The International Peer-Reviewed Journal for The the International Practicing Oncologist/Hematologist. Other Advances in Leukemia/MDS ALL AML MDS

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1 The Oncologist The International Peer-Reviewed Journal for The the International Practicing Oncologist/Hematologist Peer-Reviewed Journal for the Practicing Oncologist/Hematologist 20 th Anniversary Overview 2014 ASH Annual Meeting Overview Focus on CLL Frontline Therapy FCR Remains the Gold Standard Frontline Regimen in a Head-to-Head Challenge Against BR in Medically Fit CLL Rituximab Maintenance Improves Progression- Free Survival After First- or Second-Line Chemoimmunotherapy in CLL Oncologists Are Slow to Incorporate Newly Approved Agents for CLL Into Clinical Practice Relapsed/Refractory CLL Salvage Chemoimmunotherapy With Obinutuzumab Plus Chlorambucil Elicits High Response Rates in Patients With Chlorambucil-Refractory CLL Idelalisib Plus Rituximab Improves Response and Survival in Relapsed CLL Regardless of High-Risk Genomic Abnormalities Ibrutinib Shows Strong Efficacy in Relapsed/Refractory CLL or SLL With Del(17p) Updated Phase III RESONATE Findings Clarify Robust Clinical Activity of Ibrutinib in Relapsed/Refractory CLL Other Advances in Leukemia/MDS ALL Blinatumomab Induces Complete MRD Response in Patients With MRD-Positive ALL AML Vosaroxin Added to Cytarabine Yields Mixed Results in Relapsed/Refractory AML Venetoclax, an Oral BLC-2 Inhibitor, Shows Promising Anti-Leukemic Activity in Relapsed/Refractory AML Novel Oral Agent AG-221 Induces Durable Remissions in Advanced AML MDS Combination Regimens Show No Advantage Over Azacitidine Monotherapy in High-Risk MDS Lenalidomide Poses No Increased Risk of AML Transformation in Patients With MDS Current Prognostic Tools Predict Overall Survival But Not Best Response to Hypomethylating Agents in Patients With Higher-Risk MDS TheOncologist.com The official journal of the Published by

2 when it s time for first-line Cll treatment indication GAZYVA (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). Boxed WArninGs: HePAtitis B VirUs reactivation AnD PrOGressiVe MUltifOCAl leukoencephalopathy Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. screen all patients for HBV infection before treatment initiation. Monitor HBV positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation Progressive Multifocal leukoencephalopathy (PMl) including fatal PMl, can occur in patients receiving GAZYVA Please see the following pages for additional important safety information and brief summary of full Prescribing information, including Boxed WArninGs.

3 The Oncologist The International Peer-Reviewed Journal for the Practicing Oncologist/Hematologist Highlights from 2014 ASH Annual Meeting December 5-9, 2014, in San Francisco, CA Multidisciplinary approaches to the prevention, screening, evaluation, and management of hematologic malignancies. Overview 2014 ASH Annual Meeting Overview Focus on CLL Frontline Therapy FCR Remains the Gold Standard Frontline Regimen in a Head-to-Head Challenge Against BR in Medically Fit CLL Rituximab Maintenance Improves Progression-Free Survival After First- or Second-Line Chemoimmunotherapy in CLL Oncologists Are Slow to Incorporate Newly Approved Agents for CLL Into Clinical Practice Relapsed/Refractory CLL Salvage Chemoimmunotherapy with Obinutuzumab Plus Chlorambucil Elicits High Response Rates in Patients With Chlorambucil-Refractory CLL Idelalisib Plus Rituximab Improves Response and Survival in Relapsed CLL Regardless of High-Risk Genomic Abnormalities Ibrutinib Shows Strong Efficacy in Relapsed/Refractory CLL or SLL With Del(17p) Updated Phase III RESONATE Findings Clarify Robust Clinical Activity of Ibrutinib in Relapsed/Refractory CLL Other Advances in Leukemia/MDS ALL AML MDS Blinatumomab Induces Complete MRD Response in Patients With MRD-Positive ALL Vosaroxin Added to Cytarabine Yields Mixed Results in Relapsed/Refractory AML Venetoclax, an Oral BLC-2 Inhibitor, Shows Promising Anti-Leukemic Activity in Relapsed/Refractory AML Novel Oral Agent AG-221 Induces Durable Remissions in Advanced AML Combination Regimens Show No Advantage Over Azacitidine Monotherapy in High-Risk MDS Lenalidomide Poses No Increased Risk of AML Transformation in Patients With MDS Current Prognostic Tools Predict Overall Survival But Not Best Response to Hypomethylating Agents in Patients With Higher-Risk MDS AlphaMed Press The Oncologist

4 2014 ASH Annual Meeting Overview The 2014 American Society of Hematology (ASH) Annual Meeting, held December 5-9, 2014, in San Francisco, CA, focused on multidisciplinary approaches to the prevention, screening, evaluation, and management of hematologic malignancies. Key themes included the optimal use of established and emerging immunotherapeutic agents, as well as the individualization of therapy based on patient and disease characteristics such as high-risk genetic profiles. Several trials in the area of chronic lymphocytic leukemia (CLL) provided further support for the important role of immunotherapy in managing patients with newly diagnosed CLL and those with relapsed/refractory disease. Updated findings from the CLL11 Study showed that the combination of obinutuzumab plus chlorambucil, which is emerging as a new standard of care in patients with previously untreated CLL, is also active and safe in patients with chlorambucil-refractory CLL. ( Valentin Goede, MD, of the University Hospital Cologne, describes the role of chemoimmunotherapy with obinutuzumab plus chlorambucil in the frontline and salvage settings. ( In the phase III CLL10 Study, frontline treatment with bendamustine and rituximab (BR) failed to improve outcomes for medically fit patients with CLL when compared head-to-head with the gold-standard regimen of fludarabine, cyclophosphamide, and rituximab (FCR). The median progression-free survival (PFS) was 55.2 months in the FCR groups compared with 41.7 months in the BR arm (p <.001). However, the BR regimen demonstrated a milder side effect profile with a similar PFS in the subgroup of patients aged 65 years, suggesting a potential role as an alternative to FCR among older patients. ( New findings from a phase III trial of idelalisib plus rituximab showed the clear clinical benefits of this regimen compared with rituximab alone, including improved ORR, PFS, and overall survival, in patients with relapsed CLL who were unfit for chemotherapy. ( Importantly, idelalisib plus rituximab improved outcomes for all patients regardless of high-risk genetic abnormalities such as del(17p) and TP53 mutation, which are normally associated with poor prognosis. Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and US Oncology Research, described the potential role of idelalisib plus rituximab in the management of frail patients with relapsed CLL. ( bit.ly/d3sharmanv) Three studies provided further insight into the optimal use of ibrutinib in patients with relapsed/refractory CLL. Ibrutinib is currently approved for the treatment of relapsed/refractory CLL and for patients with del(17p) at any line of therapy. Investigators presented two long-term follow-up analyses from the phase III RESONATE trial, which compared ibrutinib with ofatumumab in patients with relapsed/refractory CLL. ( The first updated analysis confirmed a significant survival advantage with ibrutinib compared with ofatumumab, with 18-month OS rates of 85% and 75% in the two treatment groups, respectively (p <.0001). A second analysis demonstrated that ibrutinib enhances the quality of life in patients with relapsed/refractory CLL, with improvements in hematologic function, immunologic function, and patient-reported outcomes such as fatigue. Ibrutinib was also examined in the phase II RESONATE-17 trial of patients with del(17p) CLL or small lymphocytic leukemia (SLL). Single-agent ibrutinib showed robust activity in this patient population, with an ORR of 82.6% and a 12-month PFS rate of 79%. ( ly/s-obrien) The CLL AGMT 8A Mabtenance study provided the first evidence from a randomized phase III trial of a PFS benefit with rituximab maintenance after induction chemoimmunotherapy in patients with CLL. ( Richard Greil, MD, of the Salzburg Cancer Research Institute, described the implications of these interim trial findings on the management of patients with CLL who achieved partial responses or better to rituximab-containing induction therapy in the first- or second-line setting. ( D2GreilV) Treatment options for patients with CLL are rapidly expanding, with the recent approval of three new frontline regimens and evidence from ongoing clinical trials to inform practice. According to results from a national survey of hematology-oncology physicians, BR remains the most commonly selected regimen for frontline CLL treatment. The slow uptake of newly approved frontline regimens such as obinutuzumab plus chlorambucil, ofatumumab plus chlorambucil, and single-agent ibrutinib suggests missed opportunities to provide individualized evidence-based care for patients with newly diagnosed CLL. ( D3Green) One of the most promising new therapies for patients with acute lymphoblastic leukemia (ALL) is blinatumomab, the first FDA-approved agent in a novel class of drugs called bispecific T-cell engagers (BiTE). These immunotherapeutic agents direct cytotoxic T cells to target cells expressing cancer-specific surface proteins such as CD19. In the phase II BLAST trial, one cycle of blinatumomab reduced the level of residual disease by an order of magnitude among patients with ALL who had minimal residual disease (MRD) after prior chemotherapy. ( Nicola Gökbuget, MD, of Goethe University Hospital, described the rationale for using a new clinical trial endpoint, MRD complete response, to examine the anti-leukemic activity of blinatumomab. ( Novel immunotherapeutic agents also showed promising activity in the treatment of acute myelogenous leukemia

