Meeting Highlights
American Society of Hematology 56th Annual Meeting and Exposition Walter Alexander
The American Society of Hematology (ASH) 56th Annual Meeting and Exposition took place in San Francisco from December 6 to 9, 2014, with an estimated 26,280 health professionals in attendance. We review studies examining treatment and testing for mantle cell lymphoma, Hodgkin’s lymphoma, human immunodeficiency virus–related lymphoma, myelodysplastic syndrome, and myelofibrosis.
Sustained Remission With the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase 2 Study Report
• Jia Ruan, MD, PhD, Associate Professor of Clinical Medicine, Weill Cornell Medical College, New York, New York Initial and maintenance therapy for mantle cell lymphoma (MCL) with a biologic doublet consisting of lenalidomide and rituximab proved to be safe and active among a typical MCL population, according to Dr. Ruan. The noncytotoxic approach, she added, produced objective responses and meaningful durability. Dr. Ruan noted that MCL is a distinct subtype of nonHodgkin’s lymphoma for which initial treatment is nonstandardized. Chemotherapy, which has generally been the focus of initial treatment of MCL studies, is rarely curative and may not be tolerated by all patients. Lenalidomide is an immunomodulatory compound that targets both the tumor cells directly and the tumor micro environment. In single-agent MCL research, lenalidomide demonstrated an overall response (OR) rate of 28%, with complete responses (CRs) in 8%.1 The OR rate with the combination of lenalidomide and rituximab was 57%, with a 36% CR rate.2 The key eligibility criteria in Dr. Ruan’s study allowed untreated MCL with tumor mass of at least 1.5 cm, low-tointermediate-risk MIPI (Mantle Cell Lymphoma International Prognostic Index), or high-risk MIPI if the candidate declined or was ineligible for chemotherapy. The primary endpoint was OR rate. The study protocol included both an induction phase and a maintenance phase. During the induction phase, lenalidomide was administered at 20 mg daily on days 1 to 21 of a 28-day cycle for a total of 12 cycles, with dose escalation to 25 mg daily if tolerated. Standard-dose rituximab (375 mg/m2) was given weekly four times during cycle 1, then once every other cycle, for a total of nine doses. In the maintenance phase, the lenalidomide dose was 15 mg daily on days 1 to 21 of a 28-day cycle, with rituximab maintenance once every other cycle until disease progression. The author is a freelance medical writer living in New York City.
Among 38 patients enrolled, the median age was 65 years (range, 42 to 86); 71% were male. All had stage III–IV disease, with patients distributed evenly among MIPI low-, intermediate-, and high-risk scores. In the induction phase, three patients developed progressive disease and six remain in treatment; two discontinued with tumor flares. Among 27 patients in the maintenance phase, disease progressed in four and 23 are in treatment. The OR rate was 88.9% among the 36 evaluable patients, with a CR rate of 58.3% and a partial response rate of 30.6%. Median time to partial response was three months and median time to CR was 11 months. Progression-free survival (PFS) and overall survival (OS) at 24 months were 84.6% and 92.4%, respectively. Dr. Ruan observed that responding subjects (complete and partial responses), not surprisingly, were less likely to progress (12.5%) than nonresponders (75.0%, P = 0.02). The incidence and severity of adverse events were generally lower in the maintenance phase than in the induction phase. The rates for neutropenia in the overall trial, for example, were 74% (any) and 50% (grade 3 or higher), while in the maintenance phase they were 50% (any) and 32% (grade 3 or higher). Febrile neutropenia was rare (5% overall, 3% maintenance), and grade 3 or higher nonhematological infections were reported only for pneumonia (8% overall, 5% maintenance). Clinically significant nonhematological adverse events generally occurred only in the first cycle of induction. Hematological adverse events, for the most part, were asymptomatic and did not require transfusion support, Dr. Ruan said, and cytopenias were effectively managed with dose modifications. The hypothesis that a biologic, nonchemotherapy approach would be well tolerated and an active strategy as initial therapy for MCL was confirmed, Dr. Ruan concluded.
