives research funding from Celgene, CTI, Incyte, and Gilead Sciences.

The proportion of patients having at least a one-half reduction in Total Symptom Score was 24.5% with pacritinib and 6.5% with best available therapy (P < .0001).

“We did not see any significant drug-emergent thrombocytopenia,” Dr. Mesa reported. In fact, among patients who entered the trial with a platelet count of less than 50,000 per microliter, those in the pacritinib arm had a significant, steady improvement in platelet count. “This could be multifactorial, from reduced splenic sequestration amongst other beneficial features,” he proposed

Among patients who were red cell transfusion dependent at baseline, 25.7% in the pacritinib arm achieved transfusion independence, compared with none in the control arm (P = .04).

The most common nonhematologic grade 3 or 4 adverse event with pacritinib was diarrhea (5% vs. 0%), while the most common hematologic grade 3 or 4 adverse event was anemia (16.8% vs. 15.1%).

Dr. Mesa noted that an ongoing sister trial, PERSIST-2, is still open to accrual. “This is a trial exclusively for patients with thrombocytopenia and allows individuals who have previously received JAK inhibitor therapy, with patients being randomized to the dose tested in the PERSIST-1 study or a b.i.d. dosing with similar goals and endpoints,” he elaborated.

Exposure to dexrazoxane among pediatric patients with leukemia or lymphoma did not affect overall mortality during a median follow-up period of 12.6 years, according to a report published online in the Journal of Clinical Oncology.

Aggregated data from three Children’s Oncology Group trials showed that among 1,008 pediatric patients who received treatment with doxorubicin with or without dexrazoxane (DRZ) from 1996 to 2001, exposure to DRZ was not associated with an increased risk of relapse (HR, 0.81; 95% CI, 0.60-1.08) or death (HR, 1.03; 0.73-1.45). Comparing DRZ with non-DRZ treatment groups at 10 years, the cumulative incidence of relapse was 16.1% vs. 19.1% (difference, – 3.0%; 95% CI, – 7.9% to 0.2%) and overall mortality was 12.8% vs. 12.2% (difference, – 0.6%; 95% CI, – 3.5% to 4.7%). The three trials (P9404, P9425, and P9426) evaluated individually likewise did not show significant differences in relapse or mortality rates.

Although studies in adults show a positive effect of DRZ on heart failure rates after anthracycline therapy, concern over DRZ interference with cancer therapies and a possible link to second cancers have limited its use in children and prompted Dr. Eric Chow of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues to assess the effect of DRZ on mortality.

The investigators wrote that DRZ “does not appear to interfere with cancer treatment efficacy, in terms of original cancer mortality or overall risk of relapse. Although the risk for secondary cancer mortality (mainly as a result of AML/MDS [acute myeloid leukemia/myelodysplastic syndrome]) was greater among those exposed to DRZ, the overall number of events was small, and the differences were not statistically significant,” the investigators said. (J. Clin. Oncol. 2015 May 26 [doi:10.1200/JCO.2014.59.4473])

Aggregated data from the three trials shows that the 10-year mortality rate of AML/MDS was 1.4% for those treated with DRZ (seven patients), compared with 0.8% for those treated without DRZ (five patients).

The beneficial effects of DRZ in decreasing the risk of heart failure have been observed in trials of adult patients, but the results for survivors of childhood cancers have been inconclusive because heart failure may develop over a longer time period in children. With the median age of survivors in this study of 24 years, significant differences in cardiac mortality due to DRZ use are not detectable. To evaluate DRZ as a cardioprotectant, a new Children’s Oncology Group study (Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment [HEART]) will determine the cardiovascular health of individuals in the three trials P9404, P9425, and P9426.

“Given that second cancers and symptomatic cardiac disease appear to be by far the two most common categories of serious late effects (in terms of both absolute and relative risks) among long-term childhood cancer survivors as a group … with cumulative incidences of each approaching 20% by age 50 years, any strategy that offers the promise of reduced cardiotoxicity without being offset by second cancers is highly attractive,” Dr. Chow and his associates wrote.

The study was supported by the National Institutes of Health, St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society. Dr. Chow reported having no relevant financial conflicts. Three of his coauthors reported having financial relationships with industry.

Exposure to dexrazoxane among pediatric patients with leukemia or lymphoma did not affect overall mortality during a median follow-up period of 12.6 years, according to a report published online in the Journal of Clinical Oncology.