5 2 Conference Perspectives: ASH 2014 (AML). Venetoclax (ABT-199) is an oral, selective, potent small molecule inhibitor of B-cell lymphoma 2 (BCL-2). In a phase II study, venetoclax monotherapy was associated with an ORR of 19% in patients with high-risk relapsed/refractory AML and in those who are considered unfit for frontline chemotherapy. ( In the phase III VALOR study, treatment with vosaroxin plus cytarabine showed a nonsignificant trend toward improved survival compared with cytarabine alone in first relapsed or refractory AML. Importantly, the experimental regimen improved complete remission and overall survival compared with cytarabine in the subgroup of patients aged 60 years, suggesting a potential role of vosaroxin in older patients with AML. AG-221, a first-in-class oral inhibitor of mutated IDH2, also exhibited potent anti-leukemia activity in patients with advanced AML and other hematologic malignancies. IDH2 mutations are present in up to 13% of patients with AML and confer gain-of-function status to the gene encoding isocitrate dehydrogenase (IDH), a critical enzyme of the citric acid cycle. In a phase I study (n = 45), treatment with AG-221 induced complete responses in 56% of patients, including 6 complete remissions, and durable responses of 8 months or longer. ( New findings in myelodysplastic syndromes (MDS) include data demonstrating the current status of common MDS prognostic tools in estimating patient survival and response to therapy. ( Amer M. Zeidan, MBBS, MHS, of Yale University, described best practices in the use of MDS prognostic tools in the clinical setting, where estimates of patient survival help to inform patient education. ( In an updated analysis from the phase II Intergroup S1117 trial, there was no advantage to adding vorinostat or lenalidomide to standard frontline treatment with single-agent azacitidine in patients with higher-risk MDS or chronic myelomonocytic leukemia (CMML). The overall response rate (ORR) of 33% for the entire study cohort was similar across all treatment regimens and patient subgroups. ( sekeres) Findings from a retrospective study provided reassurance for patients with MDS regarding the long-term safety of lenalidomide, which poses no increased risk of transformation to AML. ( Dana E. Rollison, PhD, and Rami Komrokji, MD, of the H. Lee Moffitt Cancer Center, discussed the implications of their findings on the selection of treatment for patients with MDS. ( D1RollisonV) New clinical trial findings can shape the management of patients with leukemia and other hematologic malignancies. In an interview with The Oncologist, Timothy Graubert, MD, of Massachusetts General Hospital (MGH) Cancer Center, offered his expert perspective on the above findings and other new research presented at the 2014 ASH annual meeting. ( These key studies are examined in greater depth in this Conference Perspectives report. Related Video Interview with Timothy A. Graubert, MD The Oncologist

6 FCR Remains the Gold Standard Frontline Regimen in a Head-to-Head Challenge Against BR in Medically Fit CLL Frontline treatment with bendamustine and rituximab (BR) failed to outperform the gold-standard regimen of fludarabine, cyclophosphamide, and rituximab (FCR) in medically fit patients with CLL, according to final results from the German CLL Study Group (GCLLSG) CLL10 Study. However, the milder toxicity profile of BR suggests that BR may have a role in the upfront treatment of fit elderly patients and medically unfit patients with advanced CLL. Barbara Eichhorst, MD, of University Hospital in Cologne, Germany, presented the final analysis of the CLL10 Study at the American Society of Hematology (ASH) 2014 Annual Meeting. The phase III CLL10 study was designed to demonstrate the non-inferiority of frontline BR compared to FCR in patients with active CLL without del(17p) who were classified as medically fit (CIRS score 6, creatinine clearance 70 ml/min). Patients were randomly assigned to treatment with six courses of FCR (n = 284) or BR (n = 280). The primary endpoint was progression-free survival (PFS). Frontline FCR improved several clinical endpoints compared with BR, including PFS and complete response (CR) rate. The median PFS was 55.2 months in the FCR group compared with 41.7 months in the BR arm (p <.001). The PFS benefit of FCR compared with BR persisted in patients aged 65 years (53.6 months vs months; p <.001). In contrast, the difference between FCR and BR was no longer statistically significant among patients aged > 65 years (not reached vs months; p =.170). Patients in the FCR group were significantly more likely than those treated with BR to achieve a CR (39.7% vs. 30.8%; p =.034), although the overall response rate was equivalent in each treatment group (95.4% vs. 95.7%; p = 1.0) There was no difference in overall survival between the FCR and BR groups at 36 months (90.6% vs. 92.2%; p =.897). Differences in the toxicity profiles of these regimens favored BR, particularly in older patients. FCR significantly increased the risk of neutropenia (84.2% vs. 59.0%; p <.001), thrombocytopenia (21.5% vs. 14.4%; p =.03), and infection (39.1% vs. 26.8%; p <.001) compared with BR. An assessment of infection risk by patient age showed no difference between the FCR and BR groups among patients aged 65 years (35.2% vs. 27.5%; p =.01). However, for patients aged >65 years, FCR significantly increased the risk of infection more than 2-fold compared with BR (47.7% vs. 20.6%; p <.001). Based on prolonged PFS and higher CR rates compared with BR, FCR remains the standard frontline therapy for medically fit patients with advanced CLL. However, given the milder toxicity profile of BR, frontline BR may be an appropriate alternative to FCR in older patients and in patients who are medically unfit. Source: Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) shows superior efficacy in comparison to bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): Final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 19.