The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment Of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin’s Lymphoma • Craig H. Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York “We’ve been transplanting Hodgkin’s lymphoma now for almost 30 years,” said Dr. Moskowitz, “and unfortunately, the progression-free survival rate is fairly stable between 40% and 55%.” Dr. Moskowitz is the lead author of AETHERA, a randomized, placebo-controlled, phase 3 study that was
Vol. 40 No. 2 • February 2015 • P&T 133 ®
Meeting Highlights: American Society of Hematology designed to assess whether brentuximab vedotin consolidation could prevent disease progression after autologous stem cell transplantation (ASCT) in patients at risk for relapse or progression. Brentuximab vedotin, a CD30-directed therapy, was recently approved for management of patients when stem cell transplantation has failed and is now the standard of care in that setting. AETHERA included 329 patients at 78 sites in the United States and Europe randomized to receive 16 cycles of brentuximab vedotin or placebo. Patients in the placebo arm could cross over to brentuximab vedotin after progression. The AETHERA primary endpoint was PFS per independent review. Adverse risk factors were common in the AETHERA cohort, Dr. Moskowitz stressed. More than half of the patients needed more than one salvage therapy to achieve chemosensitive disease (a trait that gives them a 20% to 30% chance of longterm survival), and about 60% did not achieve remission with up-front chemotherapy. Median PFS, the primary endpoint, was 43 months in the brentuximab vedotin group and 24 months in the placebo group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40–0.81; P = 0.001). Two-year PFS was 63% and 51%, respectively, for brentuximab vedotin and placebo. The benefit for brentuximab vedotin was observed across all subgroups. Interim OS was similar between groups (P = 0.62). Dr. Moskowitz pointed out that his analysis was limited by the small number of events and the fact that 85% of placebo patients who progressed crossed over to brentuximab vedotin. These crossovers precluded an OS benefit at one year. When the trial was planned in 2009, median survival in this population was 24 to 28 months, but it has since increased to 42 to 48 months because of the recently available novel agents (including brentuximab and the histone deacetylase and checkpoint inhibitors). Investigators identified five risk factors for adverse outcomes: disease refractory to or relapsed after less than 12 months of front-line therapy; responding to salvage therapy with only stable disease or partial response but not complete response; extranodal disease at pre-ASCT relapse; symptomatic pre-ASCT relapse; and receiving two or more prior salvage therapies. In this study, nearly half of the patients, Dr. Moskowitz said, had at least three of these risk factors. The most common adverse event with brentuximab vedotin, peripheral neuropathy (67% all grades, 13% grade 3) resolved in 85% of patients after discontinuation or dose reduction. Two deaths occurred within 40 days of brentuximab vedotin dosing. “Brentuximab vedotin consolidation therapy is an important therapeutic option for Hodgkin’s lymphoma patients undergoing ASCT to reduce the risk of relapse or progression,” Dr. Moskowitz concluded. He noted that survival curves were flat at 24 months in all relapsed Hodgkin’s lymphoma transplant studies. “So if you’re in remission after two years after a stem cell transplant for Hodgkin’s lymphoma, you are likely to be cured. “The bottom line is that there’s a 20% difference in progression-free survival at two years with this agent. This has never been seen in patients with relapsed or refractory lymphoma,” he added. He predicted that brentuximab vedotin will become the standard of care for this patient population based on the AETHERA results.
134 P&T • ®
February 2015 • Vol. 40 No. 2
Brad S. Kahl, MD, of the University of Wisconsin Hospital and Clinics, the moderator of the ASH press conference, pointed out that AETHERA was the first study to show a significant benefit for a post-transplant strategy.