Aggregated data from three Children’s Oncology Group trials showed that among 1,008 pediatric patients who received treatment with doxorubicin with or without dexrazoxane (DRZ) from 1996 to 2001, exposure to DRZ was not associated with an increased risk of relapse (HR, 0.81; 95% CI, 0.60-1.08) or death (HR, 1.03; 0.73-1.45). Comparing DRZ with non-DRZ treatment groups at 10 years, the cumulative incidence of relapse was 16.1% vs. 19.1% (difference, – 3.0%; 95% CI, – 7.9% to 0.2%) and overall mortality was 12.8% vs. 12.2% (difference, – 0.6%; 95% CI, – 3.5% to 4.7%). The three trials (P9404, P9425, and P9426) evaluated individually likewise did not show significant differences in relapse or mortality rates.

Although studies in adults show a positive effect of DRZ on heart failure rates after anthracycline therapy, concern over DRZ interference with cancer therapies and a possible link to second cancers have limited its use in children and prompted Dr. Eric Chow of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues to assess the effect of DRZ on mortality.

The investigators wrote that DRZ “does not appear to interfere with cancer treatment efficacy, in terms of original cancer mortality or overall risk of relapse. Although the risk for secondary cancer mortality (mainly as a result of AML/MDS [acute myeloid leukemia/myelodysplastic syndrome]) was greater among those exposed to DRZ, the overall number of events was small, and the differences were not statistically significant,” the investigators said. (J. Clin. Oncol. 2015 May 26 [doi:10.1200/JCO.2014.59.4473])

Aggregated data from the three trials shows that the 10-year mortality rate of AML/MDS was 1.4% for those treated with DRZ (seven patients), compared with 0.8% for those treated without DRZ (five patients).

The beneficial effects of DRZ in decreasing the risk of heart failure have been observed in trials of adult patients, but the results for survivors of childhood cancers have been inconclusive because heart failure may develop over a longer time period in children. With the median age of survivors in this study of 24 years, significant differences in cardiac mortality due to DRZ use are not detectable. To evaluate DRZ as a cardioprotectant, a new Children’s Oncology Group study (Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment [HEART]) will determine the cardiovascular health of individuals in the three trials P9404, P9425, and P9426.

“Given that second cancers and symptomatic cardiac disease appear to be by far the two most common categories of serious late effects (in terms of both absolute and relative risks) among long-term childhood cancer survivors as a group … with cumulative incidences of each approaching 20% by age 50 years, any strategy that offers the promise of reduced cardiotoxicity without being offset by second cancers is highly attractive,” Dr. Chow and his associates wrote.

The study was supported by the National Institutes of Health, St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society. Dr. Chow reported having no relevant financial conflicts. Three of his coauthors reported having financial relationships with industry.

Exposure to dexrazoxane among pediatric patients with leukemia or lymphoma did not affect overall mortality during a median follow-up period of 12.6 years, according to a report published online in the Journal of Clinical Oncology.

Aggregated data from three Children’s Oncology Group trials showed that among 1,008 pediatric patients who received treatment with doxorubicin with or without dexrazoxane (DRZ) from 1996 to 2001, exposure to DRZ was not associated with an increased risk of relapse (HR, 0.81; 95% CI, 0.60-1.08) or death (HR, 1.03; 0.73-1.45). Comparing DRZ with non-DRZ treatment groups at 10 years, the cumulative incidence of relapse was 16.1% vs. 19.1% (difference, – 3.0%; 95% CI, – 7.9% to 0.2%) and overall mortality was 12.8% vs. 12.2% (difference, – 0.6%; 95% CI, – 3.5% to 4.7%). The three trials (P9404, P9425, and P9426) evaluated individually likewise did not show significant differences in relapse or mortality rates.

Although studies in adults show a positive effect of DRZ on heart failure rates after anthracycline therapy, concern over DRZ interference with cancer therapies and a possible link to second cancers have limited its use in children and prompted Dr. Eric Chow of the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues to assess the effect of DRZ on mortality.

The investigators wrote that DRZ “does not appear to interfere with cancer treatment efficacy, in terms of original cancer mortality or overall risk of relapse. Although the risk for secondary cancer mortality (mainly as a result of AML/MDS [acute myeloid leukemia/myelodysplastic syndrome]) was greater among those exposed to DRZ, the overall number of events was small, and the differences were not statistically significant,” the investigators said. (J. Clin. Oncol. 2015 May 26 [doi:10.1200/JCO.2014.59.4473])

Aggregated data from the three trials shows that the 10-year mortality rate of AML/MDS was 1.4% for those treated with DRZ (seven patients), compared with 0.8% for those treated without DRZ (five patients).