7 Rituximab Maintenance Improves Progression-Free Survival After First- or Second-Line Chemoimmunotherapy in CLL Maintenance therapy with rituximab significantly improves progression-free survival (PFS) compared with observation following induction chemoimmunotherapy for chronic lymphocytic leukemia (CLL), according to a preliminary interim analysis of an ongoing study. These findings provide the first evidence from a randomized phase III trial of a potential benefit from rituximab maintenance therapy in CLL. Richard Greil, MD, of the Salzburg Cancer Research Institute, presented results from the planned interim analysis of the CLL AGMT 8/a Mabtenance trial at the American Society of Hematology (ASH) 2014 Annual Meeting. The international, multicenter, phase III trial enrolled 263 patients who achieved at least a partial response (PR) to any rituximab-containing chemoimmunotherapy induction regimen in the first- or second-line settings. After completing induction therapy, patients with a PR or better were randomly assigned to rituximab maintenance therapy every 3 months (n = 134) or observation (n = 129) for up to 24 months. The primary endpoint was PFS. After a median follow-up of 17.3 months, 85.1% of patients in the rituximab maintenance arm remained free from disease progression, compared with 75.5% of patients in the observation arm (p =.007). The PFS benefit with maintenance rituximab was consistent across all patient subgroups, including those defined by response to last induction (complete vs. partial response), line of treatment (first vs. second line), minimal residual disease status (positive vs. negative), and del(11q), del(17p), and IgVH mutation status (positive vs. negative). Serious infections were more common in the rituximab maintenance arm (15.7%) than in the observation arm (7.0%). Secondary malignancies were also more common following rituximab maintenance (4.5%) than observation (1.6%). Overall, 30.6% of patients in the rituximab group and 20.2% of patients in the observation group reported any serious adverse event. An analysis of event-free survival, which accounted for secondary malignancies, treatment discontinuation due to adverse events, disease progression, and death, also found a significant benefit in favor of rituximab maintenance compared with observation (p =.03). In summary, these interim findings suggest that rituximab maintenance after first- or second-line induction chemoimmunotherapy is a safe treatment strategy that appears to prolong PFS compared with observation alone. Future analyses from the CLL AGMT 8/a Mabtenance trial will clarify the potential role of rituximab maintenance therapy in patients with CLL. Source: Greil R, Obrtlikova P, Smolej L, et al. Rituximab maintenance after chemoimmunotherapy induction in 1st and 2nd line improves progression free survival: planned interim analysis of the international randomized AGMT-CLL8/a Mabtenance trial. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 20. Related Video Interview with Richard Greil, MD

8 Oncologists Are Slow to Incorporate Newly Approved Agents for CLL Into Clinical Practice Despite the approval of three new frontline regimens for chronic lymphocytic leukemia (CLL) within the past year, the majority of oncologists prefer to use bendamustine with or without rituximab (BR) in patients with previously untreated CLL, according to findings from a national survey of hematology-oncology physicians. The prescribing preferences suggest potential missed opportunities to individualize therapy based on poor prognostic factors. Mark R. Green, MD, of Xcenda, LLC, and the Network for Oncology Communication and Research (NOCR), presented findings from the study at the American Society of Hematology (ASH) 2014 Annual Meeting. Between November 2013 and July 2014, the U.S. Food and Drug Administration approved three new regimens for the treatment of patients with previously untreated CLL: Obinutuzumab in combination with chlorambucil Ofatumumab in combination with chlorambucil for patients for whom fludarabine-based therapy is considered inappropriate (previously approved for patients refractory to fludarabine and alemtuzumab) Ibrutinib in patients with CLL with del(17p) (previously approved for patients who had received 1 or more prior therapies) With the availability of new treatment options, clinicians can tailor the selection of therapy for patients with CLL based on prognostic factors, efficacy data, safety profile, patient preferences, and other factors. To understand physician preferences regarding frontline CLL treatment, Dr. Green and colleagues conducted a survey of U.S.-based hematologyoncology physicians (n = 357). In surveys conducted in March and April 2014, physicians were asked to indicate their preferences for first-line CLL treatment across a range of hypothetical patient scenarios varying by patient age, comorbidity burden, laboratory features, and prognostic factors. The hematology-oncology physicians who participated in the survey represented a range of practice settings, including community private practice (54%), community practice at a hospital-owned cancer center (23%), academic medicine (12%), and hospital-based practice (11%). Most physicians (68%) reported seeing at least five new patients with CLL per year. The survey presented one core patient case with three additional variations in patient age, molecular abnormalities, CD38 expression level, and comorbidities to elicit treatment preferences in four representative scenarios of newly diagnosed CLL. Across all four patient case scenarios, BR was the most commonly selected regimen for frontline treatment (43%-67%). Despite evidence of benefit in patients with comorbidities, few physicians selected obinutuzumab plus chlorambucil as their first choice for upfront treatment in scenarios describing a 63-year-old patient with multiple comorbidities (2%-7%) or a 73-year-old patient with multiple comorbidities (8%-17%). To date, ibrutinib is the only agent with a specific indication for frontline treatment in CLL patients with del(17p). In a case scenario describing a 63-year-old patient with del(17p), 22% of physicians selected ibrutinib-based therapy as their first choice for upfront therapy. Other common choices for a patient with del(17p) were BR (43%) and fludarabine, cyclophosphamide, and rituximab (22%). In many cases, physicians chose to delay treatment initiation in patients with CLL. Observation rather than active treatment was the second or third most common choice (10%-14%) for managing three patients without del(17p). Across all four patient scenarios, only 1% of physicians selected ofatumumab plus chlorambucil as their first choice for frontline treatment. In summary, BR remains the most commonly selected first-choice regimen for frontline CLL treatment in realworld clinical practice. Among the agents granted new or expanded indications within the past year, ibrutinib has the highest degree of uptake, with 22% of hematologyoncology physicians selecting ibrutinib as their first choice for treatment in a patient with CLL who harbors the del(17p) mutation. Source: Green MR, Williams ME, Wiley J, et al. First-line prescribing preferences of U.S. hematology-oncology physicians for patients with CLL: impact of novel agents. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 4676.