Autologous Hematopoietic Stem Cell Transplantation in Patients With ChemotherapySensitive, Relapsed/Refractory Human Immunodeficiency Virus–Associated Lymphoma: Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial • Joseph Alvarnas, MD, Associate Clinical Professor, City of Hope Medical Center, Monrovia, California The risks of non-Hodgkin’s lymphoma and Hodgkin’s lymphoma are increased at least 25-fold in patients infected with the human immunodeficiency virus (HIV). Infection with HIV is a long-established exclusion criterion for most autologous hematopoietic stem cell transplantation therapeutic trials. Dr. Alvarnas pointed out that combination antiretroviral treatments introduced in the mid-1990s achieve profound levels of viral suppression, significant recovery of T-cell immunity, and decreased risk of opportunistic infection in HIV patients and more recently in patients with HIV-related lymphoma. Also, autologous hematopoietic stem cell transplantation has been extended to patients with relapsed/persistent HIV-related lymphoma, but this is still largely limited to centers with HIVspecific expertise. The purpose of Dr. Alvarnas’ trial (BMT CTN 0803/AMC071) was to see if this technology could be extended to non specialty centers. Included patients received a modified preparative regimen (modified BEAM—carmustine, etoposide, cytarabine, and melphalan) before transplantation. None of the 43 enrolled patients had any difficulty mobilizing stem cells, Dr. Alvarnas said, and all received blood stem cell grafts. He observed that combination antiretroviral treatments were suspended during administration of the preparative regimen and were resumed after resolution of gastrointestinal toxicities. The trial’s primary endpoint was OS. Twelve-month OS was 86.6% (95% CI, 70.8–94.2%). PFS at 12 months was 82.3% (95% CI, 66.3–91.1%), and the rate of progression at 12 months was 12.5% (95% CI, 4.5–24.8%). Using 151 controls from the Centers for International Bone Marrow Transplant Research (CIBMTR), with matching on age, performance score, disease, and disease stage, investigators conducted a case-matched analysis showing that overall mortality, treatment failure, progression rates, and treatment-related mortality rates were similar between the matched groups. OS (approximately 87% for both) was similar as well (P = 0.56). “Exclusion from clinical trials on the basis of HIV infection alone can no longer be justified,” Dr. Alvarnas concluded. “Patients with chemotherapy-sensitive, relapsed/refractory HIV-related lymphoma may be treated successfully with the modified BEAM regimen.”
Meeting Highlights: American Society of Hematology An Open-Label, Phase 2, Dose-Finding Study Of Sotatercept (ACE-011) in Patients With Low or Intermediate-1-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion
• Rami Komrokji, MD, Clinical Director, Department of Malignant Hematology Moffitt Cancer Center, Tampa, Florida Sotatercept, a novel, first-in-class activin type IIA receptor fusion protein, acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation via a mechanism distinct from that of erythropoietin. In a cohort of lowerrisk, mostly transfusion-dependent myelodysplastic syndrome (MDS) patients refractory to erythrocyte-stimulating agents and other available MDS treatments, sotatercept reduced the need for transfusion and increased hemoglobin levels. In the ongoing dose-finding phase 2 study, 54 MDS patients with anemia received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every three weeks. Patients had anemia requiring two or more red blood cell units via transfusion in the 12 weeks prior to enrollment for hemoglobin levels of 9.0 g/dL or less, and no or weak response to erythropoietin-stimulating agents. Among 53 evaluable patients, 24 (45%) had hematological improvement (International Working Group 2006 criteria). Among the 44 high-tumor-burden patients (four units or more in eight weeks), 19 responded, with a reduction of four or more transfusions during eight weeks. Four achieved red blood cell transfusion independence for 56 days or longer. Among the nine low-transfusion-dependent patients, five (56%) had hemoglobin increases of at least 1.5 g/dL for eight or more weeks and achieved red blood cell transfusion independence for 56 days or longer. Thirty-five patients discontinued sotatercept treatment, 28 for lack of treatment effect. Other causes included treatmentrelated grade 2 hemolytic anemia, grade 3 hypertension, and grade 2 muscular weakness. Sotatercept was generally well tolerated, with 20 patients (37%) experiencing one or more adverse events. The most common were fatigue (11%), headache (9.3%), decreased appetite, and nausea (both 7.4%). Dr. Komrokji noted that further exploration of higher sotatercept dose levels and longer-term treatment are planned. He concluded: “Sotatercept showed promising evidence of clinical activity in this cohort of lower-risk MDS patients who were anemic and refractory to erythrocyte-stimulating agents. It lowered their need for transfusion and increased hemoglobin levels.”