The beneficial effects of DRZ in decreasing the risk of heart failure have been observed in trials of adult patients, but the results for survivors of childhood cancers have been inconclusive because heart failure may develop over a longer time period in children. With the median age of survivors in this study of 24 years, significant differences in cardiac mortality due to DRZ use are not detectable. To evaluate DRZ as a cardioprotectant, a new Children’s Oncology Group study (Effects of Dexrazoxane Hydrochloride on Biomarkers Associated With Cardiomyopathy and Heart Failure After Cancer Treatment [HEART]) will determine the cardiovascular health of individuals in the three trials P9404, P9425, and P9426.

“Given that second cancers and symptomatic cardiac disease appear to be by far the two most common categories of serious late effects (in terms of both absolute and relative risks) among long-term childhood cancer survivors as a group … with cumulative incidences of each approaching 20% by age 50 years, any strategy that offers the promise of reduced cardiotoxicity without being offset by second cancers is highly attractive,” Dr. Chow and his associates wrote.

The study was supported by the National Institutes of Health, St. Baldrick’s Foundation, and the Leukemia and Lymphoma Society. Dr. Chow reported having no relevant financial conflicts. Three of his coauthors reported having financial relationships with industry.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

Chromosomes in red with

telomeres in green

Image by Claus Azzalin

New research has revealed a direct link between telomere degeneration and myelodysplastic syndromes (MDS).

“MDS risk correlates with advancing age, therapy-induced DNA damage, and/or shorter telomeres, but whether telomere erosion directly causes MDS is unknown,” said Simona Colla, PhD, of the MD Anderson Cancer Center in Houston, Texas.

“Our study provided genetic evidence that DNA damage caused by telomere loss is linked to this disorder.”

Dr Colla and her colleagues described this study in Cancer Cell.

The team’s in vitro and in vivo work showed that DNA damage caused by dysfunctional telomeres resulted in repressed expression of the gene SRSF2.

SRSF2 is an RNA splicing gene that plays a role in cellular processes. This change impacted common myeloid progenitors (CMPs), affecting their ability to differentiate or fully mature.

“This study established an intimate link across telomere biology, aberrant RNA splicing, and CMP differentiation,” said Ron DiPinho, MD, also of the MD Anderson Cancer Center.

“This may suggest that strategies to mitigate this DNA damage may be useful for preventing and/or treating MDS.”

Dr Colla added that the researchers’ findings “were consistent with long-standing observations that poor prognosis in MDS correlates strongly with short telomeres and elevated DNA damage in CMP cells.”

“This improved understanding should provide highly specific risk biomarkers for preventing and treating this incurable disease,” she said.

Lenalidomide

Photo courtesy of Celgene

WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.

About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.

Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.

The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.

Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.

Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).

Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).

Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.

The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).

The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.

As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).

Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).

Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.

Lenalidomide

Photo courtesy of Celgene

WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.

About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.

Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.

The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.

Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.

Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).

Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).

Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.

The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).

The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.

As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).

Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).

Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.

Lenalidomide

Photo courtesy of Celgene

WASHINGTON, DC—Results of a phase 3 trial support the use of lenalidomide in patients with lower-risk myelodysplastic syndromes (MDS) without 5q deletion who are unresponsive or refractory to erythropoiesis-stimulating agents (ESAs), according to researchers.

About 27% of patients who received lenalidomide achieved transfusion independence for 8 weeks or more, and about 18% were transfusion-independent for 24 weeks or more.

Valeria Santini, MD, of AOU Careggi in Florence, Italy, and her colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 115). The trial, MDS-005, was supported by Celgene Corporation, the company developing lenalidomide.

The trial was a comparison of lenalidomide and placebo in 239 patients with non-del-5q MDS who had failed treatment with ESAs. The patients were transfusion-dependent and had low- or intermediate-1-risk disease according to the International Prognostic Scoring System.

Patients were randomized 2:1 to receive oral lenalidomide at 10 mg once daily on days 1 to 28 of 28-day cycles (5 mg for patients with creatinine clearance 40 to 60 mL/min) or placebo.

Significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 8 weeks or more—26.9% vs 2.5% (P<0.001).

Likewise, significantly more patients in the lenalidomide arm than in the placebo arm achieved transfusion independence for 24 weeks or more—17.5% vs 0% (P<0.001).

Ninety percent of the lenalidomide-treated patients who achieved transfusion independence for 8 weeks or more responded within 4 cycles of treatment. The median duration of response was 32.9 weeks.

The median follow-up was 1.6 years (range, 0-3.6) in the lenalidomide arm and 1.3 years (range, 0-4.0) in the placebo arm. Within these time periods, patients in the placebo arm were more likely than those who received lenalidomide to progress to acute myeloid leukemia (AML) or to develop second primary malignancies (SPMs).

The AML incidence rate per 100 person-years was 1.91 in the lenalidomide arm and 2.46 in the placebo arm. And the SPM incidence rate per 100 person-years was 2.19 in the lenalidomide arm and 2.27 in the placebo arm.

As expected, treatment-emergent adverse events (AEs) were more common in the lenalidomide arm than in the placebo arm. AEs included neutropenia (64.4% vs 12.7%), thrombocytopenia (39.4% vs 7.6%), diarrhea (42.5% vs 22.8%), constipation (22.5% vs 12.7%), infections (51.9% vs 43%), hemorrhage (20.6% vs 10.1%), hepatic disorders (14.4% vs 5.1%), cardiac arrhythmia (11.3% vs 8.9%), and cutaneous reactions (10% vs 1.3%).

Grade 3-4 AEs in the lenalidomide arm included neutropenia (61.9%), thrombocytopenia (35.6%), infections (14.4%), hepatic disorders (5%), diarrhea (2.5%), hemorrhage (1.9%), deep vein thrombosis (1.9%), cardiac arrhythmia (1.3%), and cutaneous reactions (1.3%).

Based on the results of this trial, Celgene plans to submit a regulatory filing with the US Food and Drug Administration in the second half of 2015. Lenalidomide is not approved in the US to treat patients with non-del-5q MDS.

Micrograph showing MDS

WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.

Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.

However, rigosertib did improve OS in patients with poor prognosis.

Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).

The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).

Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.

The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.

The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.

The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).

On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).

For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).

And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).

The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.

Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.

Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).

Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.

Micrograph showing MDS

WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.

Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.

However, rigosertib did improve OS in patients with poor prognosis.

Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).

The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).

Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.

The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.

The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.

The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).

On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).

For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).

And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).

The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.

Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.

Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).

Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.

Micrograph showing MDS

WASHINGTON, DC—A small-molecule inhibitor can improve overall survival (OS) in certain patients with previously treated myelodysplastic syndromes (MDS), results of a phase 3 trial suggest.

Overall, patients who received the dual PI3K/PLK pathway inhibitor rigosertib along with best supportive care (BSC) did not see a significant improvement in OS compared to patients who received BSC alone.

However, rigosertib did improve OS in patients with poor prognosis.

Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston, Texas, and his colleagues presented these results at the 13th International Symposium on Myelodysplastic Syndromes (abstract 112).

The trial, known as ONTIME, was sponsored by Onconova Therapeutics, Inc., the company developing rigosertib.

The trial included 299 higher-risk MDS patients with excess blasts (5% to 30% bone marrow blasts) who had failed to respond to (25%), progressed on (37%), or relapsed after (38%) treatment with hypomethylating agents (HMAs).

Patients were randomized 2:1 to receive rigosertib plus BSC or BSC alone. Patients treated with rigosertib received 1800 mg every 24 hours for 72 hours as a continuous, intravenous, ambulatory infusion, every 2 weeks for the first 16 weeks, then every 4 weeks.

The treatment arms were generally balanced in terms of baseline characteristics. The majority of patients were male (66%) and white (82%). The median age was 74 years. Most patients (85%) had an Eastern Cooperative Oncology Group score of 0 or 1.

The median duration of the last HMA therapy was 8.8 months for patients in the rigosertib arm and 10.3 months for patients in the BSC arm.

The researchers found no significant difference in OS between the treatment arms. The median OS was 8.4 months in the rigosertib arm and 5.9 months in the BSC arm, and the 12-month OS was 35% and 25%, respectively (hazard ratio[HR]=0.87, P=0.31).

On the other hand, certain patients did see a significant improvement in OS with rigosertib. Among patients with primary HMA failure (those who failed to respond to or progressed during HMA therapy), the median OS was 8.6 months in the rigosertib arm and 5.3 months in the BSC arm (HR=0.69, P=0.040).