9 Salvage Chemoimmunotherapy With Obinutuzumab Plus Chlorambucil Elicits High Response Rates in Patients with Chlorambucil-Refractory CLL Obinutuzumab plus chlorambucil is an active salvage regimen in patients with chronic lymphocytic leukemia (CLL) refractory to frontline treatment with chlorambucil alone, according to new subgroup results from the CLL11 study. These findings expand the potential role of chemoimmunotherapy with obinutuzumab plus chlorambucil, which was found to improve overall survival compared with frontline chlorambucil alone in the primary analysis of the CLL11 study. [1] Valentin Goede, MD, of the University Hospital Cologne, presented updated findings from the German CLL Study Group CLL11 Study at the American Society of Hematology (ASH) 2014 Annual Meeting. The current subgroup analysis includes 30 patients who received chlorambucil monotherapy in the CLL11 study and crossed over to salvage therapy with obinutuzumab plus chlorambucil after developing progressive disease within 6 months of completing frontline treatment. Obinutuzumab, an anti-cd20 antibody, was given intravenously at a dose of 100 mg on day 1, 900 mg on day 2, and 1000 mg on day 8 and 15 of the first 28-day cycle, followed by 1000 mg on day 1 of cycles 2-6. Patients also received chlorambucil 0.5 mg/kg on day 1 and day 15 of each cycle. The median patient age was 72 years. Patients had a high comorbidity burden, with a mean cumulative illness rating scale total score of 8 and reduced renal function (mean creatinine clearance, 67 ml/min). Genetic analysis revealed del(11q) in 12% of patients, del(17p) in 20% of patients, and unmutated IGHV genes in 64% of patients. Most patients (93%) crossing over to salvage therapy had not responded to frontline chlorambucil treatment. Two patients demonstrated a transient partial response to chlorambucil monotherapy, but relapsed early (median time from crossover, 9.7 months). The overall response rate was 87%, including complete response (CR) in 7% of patients, incomplete CR in 3% of patients, and partial response in 77% of patients. After crossing over to salvage therapy, 23% of patients achieved minimal residual disease negativity in the bone marrow and/or peripheral blood. The median progression-free survival was 17.2 months from the start of chemoimmunotherapy. The most common grade 3/4 adverse events were neutropenia (33%), infusion-related reactions (17%), infection (13%), thrombocytopenia (10%), and anemia (7%). Although obinutuzumab plus chlorambucil is active when given as salvage therapy in patients with chlorambucilrefractory CLL, overall results from the CLL11 trial provide a strong rationale for giving chemoimmunotherapy upfront rather than later in the treatment sequence. References 1. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370: Source: Goede V, Engelke A, Fischer K, et al. Salvage therapy with obinutuzumab (GA101) plus chlorambucil (Clb) after treatment failure of Clb alone in patients with chronic lymphocytic leukemia (CLL) and comorbidities: results of the CLL11 Study. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract Related Video Interview with Valentin Goede, MD

10 Idelalisib Plus Rituximab Improves Response and Survival in Relapsed CLL Regardless of High-Risk Genomic Abnormalities Idelalisib plus rituximab significantly increases response and survival compared with rituximab alone across all genetic and clinical subgroups in patients with relapsed chronic lymphocytic leukemia (CLL), according to updated findings from an ongoing phase III trial. These findings suggest a role for idelalisib plus rituximab in patients with the del(17p) mutation and other alterations associated with poor prognosis in CLL. Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and US Oncology Research, presented subgroup results from the second interim analysis of the ongoing trial at the American Society of Hematology (ASH) 2014 Annual Meeting. The trial enrolled 220 patients with CLL who developed progressive disease within 24 months of prior treatment and who were considered unfit for cytotoxic chemotherapy. Patients were randomly assigned to continuous treatment with idelalisib 150 mg BID plus 6 months of rituximab (n = 110) or placebo BID plus 6 months of rituximab (n = 110). Idelalisib, a first-in-class, oral, highly selective, inhibitor of phosphoinositide 3-kinase delta (PI3Kd), was recently approved in combination with rituximab for the treatment of relapsed CLL. At disease progression, patients could enroll into a blinded extension study that involved crossover to idelalisib for patients initially treated with placebo, or dose escalation of idelalisib to 300 mg BID plus rituximab in patients initially treated with combination therapy. Of those eligible, 46% of patients crossed over to idelalisib and 76% of patients continued on higher-dose idelalisib. The trial was stopped early due to overwhelming efficacy in favor of idelalisib at the first interim analysis, an advantage that was confirmed in the second interim analysis.[1, 2] Here, Dr. Sharman and colleagues reported outcomes in patient subgroups defined by the presence of poor prognostic factors. In the idelalisib group, the prevalence of highrisk genetic features was as follows: unmutated IGHV (84%); del(17p) and/or TP53 mutation (43%); and del(11q) (34%). Idelalisib significantly improved the overall response rate (ORR) compared with placebo in the overall study population (77% vs. 15%; OR, 19.6). The substantial advantage of idelalisib in terms of ORR was consistent across all patient subgroups compared with placebo, including patients with unmutated IGHV (77% vs. 16%), del(17p)/tp53 mutation (82% vs. 13%), and del(11q) (68% vs. 17%). Idelalisib was also associated with a marked improvement in progression-free survival (PFS). The median PFS was not reached (NR) in the idelalisib arm and 5.5 months with placebo (HR, 0.18). The magnitude of PFS benefit with idelalisib plus rituximab versus placebo plus rituximab was similar for patients with unmutated IGHV (NR vs. 4.0 months); del(17p)/tp53 mutation (NR vs. 4.0 months); and del(11q) (10.7 months vs. 6.9 months). Despite the crossover trial design, median overall survival (OS) also significantly favored idelalisib compared with placebo (NR vs months; HR, 0.32; p =.0001). The significant improvement in OS with idelalisib versus placebo was consistent for patients with unmutated IGHV (NR vs months; HR, 0.35; p =.0003) and in those with del(17p) or TP53 mutation (NR vs months; HR, 0.31; p =.001). Combination therapy with idelalisib plus rituximab had a manageable safety profile. The most common grade 3/4 adverse events in the idelalisib arm were diarrhea/colitis (16%), pneumonia (13%), pyrexia (6%), dyspnea (6%), and fatigue (5%). Grade 3/4 laboratory abnormalities included neutropenia (41%), thrombocytopenia (14%), liver enzyme elevation (10%), and anemia (8%). In summary, idelalisib plus rituximab demonstrated a substantial improvement in ORR, PFS, and OS compared with rituximab alone in frail patients with relapsed CLL who were unable to undergo treatment with chemotherapy. The benefit was consistent across all patient subgroups, regardless of high-risk genetic markers such as unmutated IGVH, del(17p), TP53 mutation, and del(11q). References 1. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370: Coutre SE, Furman RR, Sharman JP, et al. American Society of Clinical Oncology (ASCO) 2014 annual meeting. Abstract Source: Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (Zydelig ) plus rituximab for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 330. Related Video Interview with Jeff P. Sharman, MD