JUMP: Safety and Efficacy of Ruxolitinib in an Open-Label, Multicenter, Single-Arm, ExpandedAccess Study in Patients With Myelofibrosis: an 1144-Patient Update
• Bruno Martino, MD, Azienda Ospedaliera Bianchi-MelacrinoMorelli, Reggio Calabria, Italy
the largest myelofibrosis (MF) cohort treated with ruxolitinib to date. Ruxolitinib, a potent Janus kinase (JAK) 1/JAK2 inhibitor, has demonstrated durable improvements in splenomegaly, MF-related symptoms, and quality-of-life measures for MF patients. It has also been associated with improved survival compared with placebo and best available therapy, Dr. Martino said. He added that JUMP is a phase 3b expanded-access trial for patients in countries without access to ruxolitinib outside of a clinical study. Eligibility criteria included primary or secondary MF classified as high risk, intermediate-2 risk, or intermediate-1 risk with a palpable spleen (5 cm or more from the costal margin). Patients (mean age, 68.0 years) received starting doses of ruxolitinib based on platelet counts at baseline: 5 mg twice daily (50 to less than 100 x 109/L), 15 mg twice daily (100 to less than 200 x 109/L), or 20 mg twice daily (200 or more x 109/L). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional endpoints included a greater than 50% reduction in spleen length; patient-reported outcomes; and PFS, OS, and leukemia-free survival. Most patients achieved a greater than 50% reduction from baseline in palpable spleen length at weeks 24 (55%) and 48 (61%). Twenty-three percent of patients had a spleen that became nonpalpable. Also, 23% and 18% had 25% to 50% reductions in spleen length at weeks 24 and 48, respectively. Among patient-reported outcomes, responses were observed in about 45% of patients on the FACT-L ym (Functional Assessment of Cancer Therapy, Lymphoma) total score and 49% on the FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy, Fatigue) score. Anemia (56.3%; grade 3/4, 33.0%), thrombocytopenia (42.2%; grade 3/4, 12.5%), and neutropenia (5.5%; grade 3/4, 3.8%) were the most common hematological adverse events. Anemia, thrombocytopenia, and neutropenia led to discontinuation in only 2.6%, 3.2%, and 0.3%, respectively. During the study, nine deaths attributable to MF were reported. Serious adverse events occurred in 32.3% of patients, with anemia the most common (4.5%). The most common infections (all grades) occurring in at least 5% of patients were nasopharyngitis (6.3%), urinary tract infections (6.0%), and pneumonia (5.3%). Most nonhematological adverse events were low-grade except for pneumonia, which was reported at grade 3 or higher in 3.6% of patients with a 0.5% discontinuation rate. “The JUMP safety profile is consistent with the other ruxolitinib studies, and the majority of patients experienced clinically meaningful reductions in spleen size and improvements in disease-related symptoms,” Dr. Martini concluded.
REFERENCES 1.
2.
Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractor y to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 2013;31(29):3688–3695. Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 2012;13(7):716–723. n
The ongoing JUMP (JAK Inhibitor RUxolitinib in Myelofibrosis Patients) trial, with 1,144 patients enrolled, has
Vol. 40 No. 2 • February 2015 • P&T 135 ®
American Society of Hematology 56th Annual Meeting and Exposition Walter Alexander
The American Society of Hematology (ASH) 56th Annual Meeting and Exposition took place in San Francisco from December 6 to 9, 2014, with an estimated 26,280 health professionals in attendance. We review studies examining treatment and testing for mantle cell lymphoma, Hodgkin’s lymphoma, human immunodeficiency virus–related lymphoma, myelodysplastic syndrome, and myelofibrosis.