For patients who received HMAs for less than 9 months, the median OS was 7.7 months in the rigosertib arm and 4.5 months in the BSC arm (HR=0.55, P=0.003). Among patients younger than 75 years of age, the median OS was 9.7 months in the rigosertib arm and 4.1 months in the BSC arm (HR=0.52, P=0.0004).

And for patients with very high-risk disease according to the Revised International Prognostic Scoring System, the median OS was 7.6 months in the rigosertib arm and 3.2 months in the BSC arm (HR=0.56, P=0.005).

The researchers said there were no obvious differences between the treatment arms with regard to overall adverse events (AEs) or grade 3 or higher AEs.

Overall, 99% of patients in the rigosertib arm and 85% in the BSC arm experienced treatment-emergent AEs. The incidence of grade 3 or higher AEs was 79% and 68%, respectively.

Treatment-emergent AEs of all grades—occurring in the rigosertib and BSC arms, respectively—included nausea (35% vs 18%), diarrhea (33% vs 20%), constipation (31% vs 11%), fatigue (30% vs 18%), pyrexia (27% vs 21%), anemia (23% vs 9%), peripheral edema (21% vs 16%), and thrombocytopenia (21% vs 8%).

Considering the study results together, Dr Garcia-Manero and his colleagues concluded that rigosertib is likely most effective in high-risk MDS patients with the worst prognosis, and these patients can safely receive the drug.

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

Micrograph showing MDS

WASHINGTON, DC—An investigational drug can increase hemoglobin levels and eliminate transfusion dependence in patients with lower-risk myelodysplastic syndromes (MDS), results of a phase 2 trial suggest.

The drug, luspatercept, is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the TGF-β superfamily involved in the late stages of erythropoiesis.

Luspatercept regulates late-stage erythrocyte precursor differentiation and maturation.

Uwe Platzbecker, MD, of the University Hospital in Dresden, Germany, presented results from an ongoing phase 2 study of luspatercept at the 13th International Symposium on Myelodysplastic Syndromes (abstract 53).

The trial is supported by Acceleron Pharma Inc. and Celgene Corporation, the companies developing luspatercept.

“We are excited by the results in lower-risk MDS patients, which confirm and extend our previous findings,” Dr Platzbecker said. “Luspatercept may be useful early in the treatment of lower-risk MDS patients, either as the initial treatment for anemia or in patients who do not respond or become refractory to treatment with erythropoiesis-stimulating agents.”

Patient and dosing details

The researchers enrolled 58 patients in this study. Twenty-seven have completed treatment as part of the dose-escalation cohort. These patients received luspatercept at 7 doses ranging from 0.125 mg/kg to 1.75 mg/kg.

Thirty-one patients are still receiving treatment in the expansion cohort. The starting dose in this cohort is 1.0 mg/kg, and patients are receiving individual dose titration up to 1.75 mg/kg. Seventeen patients from this cohort received at least 4 cycles of treatment or discontinued early and were included in the analysis presented at the meeting.

In all, Dr Platzbecker presented results in 44 patients. Their median age was 71 (range, 27-88), and 57% were male. The median time since diagnosis was 2.5 years (range, 0.2-13.6 years). Sixty-one percent of patients had received prior treatment with erythropoiesis-stimulating agents, and 21% had received lenalidomide.

Fifteen patients had a low transfusion burden (LTB), as they received less than 4 units of red blood cells (RBCs) over 8 weeks. For these patients, the median hemoglobin at baseline was 9.0 g/dL (range, 6.8-10.1), and the median number of RBCs transfused over 8 weeks was 2 (range, 2-2).

Twenty-nine patients had a high transfusion burden (HTB) and received 4 or more RBC units over 8 weeks. The median number of RBCs transfused in this group was 6 (range, 4-14).

Fifty percent of patients had low-risk MDS according to IPSS, 46% had intermediate-1-risk disease, and 4% had intermediate-2-risk MDS. Eighty-one percent of patients were positive for ring sideroblasts, and 58% had the SF3B1 splicing mutation.

Efficacy and safety

The study’s primary efficacy endpoint was an increase in hemoglobin and/or a reduction in transfusion use. For LTB patients, the endpoint was a hemoglobin increase of 1.5 g/dL or more for 2 weeks or longer. For HTB patients, it was decrease in transfusion of 4 or more RBC units or a 50% or greater reduction in transfusion over 8 weeks.