11 Ibrutinib Shows Strong Efficacy in Relapsed/Refractory CLL or SLL With Del(17p) Single-agent ibrutinib induced an overall response rate (ORR) of 82.6% and a 12-month progression-free survival (PFS) rate of 79% in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who have the del(17p) mutation, according to new findings from the largest prospective to examine this patient population. Susan O'Brien, MD, of the University of Texas MD Anderson Cancer Center, presented findings from the phase II RESONATE-17 study at the American Society of Hematology (ASH) 2014 Annual Meeting. Patients with CLL with del(17p) typically follow an aggressive clinical course with a median survival of less than 2 years in the relapsed/refractory setting. Ibrutinib, a first-in-class covalent inhibitor of Bruton s tyrosine kinase (BTK), is currently approved for the treatment of relapsed/refractory CLL and for patients with CLL with del(17p) at any line of therapy. The approval of ibrutinib was based upon results from the pivotal phase III RESONATE trial, which compared ibrutinib and ofatumumab in patients with CLL who had at least one prior therapy [1]. The phase II RESONATE-17 (PCYC-1117) study was designed to evaluate the anti-leukemic efficacy and safety of ibrutinib monotherapy in patients with CLL (n = 137) or SLL (n = 7) with del(17p). The median patient age was 64 years, and all patients had del(17p). Patients had been treated with a median of two prior therapies (range, 1 to 7). All patients received ibrutinib 420 mg once daily until disease progression. At the time of the analysis, the median treatment duration was 11.1 months, and 70% of patients continued on treatment with ibrutinib. The primary endpoint was ORR. The investigator-assessed ORR was 82.6%. This included a complete response (CR) or complete response with incomplete bone marrow recovery (CRi) in three patients and partial responses with lymphocytosis in 17.4% of patients. At a median follow up of 13 months, neither the median duration of response nor the median PFS had been reached. At 12 months, the overall PFS rate was 79.3%, and 88.3% of responding patients were progression-free. Progressive disease was reported in 20 patients (13.9%), including 11 patients (7.6%) who underwent Richter transformation and 1 patient who was diagnosed with prolymphocytic leukemia. Treatment with ibrutinib was associated with a favorable risk-benefit profile, with toxicity consistent with previous reports of single-agent ibrutinib [1]. The most common grade 3/4 adverse events were neutropenia (14%), anemia (8%), pneumonia (8%) and hypertension (8%). Common adverse events of any grade included diarrhea (36%), fatigue (30%), cough (24%), and arthralgia (22%). The safety analysis showed atrial fibrillation of any grade in 11 patients (7.6%). Secondary malignancies included basal or squamous cell skin cancer (n = 7) and plasma cell myeloma (n = 1). Dr. O Brien noted that the PFS in this cohort of patients with previously treated CLL compares favorably to that observed in treatment-naïve patients with del(17p) CLL who received fludarabine, cyclophosphamide, and rituximab [2] or alemtuzumab [3], with a median PFS of approximately 11 months in both frontline trials. In summary, findings from the phase II RESONATE-17 trial support the use of single-agent ibrutinib in patients with del(17p) CLL or SLL. references 1. Byrd JC, Brown JR, O'Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3): Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376: Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25: Source: O Brien S, Jones JA, Coutre S, et al. Efficacy and safety of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia with 17p deletion: results from the phase II RESONATE -17 trial. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 327.

12 Updated Phase III RESONATE Findings Clarify Robust Clinical Activity of Ibrutinib in Relapsed/Refractory CLL Two follow-up analyses from the pivotal phase III RESONATE trial provide additional support for the role of ibrutinib in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Ibrutinib is a first-in-class covalent inhibitor of Bruton s tyrosine kinase (BTK) that is currently approved for patients with relapsed/refractory CLL and for those with CLL with del(17p) at any line of therapy. Ibrutinib gained full FDA approval for these indications based upon findings from the phase III RESONATE trial. In the primary analysis of the RESO- NATE trial, after a median follow-up of 9.4 months ibrutinib significantly improved progression-free survival (PFS) (HR, 0.22; p <.001) and overall survival (OS) (HR, 0.43; p =.005) compared with ofatumumab in patients with CLL who had at least one prior therapy [1]. Jennifer R. Brown, MD, PhD, of the Dana-Farber Cancer Institute, and Jacqueline C. Barrientos, MD, of the North Shore-LIJ Cancer Institute, presented the updated findings at the American Society of Hematology (ASH) 2014 Annual Meeting. 16-Month Follow-Up Data In the first updated analysis, Brown and colleagues presented updated results from the multicenter, randomized, open-label RESONATE trial (n = 391) according to baseline genetic and clinical subgroups. After 16 months of follow-up, the median progression-free survival (PFS) was not reached in the ibrutinib group, compared with 8.1 months in the ofatumumab group (HR, 0.106; p <.0001). The 12-month PFS rates were 84% and 19% in the ibrutinib and ofatumumab groups, respectively. The PFS benefit of ibrutinib compared with ofatumumab was consistent across all patient subgroups defined by the presence of lymphocytosis, the number of prior therapies, the presence of del(17p) or del(11q), and complex cytogenetics (p <.001 for all categories). Patients in the ibrutinib arm experienced better outcomes when treated in the second-line setting rather than salvaged in later lines of therapy. An exploratory analysis of patients treated with ibrutinib showed that the 12-month PFS rate was higher when ibrutinib was given after only one prior therapy (94%) than after two or more prior therapies (82%; p =.01). In contrast, there was no difference in the PFS rate among ibrutinib-treated patients with or without del(17p), indicating that the high-risk del(17p) mutation did not reduce the anti-leukemic activity of ibrutinib. The median overall survival (OS) was not reached in either treatment arm, with 18-month OS rates of 85% vs. 78% in the ibrutinib and ofatumumab groups, respectively. The overall response rate was 90% in the ibrutinib group, compared with 25% in the ofatumumab group (p <.0001). Overall, the 16-month follow-up results provide further evidence of the robust activity of ibrutinib in patients with relapsed/refractory CLL, regardless of number of prior therapies or high-risk genetic abnormalities. Patient Well-Being and Quality of Life Outcomes In another subanalysis from the RESONATE trial, Barrientos and colleagues evaluated several measures of patient wellbeing, including hematologic and immunologic function and quality of life, following treatment with ibrutinib or ofatumumab. Ibrutinib was associated with significantly greater improvements in hematologic function compared with ofatumumab. At baseline, 63% of all patients had cytopenias, including anemia (45%), thrombocytopenia (35%), and neutropenia (20%). In the ibrutinib arm, 69% of patients with baseline cytopenias experienced sustained improvement in blood counts, compared with 43% of patients in the ofatumumab arm (p <.0001). In particular, ibrutinib was more likely than ofatumumab to provide a sustained improvement in platelet counts (72% vs. 22%, respectively; p <.0001) and absolute neutrophil counts (64% vs. 32%, respectively; p =.0047). Patient-reported outcomes also favored treatment with ibrutinib. At week 24, patients in the ibrutinib arm were more likely than those in the ofatumumab arm to have clinically meaningful improvement in composite fatigue scores (59% vs. 46%, respectively; p =.06). Ibrutinib-treated patients were also less likely to show a deterioration of fatigue score compared with ofatumumab-treated patients (14% vs. 24%, respectively; p =.08). Neither treatment group showed a reduction in serum immunoglobulins (IgA, IgG, IgM) during follow-up. IgA levels increased only in the ibrutinib group, with a mean increase of 41% at week 24 compared with baseline. In summary, based on improvements in hematologic and immunologic function as well as patient-reported outcomes, ibrutinib appears to enhance quality of life while improving ORR, PFS, and OS compared with ofatumumab in patients with relapsed/refractory CLL. references 1. Byrd JC, Brown JR, O'Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3): Source: Brown JR, Hillmen P, O Brien S, et al. Updated efficacy including genetic and clinical subgroup analysis and overall safety in the phase 3 RESONATE trial of ibrutinib versus ofatumumab in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract Source: Barrientos JC, O Brien S, Brown JR, et al. hematologic and immunologic function and patient well-being for the phase III RESONATE study of ibrutinib vs ofatumumab in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 4696.