Sustained Remission With the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase 2 Study Report
• Jia Ruan, MD, PhD, Associate Professor of Clinical Medicine, Weill Cornell Medical College, New York, New York Initial and maintenance therapy for mantle cell lymphoma (MCL) with a biologic doublet consisting of lenalidomide and rituximab proved to be safe and active among a typical MCL population, according to Dr. Ruan. The noncytotoxic approach, she added, produced objective responses and meaningful durability. Dr. Ruan noted that MCL is a distinct subtype of nonHodgkin’s lymphoma for which initial treatment is nonstandardized. Chemotherapy, which has generally been the focus of initial treatment of MCL studies, is rarely curative and may not be tolerated by all patients. Lenalidomide is an immunomodulatory compound that targets both the tumor cells directly and the tumor micro environment. In single-agent MCL research, lenalidomide demonstrated an overall response (OR) rate of 28%, with complete responses (CRs) in 8%.1 The OR rate with the combination of lenalidomide and rituximab was 57%, with a 36% CR rate.2 The key eligibility criteria in Dr. Ruan’s study allowed untreated MCL with tumor mass of at least 1.5 cm, low-tointermediate-risk MIPI (Mantle Cell Lymphoma International Prognostic Index), or high-risk MIPI if the candidate declined or was ineligible for chemotherapy. The primary endpoint was OR rate. The study protocol included both an induction phase and a maintenance phase. During the induction phase, lenalidomide was administered at 20 mg daily on days 1 to 21 of a 28-day cycle for a total of 12 cycles, with dose escalation to 25 mg daily if tolerated. Standard-dose rituximab (375 mg/m2) was given weekly four times during cycle 1, then once every other cycle, for a total of nine doses. In the maintenance phase, the lenalidomide dose was 15 mg daily on days 1 to 21 of a 28-day cycle, with rituximab maintenance once every other cycle until disease progression. The author is a freelance medical writer living in New York City.
Among 38 patients enrolled, the median age was 65 years (range, 42 to 86); 71% were male. All had stage III–IV disease, with patients distributed evenly among MIPI low-, intermediate-, and high-risk scores. In the induction phase, three patients developed progressive disease and six remain in treatment; two discontinued with tumor flares. Among 27 patients in the maintenance phase, disease progressed in four and 23 are in treatment. The OR rate was 88.9% among the 36 evaluable patients, with a CR rate of 58.3% and a partial response rate of 30.6%. Median time to partial response was three months and median time to CR was 11 months. Progression-free survival (PFS) and overall survival (OS) at 24 months were 84.6% and 92.4%, respectively. Dr. Ruan observed that responding subjects (complete and partial responses), not surprisingly, were less likely to progress (12.5%) than nonresponders (75.0%, P = 0.02). The incidence and severity of adverse events were generally lower in the maintenance phase than in the induction phase. The rates for neutropenia in the overall trial, for example, were 74% (any) and 50% (grade 3 or higher), while in the maintenance phase they were 50% (any) and 32% (grade 3 or higher). Febrile neutropenia was rare (5% overall, 3% maintenance), and grade 3 or higher nonhematological infections were reported only for pneumonia (8% overall, 5% maintenance). Clinically significant nonhematological adverse events generally occurred only in the first cycle of induction. Hematological adverse events, for the most part, were asymptomatic and did not require transfusion support, Dr. Ruan said, and cytopenias were effectively managed with dose modifications. The hypothesis that a biologic, nonchemotherapy approach would be well tolerated and an active strategy as initial therapy for MCL was confirmed, Dr. Ruan concluded.