Among the 9 patients who received lower doses of luspatercept (0.125-0.5 mg/kg), 33% met the primary efficacy endpoint. And 63% of the 35 patients in the higher dose group (0.75-1.75 mg/kg) achieved the primary efficacy endpoint.

Twenty-two percent of patients in the lower dose group achieved the International Working Group (IWG) hematologic improvement-erythroid (HI-E) threshold of efficacy, as did 54% of patients in the higher dose group.

Fourteen percent of patients in the lower dose group achieved transfusion independence, as did 36% of patients in the higher dose group. In the higher dose group, this included 4 of 6 patients with LTB and 6 of 22 patients with HTB.

Among patients who were ring-sideroblast-positive and received higher doses of luspatercept, 39% achieved transfusion independence, and 63% achieved IWG HI-E.

The majority of adverse events (AEs) were mild to moderate (grade 1 or 2). AEs included nasopharyngitis (14%), diarrhea (14%), myalgia (11%), bone pain (9%), bronchitis (9%), headache (9%), and muscle spasms (9%).

There were 2 serious AEs—grade 3 muscle pain and grade 3 worsening of general condition—that were considered possibly related to treatment. One non-serious grade 3 AE of blast cell count increase was considered possibly treatment-related as well.

In closing, Dr Platzbecker said luspatercept was generally safe and well-tolerated, in addition to providing “robust hematologic improvement.” And these results support further study of the drug in patients with lower-risk MDS.

The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.

The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.

Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.

Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.

Full prescribing information is available at http://tinyurl.com/nspjlek.

[email protected]

The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.

The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.

Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.

Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.

Full prescribing information is available at http://tinyurl.com/nspjlek.

[email protected]

The Food and Drug Administration approved a new formulation of deferasirox as a once-daily oral tablet for iron chelation, Novartis announced.

The product, to be marketed as Jadenu, is indicated for chronic iron overload due to blood transfusions in patients 2 years of age and older, and chronic iron overload in non–transfusion-dependent thalassemia in patients 10 years of age or older. Novartis said it is the only once-daily oral iron chelator that can be swallowed whole, with or without food.

Jadenu is a reformulation of Exjade, a dispersible tablet that must be mixed in liquid and taken on an empty stomach.

The new product received its green light under the FDA’s accelerated approval process based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials, Novartis said.

Nausea, vomiting, diarrhea, stomach pain, increases in kidney laboratory values, and skin rash were the most common side effects reported in deferasirox clinical trials. Novartis warned that the drug may cause serious kidney problems, liver problems, and bleeding in the stomach or intestines, and in some cases, death from these complications. The company added that it is not known if Jadenu is safe or effective when taken with other iron chelation therapy, and controlled clinical trials of deferasirox for patients with myelodysplastic syndromes and chronic iron overload due to blood transfusions have not been performed.

Full prescribing information is available at http://tinyurl.com/nspjlek.

[email protected]

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Colony of iPSCs

Image by James Thomson

A new study has improved researchers’ understanding of a genetic defect associated with myelodysplastic syndromes (MDS), and the team hopes this will ultimately help us correct the defect in patients.

The researchers used induced pluripotent stem cells (iPSCs) to study del(7q), a chromosomal abnormality found in patients with MDS.

This provided the team with new insight into how the deletion contributes to MDS development.

Steven D. Nimer, MD, of the Sylvester Comprehensive Cancer Center at the University of Miami in Florida, and his colleagues described this work in Nature Biotechnology.

To determine how del(7q) contributes to MDS development, the researchers isolated hematopoietic cells from a patient with del(7q) and reprogrammed them into iPSCs. These iPSCs recapitulated MDS-associated phenotypes, including impaired hematopoietic differentiation.

The researchers also showed that, by engineering heterozygous chromosome 7q loss, they could recapitulate in normal iPSCs the characteristics they observed in the del(7q) iPSCs.

So the team was not surprised to find that disease phenotypes were rescued when del(7q) iPSC lines acquired a duplicate copy of chromosome 7q material.

The researchers also found that hemizygosity of chromosome 7q reduced the expression of many genes in the chromosome7q-deleted region. But gene expression was restored upon chromosome 7q dosage correction.