13 Blinatumomab Induces Complete MRD Response in Patients With MRD-Positive ALL In patients with acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD) after chemotherapy, one cycle of blinatumomab reduced the level of residual disease by an order of magnitude, according to findings from the phase II BLAST trial. The trial incorporated the novel endpoint of complete MRD response, which describes the absence of residual disease detected at the level of 1 blast cell in 10,000 normal cells. Nicola Gökbuget, MD, of Goethe University Hospital, presented results from the ongoing BLAST trial at the American Society of Hematology (ASH) 2014 Annual Meeting. In current practice, nearly all patients with MRD-positive ALL will experience disease relapse despite treatment with continued chemotherapy. Persistent MRD indicates a resistance to conventional treatment and identifies patients who require new treatment approaches to improve prognosis. Blinatumomab is the first agent in a novel class of immunotherapeutic drugs called bispecific T-cell engagers (BiTE). Blinatumomab induces B-cell lysis by directing cytotoxic T cells to target cells expressing CD19, a highly specific B-cell marker present on more than 90% of B-cell cancers. On December 3, 2014, the U.S. Food and Drug Administration approved blinatumomab for the treatment of patients with Philadelphia chromosome-negative precursor B-cell ALL. The multicenter, open-label BLAST trial enrolled 116 patients with B-precursor ALL who were in complete hematologic remission (< 5% blast cells) after three or more chemotherapy treatments but showed evidence of MRD, defined as the presence of blast cells detected by quantitative analysis with a sensitivity of 10-3 (0.01%). No prior allogeneic hematopoietic stem cell transplantation (HSCT) was permitted. Blinatumomab was given by continuous IV infusion 15 µg/m2 per day for 28 days on a schedule of four weeks on followed by two weeks off (one cycle) for a maximum of four cycles. The primary endpoint was complete MRD response, defined as the absence of MRD as detected by quantitative analysis with a sensitivity of 10-4 (0.001%). After one cycle of blinatumomab, 78% of patients achieved complete MRD response. Among patients who completed all four cycles of therapy, the complete MRD response rate was 80%. Response to blinatumomab was consistent across all patient subgroups defined by baseline age, gender, line of treatment, and MRD burden. The most common adverse events occurring in 20% or more patients included pyrexia (88%), headache (38%), tremor (29%), chills (25%), fatigue (24%), nausea (22%) and vomiting (22%). Most adverse events were mild, with the exception of grade 3 neutropenia in 16% of patients and grade 3 tremor in 5% of patients. After the first cycle of blinatumomab, transplant-eligible patients with an available donor underwent allogeneic HSCT. The planned follow-up for all patients is 2 years. Future analyses from the ongoing BLAST trial will evaluate the implications of complete MRD response on long-term outcomes including remission and overall survival. Source: Gökbuget N, Dombret H, Bonifacio M, et al. BLAST: A confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-cell engager (BiTE ) antibody construct, in patients with minimal residual disease B-precursor acute lymphoblastic leukemia (ALL). American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 379. Related Video Interview with Nicola Gökbuget, MD

14 Vosaroxin Added to Cytarabine Yields Mixed Results in Relapsed/Refractory AML Vosaroxin plus cytarabine showed a modest and nonsignificant improvement of 1.4 months in median overall survival (OS) compared with cytarabine alone in patients with first relapsed or refractory acute myeloid leukemia (AML), according to new findings from the VALOR trial. Although the trial failed to meet its primary endpoint, secondary analyses point to a potential clinical benefit in older patients with AML. Farhad Ravandi, MD, of the University of Texas MD Anderson Cancer Center, presented findings from the phase III study at the American Society of Hematology (ASH) 2014 Annual Meeting. The randomized, double-blind, placebo-controlled trial randomly assigned 711 adult patients with first relapsed or refractory AML to receive vosaroxin plus cytarabine (n = 356) or placebo plus cytarabine (n = 355). All patients had received 1-2 cycles of prior induction chemotherapy, including at least 1 cycle of cytarabine and anthracycline (or anthracenedione). Patients were stratified at baseline by disease status (refractory vs. early relapse vs. late relapse), age (< 60 vs. 60 years), and geography (U.S. vs. non-u.s.). Vosaroxin was given intravenously (IV) at a dose of 90 mg/m 2 over 10 minutes on days 1 and 4 and 70 mg/m 2 in subsequent cycles. All patients received IV cytarabine 1 g/m 2 over 2 hours on days 1 to 5. Patients completed up to 2 induction cycles and 2 consolidation cycles. The primary endpoint was overall survival (OS). In the intent-to-treat analysis, the median OS was 7.5 months with vosaroxin plus cytarabine compared with 6.1 months with cytarabine alone (p =.06). Several secondary endpoints favored treatment with vosaroxin plus 60 years. The complete remission (CR) rate was significantly higher with vosaroxin plus cytarabine compared with cytarabine alone in the overall study population (30.1% vs. 16.3% p <.0001). The CR rate was also higher with vosaroxin compared with placebo among older patients (p <.0001), but not among those younger than age 60 years (p =.24). An analysis of median OS by age group also showed a significant survival advantage with vosaroxin compared with placebo in patients aged 60 years (7.1 months vs. 5.0 months; HR, 0.76; p =.006), but not for those aged < 60 years (9.1 months vs. 7.9 months; HR, 1.08; p = 1.0). Vosaroxin also improved survival compared with placebo among patients in early relapse, defined as relapse between 90 days and 12 months from prior response (6.7 months vs. 5.2 months; HR, 0.77; p =.05). However, there was no difference in OS between treatment groups for patients in late relapse (HR, 0.98; p =.94) or for those with refractory disease (HR, 0.87; p =.26). In a preplanned analysis of OS censored for allogeneic stem cell transplantation (ASCT), vosaroxin improved the median OS compared with placebo (6.7 months vs. 5.3 months; p =.02). Approximately 29.5% of patients underwent ASCT, including 45.8% of patients aged < 60 years and 20.2% of patients aged 60 years. The safety analysis showed that vosaroxin increased the risk of toxicity compared with placebo, particularly febrile neutropenia (11.3% vs. 7.4%), sepsis (8.7% vs. 4.3%), pneumonia (7.6% vs. 4.9%), bacteremia (8.5% vs. 2.9%), and stomatitis (3.4% vs. 1.4%). However, the vosaroxin and placebo groups showed similar rates of 30-day mortality (7.9% vs. 6.6%) and 60-day mortality (19.7% vs. 19.4%). In summary, vosaroxin plus cytarabine showed a nonsignificant trend toward improved survival compared with cytarabine alone in patients with relapsed/refractory AML. The clinical benefit may be underestimated in younger patients due to the higher rate of ASCT in patients aged < 60 years. Vosaroxin significantly prolonged survival by 2.1 months compared with placebo among patients aged 60 years, suggesting a potential role for vosaroxin plus cytarabine as salvage therapy in older patients with AML. Source: Ravandi F, Ritchie E, Sayar H, et al. Improved survival in patients with first relapsed or refractory acute myeloid leukemia (AML) treated with vosaroxin plus cytarabine versus placebo plus cytarabine: results of a phase 3 double-blind randomized controlled multinational study (VALOR). American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract LBA-6.