The AETHERA Trial: Results of a Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Brentuximab Vedotin in the Treatment Of Patients at Risk of Progression Following Autologous Stem Cell Transplant for Hodgkin’s Lymphoma • Craig H. Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York, New York “We’ve been transplanting Hodgkin’s lymphoma now for almost 30 years,” said Dr. Moskowitz, “and unfortunately, the progression-free survival rate is fairly stable between 40% and 55%.” Dr. Moskowitz is the lead author of AETHERA, a randomized, placebo-controlled, phase 3 study that was
Vol. 40 No. 2 • February 2015 • P&T 133 ®
Meeting Highlights: American Society of Hematology designed to assess whether brentuximab vedotin consolidation could prevent disease progression after autologous stem cell transplantation (ASCT) in patients at risk for relapse or progression. Brentuximab vedotin, a CD30-directed therapy, was recently approved for management of patients when stem cell transplantation has failed and is now the standard of care in that setting. AETHERA included 329 patients at 78 sites in the United States and Europe randomized to receive 16 cycles of brentuximab vedotin or placebo. Patients in the placebo arm could cross over to brentuximab vedotin after progression. The AETHERA primary endpoint was PFS per independent review. Adverse risk factors were common in the AETHERA cohort, Dr. Moskowitz stressed. More than half of the patients needed more than one salvage therapy to achieve chemosensitive disease (a trait that gives them a 20% to 30% chance of longterm survival), and about 60% did not achieve remission with up-front chemotherapy. Median PFS, the primary endpoint, was 43 months in the brentuximab vedotin group and 24 months in the placebo group (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.40–0.81; P = 0.001). Two-year PFS was 63% and 51%, respectively, for brentuximab vedotin and placebo. The benefit for brentuximab vedotin was observed across all subgroups. Interim OS was similar between groups (P = 0.62). Dr. Moskowitz pointed out that his analysis was limited by the small number of events and the fact that 85% of placebo patients who progressed crossed over to brentuximab vedotin. These crossovers precluded an OS benefit at one year. When the trial was planned in 2009, median survival in this population was 24 to 28 months, but it has since increased to 42 to 48 months because of the recently available novel agents (including brentuximab and the histone deacetylase and checkpoint inhibitors). Investigators identified five risk factors for adverse outcomes: disease refractory to or relapsed after less than 12 months of front-line therapy; responding to salvage therapy with only stable disease or partial response but not complete response; extranodal disease at pre-ASCT relapse; symptomatic pre-ASCT relapse; and receiving two or more prior salvage therapies. In this study, nearly half of the patients, Dr. Moskowitz said, had at least three of these risk factors. The most common adverse event with brentuximab vedotin, peripheral neuropathy (67% all grades, 13% grade 3) resolved in 85% of patients after discontinuation or dose reduction. Two deaths occurred within 40 days of brentuximab vedotin dosing. “Brentuximab vedotin consolidation therapy is an important therapeutic option for Hodgkin’s lymphoma patients undergoing ASCT to reduce the risk of relapse or progression,” Dr. Moskowitz concluded. He noted that survival curves were flat at 24 months in all relapsed Hodgkin’s lymphoma transplant studies. “So if you’re in remission after two years after a stem cell transplant for Hodgkin’s lymphoma, you are likely to be cured. “The bottom line is that there’s a 20% difference in progression-free survival at two years with this agent. This has never been seen in patients with relapsed or refractory lymphoma,” he added. He predicted that brentuximab vedotin will become the standard of care for this patient population based on the AETHERA results.
134 P&T • ®
February 2015 • Vol. 40 No. 2
Brad S. Kahl, MD, of the University of Wisconsin Hospital and Clinics, the moderator of the ASH press conference, pointed out that AETHERA was the first study to show a significant benefit for a post-transplant strategy.