“[W]e were able to pinpoint a region on chromosome 7 that is critical and were able to identify candidate genes residing there that may cause this disease,” said study author Eirini Papapetrou, MD, PhD, of the Icahn School of Medicine at Mount Sinai in New York, New York.

Focusing on hits residing in this region, 7q32.3–7q36.1, the researchers found 10 genes that were enriched (by >1.5-fold) recurrently.

Further investigation confirmed that 4 of these genes—HIPK2, ATP6V0E2, LUC7L2, and EZH2—could partially rescue the emergence of CD45⁺ hematopoietic progenitors when overexpressed in del(7q) iPSCs.

The researchers conducted additional experiments focusing on EZH2 alone and found that haploinsufficiency of EZH2 decreases cells’ hematopoietic potential.

But it seems the hematopoietic defects caused by chromosome 7q hemizygosity are mediated through the haploinsufficiency of EZH2 in combination with 1 or more additional genes, which might include LUC7L2, HIPK2, ATP6V0E2, and/or other genes.

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).

Attendees at ASH 2014

Photo courtesy of ASH

SAN FRANCISCO—Iron chelation therapy significantly improves survival for patients with lower-risk myelodysplastic syndrome (MDS) and delays the progression to acute myeloid leukemia (AML), a new study suggests.

“There is a signal for survival with an impressive difference with chelation therapy,” said study investigator Roger Lyons, MD, of Cancer Care Centers of South Texas in San Antonio.

“If this is real, then everyone with lower-risk MDS will go on chelation therapy upfront.”

Dr Lyons presented the results of this research at the 2014 ASH Annual Meeting (abstract 1350).

He and his colleagues initiated a US registry to collect prospective data on clinical outcomes of patients with lower-risk MDS who received chelation or non-chelation therapy.

The registry enrolled 599 adult patients, with a median age of 76 years, from 107 US centers. The patients had transfusional iron overload with serum ferritin ≥ 1000 µg/L and/or ≥ 20 packed red blood cell units and/or ≥ 6 units every 12 weeks.

Patients were divided into 2 groups: those who had never been chelated and those who had used iron chelation. The researchers also looked at a subgroup of patients: those who received chelation therapy for 6 months or more.

The team evaluated patients every 5 months for 5 years or until death, assessing patient characteristics, survival, disease status, comorbidities, cause of death, and MDS therapy.

At enrollment, the 271 chelated patients had a greater median number of lifetime units transfused compared to the 328 non-chelated patients. Additionally, fewer patients receiving chelation therapy had cardiac, vascular, or endocrine concomitant conditions.

Of the chelated patients, 187 (69%) were chelated with deferasirox, 40 (14.8%) with deferasirox and deferoxamine, and 32 (11.8%) with deferoxamine. For 12 patients (4.5%), the researchers did not know which chelator was used.

The cumulative duration of chelation was 18.9 months in patients who had ever used iron chelation and 27 months in patients with at least 6 months of iron chelation.

Patient outcomes

“From the date of diagnosis, the overall survival for patients receiving chelation therapy was significantly longer than for patients receiving non-chelation therapy, including those with cardiovascular or endocrine concomitant conditions,” Dr Lyons noted.

However, there was a potential clinical bias in patient selection, since patients with longer predicted survival may have been chosen for chelation therapy.

At 5 years of follow-up, the mortality rate was 72.9% for non-chelated patients and 59.4% for patients who received chelation therapy (P=0.0005).

Among patients chelated for 6 months or more, the mortality rate was 56.9% (P=0.0002, compared to non-chelated patients). The most common causes of death were MDS/AML and cardiac conditions.

The time from MDS diagnosis to AML progression was significantly longer for chelated patients than for non-chelated patients—72.1 months and 46.4 months, respectively (P<0.0001).

Among patients chelated for 6 months or more, the time to AML transformation was 78.8 months (P<0.0001, compared to non-chelated patients).

Twice as many patients developed AML in the non-chelation group (n=34, 10.4%) than in the chelation group (n=17, 6.3%). However, this difference was not statistically significant.

Taken together, these results suggest chelation can benefit patients with lower-risk MDS, according to Dr Lyons and his colleagues.

“If you think a lower-risk MDS patient will live 1 or 2 years or is a candidate for transplant, get the patient’s iron levels down by chelation, if possible,” Dr Lyons advised.

Three researchers involved in this study are employed by Novartis, and 1 reported research funding from the company, which manufactures deferasirox (Exjade).