15 Venetoclax, an Oral BLC-2 Inhibitor, Shows Promising Anti-Leukemic Activity in Relapsed/Refractory AML Single-agent oral venetoclax (ABT-199) is active in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) and in patients who are considered unfit for frontline chemotherapy, according to new findings from a phase II trial. Marina Konopleva, MD, PhD, of the University of Texas MD Anderson Cancer Center, presented results from the multicenter, open-label study at the American Society of Hematology (ASH) 2014 Annual Meeting. Venetoclax is an investigational, selective, potent small molecule inhibitor of B-cell lymphoma 2 (BCL-2). BCL-2 has been implicated in drug resistance and poor prognosis in patients with hematologic malignancies. Patients with relapsed/refractory AML have few available treatment options and limited overall survival. The trial enrolled 32 patients with relapsed/refractory AML (n = 30) or patients with previously untreated AML who were unfit for chemotherapy (n = 2). All patients received single-agent, oral venetoclax at a starting dose of 20 mg/day, with daily dose escalation to a target dose of 800 mg/day by day 6. At the end of week 4, patients without a complete response (CR) were eligible for further dose escalation to 1200 mg/day. The median time on study drug was 63 days (range, days). The median patient age was 71 years (range, years) and the median time on study was 81 days. Among patients with relapsed/refractory AML, 14 (44%) had received 4 or more prior treatments and 22% had been treated with one or both hypomethylating agents. Isocitrate dehydrogenase (IDH) 1 and 2 mutations were present in 2 patients (6%) and 9 patients (28%) respectively. The objective response rate was 19%, including a CR in 2 patients (6%) and an complete response with incomplete blood count recovery (CRi) in 4 patients (13%). Patients with IDH mutations may be particularly sensitive to treatment with venetoclax. The objective response rate among patients with IDH mutations was 36%, including a CR in 18% and a CRi in 18%. Treatment with venetoclax reduced the median marrow blast count by 36%, from 50% at baseline to 21% at 4 weeks. Six patients (19%) had a bone marrow blast reduction of at least 50%. In an exploratory biomarker analysis (n = 12), BH3 profiling significantly predicted the blast cell response (p =.006). The most common adverse events of any grade were nausea (56%), diarrhea (53%), vomiting (41%), pneumonia (34%), hypomagnesemia (38%), fatigue (34%), and headache (34%). Grade 3/4 adverse events included febrile neutropenia, anemia and pneumonia. One patient (3%) discontinued treatment due to an adverse event. There were no toxicity-related deaths, and no reports of clinical or laboratory tumor lysis syndrome. Based on these phase II findings, venetoclax is undergoing further evaluation in combination with hypomethylating agents and chemotherapy in patients with AML. Researchers are also exploring the potential use of predictive biomarkers to identify patients who are more likely to benefit from venetoclax treatment. Source: Konopleva M, Pollyea DA, Potluri J, et al. A phase 2 study of ABT-199 (GDC-0199) in patients with acute myelogenous leukemia. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 118.

16 Novel Oral Agent AG-221 Induces Durable Remissions in Advanced AML AG-221, a novel, oral, first-in-class inhibitor of mutated isocitrate dehydrogenase 2 (IDH2), induced durable remissions with potent anti-leukemic activity in patients with advanced acute myelogenous leukemia (AML) and other hematologic malignancies, according to findings of a phase I study. Eytan M. Stein, MD, of the Memorial Sloan-Kettering Cancer Center, presented interim results from the phase I dose-escalation trial at the American Society of Hematology (ASH) 2014 Annual Meeting. Isocitrate dehydrogenase (IDH) is a key enzyme of the citric acid cycle. Gain-of-function somatic mutations in the genes encoding IDH result in impaired cellular differentiation due to increased histone and DNA methylation and the accumulation of metabolites. The IDH2 mutations occur in approximately 9% to 13% of AML patients and 3% to 6% of patients with myelodysplastic syndrome (MDS). IDH1 mutations are also present in up to 10% of AML patients and 3% of MDS patients. AG-221 selectively inhibits mutated IDH2, blocking the accumulation of epigenetic changes and triggering leukemic blast cells to undergo normal differentiation. To date, the ongoing phase I study has enrolled 73 patients with relapsed/refractory AML (n = 55), MDS (n = 6), untreated AML (n = 5), chronic myelomonocytic leukemia (n = 5), or myeloid sarcoma (n = 1). All patients received continuous oral dosing of AG-221 once or twice daily in 28-day cycles across multiple dose cohorts. The highest cumulative daily dose was 300 mg. The primary safety endpoint was to determine the maximum tolerated dose (MTD) for future dose expansion cohorts and phase II studies. Among 45 evaluable patients, the overall response rate was 56%, including six complete responses. The estimated duration of response is 3 months in 90% of responding patients. One patient who remains on the study has responded for longer than 8 months. The maximum tolerated dose of AG-221 was not reached. The most common adverse events were nausea, pyrexia, diarrhea, and fatigue. Severe adverse events included leukocytosis (n = 3), disseminated intravascular coagulopathy (n = 2), and tumor lysis syndrome (n = 2). One grade 5 adverse event (hypoxia) occurred in a patient with unrelated fungal pneumonia and sepsis. Two additional deaths possibly related to the study drug included sepsis/ hypoxia and atrial flutter. Overall, AG-221 was well tolerated and induced durable remissions, including complete responses, in patients with advanced AML and MDS. These phase I results support the potential role of mutant IDH2 as a therapeutic target in hematologic malignancies. Based on these promising interim findings, an expansion of the AG mg oncedaily dose cohort is currently under way. Source: Stein EM, Altman JK, Collins R, et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant metabolic enzyme, induces durable remissions in a phase I study in patients with IDH2 mutation positive advanced hematologic malignancies. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract 115.