Autologous Hematopoietic Stem Cell Transplantation in Patients With ChemotherapySensitive, Relapsed/Refractory Human Immunodeficiency Virus–Associated Lymphoma: Results From the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0803)/AIDS Malignancy Consortium (AMC-071) Trial • Joseph Alvarnas, MD, Associate Clinical Professor, City of Hope Medical Center, Monrovia, California The risks of non-Hodgkin’s lymphoma and Hodgkin’s lymphoma are increased at least 25-fold in patients infected with the human immunodeficiency virus (HIV). Infection with HIV is a long-established exclusion criterion for most autologous hematopoietic stem cell transplantation therapeutic trials. Dr. Alvarnas pointed out that combination antiretroviral treatments introduced in the mid-1990s achieve profound levels of viral suppression, significant recovery of T-cell immunity, and decreased risk of opportunistic infection in HIV patients and more recently in patients with HIV-related lymphoma. Also, autologous hematopoietic stem cell transplantation has been extended to patients with relapsed/persistent HIV-related lymphoma, but this is still largely limited to centers with HIVspecific expertise. The purpose of Dr. Alvarnas’ trial (BMT CTN 0803/AMC071) was to see if this technology could be extended to non specialty centers. Included patients received a modified preparative regimen (modified BEAM—carmustine, etoposide, cytarabine, and melphalan) before transplantation. None of the 43 enrolled patients had any difficulty mobilizing stem cells, Dr. Alvarnas said, and all received blood stem cell grafts. He observed that combination antiretroviral treatments were suspended during administration of the preparative regimen and were resumed after resolution of gastrointestinal toxicities. The trial’s primary endpoint was OS. Twelve-month OS was 86.6% (95% CI, 70.8–94.2%). PFS at 12 months was 82.3% (95% CI, 66.3–91.1%), and the rate of progression at 12 months was 12.5% (95% CI, 4.5–24.8%). Using 151 controls from the Centers for International Bone Marrow Transplant Research (CIBMTR), with matching on age, performance score, disease, and disease stage, investigators conducted a case-matched analysis showing that overall mortality, treatment failure, progression rates, and treatment-related mortality rates were similar between the matched groups. OS (approximately 87% for both) was similar as well (P = 0.56). “Exclusion from clinical trials on the basis of HIV infection alone can no longer be justified,” Dr. Alvarnas concluded. “Patients with chemotherapy-sensitive, relapsed/refractory HIV-related lymphoma may be treated successfully with the modified BEAM regimen.”
Meeting Highlights: American Society of Hematology An Open-Label, Phase 2, Dose-Finding Study Of Sotatercept (ACE-011) in Patients With Low or Intermediate-1-Risk Myelodysplastic Syndromes (MDS) or Non-Proliferative Chronic Myelomonocytic Leukemia (CMML) and Anemia Requiring Transfusion
• Rami Komrokji, MD, Clinical Director, Department of Malignant Hematology Moffitt Cancer Center, Tampa, Florida Sotatercept, a novel, first-in-class activin type IIA receptor fusion protein, acts on late-stage erythropoiesis to increase mature erythrocyte release into the circulation via a mechanism distinct from that of erythropoietin. In a cohort of lowerrisk, mostly transfusion-dependent myelodysplastic syndrome (MDS) patients refractory to erythrocyte-stimulating agents and other available MDS treatments, sotatercept reduced the need for transfusion and increased hemoglobin levels. In the ongoing dose-finding phase 2 study, 54 MDS patients with anemia received subcutaneous sotatercept at dose levels of 0.1, 0.3, 0.5, or 1.0 mg/kg once every three weeks. Patients had anemia requiring two or more red blood cell units via transfusion in the 12 weeks prior to enrollment for hemoglobin levels of 9.0 g/dL or less, and no or weak response to erythropoietin-stimulating agents. Among 53 evaluable patients, 24 (45%) had hematological improvement (International Working Group 2006 criteria). Among the 44 high-tumor-burden patients (four units or more in eight weeks), 19 responded, with a reduction of four or more transfusions during eight weeks. Four achieved red blood cell transfusion independence for 56 days or longer. Among the nine low-transfusion-dependent patients, five (56%) had hemoglobin increases of at least 1.5 g/dL for eight or more weeks and achieved red blood cell transfusion independence for 56 days or longer. Thirty-five patients discontinued sotatercept treatment, 28 for lack of treatment effect. Other causes included treatmentrelated grade 2 hemolytic anemia, grade 3 hypertension, and grade 2 muscular weakness. Sotatercept was generally well tolerated, with 20 patients (37%) experiencing one or more adverse events. The most common were fatigue (11%), headache (9.3%), decreased appetite, and nausea (both 7.4%). Dr. Komrokji noted that further exploration of higher sotatercept dose levels and longer-term treatment are planned. He concluded: “Sotatercept showed promising evidence of clinical activity in this cohort of lower-risk MDS patients who were anemic and refractory to erythrocyte-stimulating agents. It lowered their need for transfusion and increased hemoglobin levels.”
JUMP: Safety and Efficacy of Ruxolitinib in an Open-Label, Multicenter, Single-Arm, ExpandedAccess Study in Patients With Myelofibrosis: an 1144-Patient Update
• Bruno Martino, MD, Azienda Ospedaliera Bianchi-MelacrinoMorelli, Reggio Calabria, Italy
the largest myelofibrosis (MF) cohort treated with ruxolitinib to date. Ruxolitinib, a potent Janus kinase (JAK) 1/JAK2 inhibitor, has demonstrated durable improvements in splenomegaly, MF-related symptoms, and quality-of-life measures for MF patients. It has also been associated with improved survival compared with placebo and best available therapy, Dr. Martino said. He added that JUMP is a phase 3b expanded-access trial for patients in countries without access to ruxolitinib outside of a clinical study. Eligibility criteria included primary or secondary MF classified as high risk, intermediate-2 risk, or intermediate-1 risk with a palpable spleen (5 cm or more from the costal margin). Patients (mean age, 68.0 years) received starting doses of ruxolitinib based on platelet counts at baseline: 5 mg twice daily (50 to less than 100 x 109/L), 15 mg twice daily (100 to less than 200 x 109/L), or 20 mg twice daily (200 or more x 109/L). The primary endpoint was assessment of safety and tolerability of ruxolitinib. Additional endpoints included a greater than 50% reduction in spleen length; patient-reported outcomes; and PFS, OS, and leukemia-free survival. Most patients achieved a greater than 50% reduction from baseline in palpable spleen length at weeks 24 (55%) and 48 (61%). Twenty-three percent of patients had a spleen that became nonpalpable. Also, 23% and 18% had 25% to 50% reductions in spleen length at weeks 24 and 48, respectively. Among patient-reported outcomes, responses were observed in about 45% of patients on the FACT-L ym (Functional Assessment of Cancer Therapy, Lymphoma) total score and 49% on the FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy, Fatigue) score. Anemia (56.3%; grade 3/4, 33.0%), thrombocytopenia (42.2%; grade 3/4, 12.5%), and neutropenia (5.5%; grade 3/4, 3.8%) were the most common hematological adverse events. Anemia, thrombocytopenia, and neutropenia led to discontinuation in only 2.6%, 3.2%, and 0.3%, respectively. During the study, nine deaths attributable to MF were reported. Serious adverse events occurred in 32.3% of patients, with anemia the most common (4.5%). The most common infections (all grades) occurring in at least 5% of patients were nasopharyngitis (6.3%), urinary tract infections (6.0%), and pneumonia (5.3%). Most nonhematological adverse events were low-grade except for pneumonia, which was reported at grade 3 or higher in 3.6% of patients with a 0.5% discontinuation rate. “The JUMP safety profile is consistent with the other ruxolitinib studies, and the majority of patients experienced clinically meaningful reductions in spleen size and improvements in disease-related symptoms,” Dr. Martini concluded.
REFERENCES 1.
2.
Goy A, Sinha R, Williams ME, et al. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractor y to bortezomib: phase II MCL-001 (EMERGE) study. J Clin Oncol 2013;31(29):3688–3695. Wang M, Fayad L, Wagner-Bartak N, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol 2012;13(7):716–723. n
The ongoing JUMP (JAK Inhibitor RUxolitinib in Myelofibrosis Patients) trial, with 1,144 patients enrolled, has
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