17 Combination Regimens Show No Advantage Over Azacitidine Monotherapy in High-Risk MDS Compared with azacitidine alone, the addition of vorinostat or lenalidomide to azacitidine failed to improve response in patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), according to findings from an ongoing phase II trial. Mikkael A. Sekeres, MD, MS, of the Cleveland Clinic, presented findings from the Intergroup S1117 study at the American Society of Hematology (ASH) 2014 Annual Meeting. Frontline treatment with a hypomethylating agent such as azacitidine is considered the standard of care for patients with newly diagnosed, higher-risk MDS and CMML. The Intergroup S1117 study examined whether combining agents with different mechanisms of action might improve the anti-leukemic effects of single-agent azacitidine in these patients. Vorinostat is a histone deacetylase inhibitor that acts synergistically with azacitidine to reactivate epigenetically silenced genes. Lenalidomide is an immunomodulating agent with activity in the bone marrow microenvironment. The phase II study included 276 evaluable patients with higher-risk MDS, defined as intermediate-2 or high-risk IPSS score and/or bone marrow blasts 5% (n = 226), as well as patients with CMML and < 20% blasts (n = 50). Patients were randomly assigned to 1 of 3 treatment arms: azacitidine 75 mg/m2 on days 1-7 of each 28-day cycle (n = 92); azacitidine plus lenalidomide 10 mg/day on days 1-21 (n = 93); or azacitidine plus vorinostat 300 mg BID on days 3-9 (n = 91). Patients continued treatment until progression, relapse, lack of response, or unacceptable toxicity. The median treatment duration was 23 weeks. The primary endpoint was improvement in overall response rate (ORR). After a median follow-up of 9 months, the ORR was 33% for all azacitidine-based regimens. This included a complete remission (CR) in 19% of patients, a partial response (PR) in 1% of patients, and hematologic improvement (HI) in 13%. The median duration of relapse-free survival was 7 months. The ORR was similar for all patients regardless of treatment with single-agent azacitidine (36%), azacitidine plus lenalidomide (37%; p = 1.0 vs. azacitidine monotherapy), or azacitidine plus vorinostat (22%; p =.07 vs. azacitidine monotherapy). Moreover, the distribution of patients achieving CR, PR, and HI was similar across all treatment groups. No patient subgroup appeared to derive a greater magnitude of benefit from one regimen over the others. The ORR was similar across all treatment arms in subgroup analyses of patients defined by diagnosis (MDS vs. CMML), treatment-related MDS, baseline transfusion dependence, and IPSS risk group. Compared with azacitidine monotherapy, the combination arms were associated with an increase in adverse events. The most common grade 3 adverse events in all treatment arms were febrile neutropenia, gastrointestinal symptoms, infections, and rash. These findings support the role of hypomethylating agents as standard first-line therapy for patients with higher risk MDS and CMML. Longer-term results from the S1117 trial will examine the potential effects of azacitidinebased combination therapy on disease-free survival and other outcomes compared with azacitidine alone. Source: Sekeres MA, Othus M, List AF, et al. A randomized phase II study of azacitidine combined with lenalidomide or with vorinostat vs. azacitidine monotherapy in higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML): North American Intergroup Study SWOG S1117. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract LBA-5.

18 Lenalidomide Poses No Increased Risk of AML Transformation in Patients With MDS Physicians and their patients with myelodysplastic syndrome (MDS) can be assured that treatment with lenalidomide does not increase the risk of transformation to acute myeloid leukemia (AML), according to new findings from a retrospective cohort study. Dana E. Rollison, PhD, of the H. Lee Moffitt Cancer Center (MCC), presented findings from the largest cohort study examining AML transformation in MDS to date at the American Society of Hematology (ASH) 2014 Annual Meeting. Lenalidomide is currently approved for the treatment of lower-risk deletion 5q [del(5q)] MDS, but it is often also used in patients with non-del(5q) MDS in accordance with national guidelines. Little is known about the risk of AML transformation in lenalidomide-treated patients with nondel(5q) MDS, or in patients with del(5q) MDS treated in the real-world setting. The retrospective cohort study included data from 1,248 patients with MDS who were treated with lenalidomide (n = 210) or a non-lenalidomide regimen (n = 1,038) at MCC from 2004 to MDS patients who were treated with lenalidomide were more likely than those who did not receive lenalidomide to be older, have a longer follow-up time, and have lowerrisk IPSS (low and intermediate-1). To control for these confounders, researchers conducted a nested case-control analysis of patients who developed AML (n = 150) matched to a sample of patients who did not develop AML (n = 150). During a mean follow-up of 30 months, lenalidomide was associated with a significantly reduced risk of AML transformation in the overall study population (HR, 0.44; 95% CI, ; p =.0026). The AML transformation rates were 2.44 per 100 person-years and 5.5 per 100 person years in the lenalidomide and non-lenalidomide groups, respectively. The protective effect of lenalidomide against AML transformation was especially pronounced in patients with lower-risk IPSS (HR, 0.27; 95% CI, ). For patients with higher-risk IPSS (intermediate-2 and high), there was no association between lenalidomide treatment and AML (HR, 0.99; 95% CI, ). Only two of the patients who transformed to AML (n = 150) had MDS del(5q). Results from the case-control study, however, indicate that lenalidomide had no effect on the risk of AML. After controlling for potential confounders, there was no statistically significant association between lenalidomide and AML transformation in any patient subgroup, even among patients with lower-risk IPSS. These findings should reassure patients of the safety of lenalidomide, as it relates to AML transformation, in the treatment of MDS. Source: Rollison DE, Shain KH, Lee JH, et al. Lenalidomide and risk of acute myeloid leukemia transformation among myelodysplastic syndrome patients. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract Related Video Interview with Dana Rollison, PhD and Rami Komrokji, MD

19 Current Prognostic Tools Predict Overall Survival But Not Best Response to Hypomethylating Agents in Patients With Higher-Risk MDS Several commonly used myelodysplastic syndromes (MDS) prognostic tools are able to facilitate patient counseling by predicting overall survival in patients with higher-risk MDS, according to new findings from a comparative analysis of riskassessment models. However, the ability to guide upfront therapy by predicting best response to hypomethylating agents (HMAs) for higher-risk MDS remains elusive. Amer M. Zeidan, MBBS, MHS, of Yale University, presented findings from the largest direct comparison of major MDS prognostic models among patients treated with HMAs at the American Society of Hematology (ASH) 2014 Annual Meeting. Although HMAs are the current standard of care for higher-risk MDS, response rates are often < 50% and may be delayed for up to 6 months. In current practice, less than 5% of patients with higher-risk MDS undergo upfront curative therapy with hematopoietic cell transplantation (HCT). There is an urgent need for tools to identify patients who have a low likelihood of response to HMAs and should instead receive upfront HCT or referral for clinical trial enrollment. In the study, Dr. Zeidan and colleagues first examined databases from six cancer centers in the MDS Clinical Research Consortium to identify patients with higher-risk MDS (n = 626) who received upfront therapy with azacitidine (67.8%) or decitabine (32.2%). The overall response rate to frontline treatment HMAs was 43%, including a complete response in 20.7% and a partial response in 9.5% of patients. The median duration of follow-up was 15.5 months, and the median overall survival was 16.9 months. Researchers then compared the prognostic utility of five established MDS prognostic systems in the same cohort of patients with higher-risk MDS: International Prognostic Scoring System (IPSS) Revised IPSS (IPSS-R) MD Anderson Prognostic Scoring System (MDAPSS) French Prognostic Scoring System (FPSS) World Health Organization (WHO)-based Prognostic Scoring System (WPSS) Each tool was able to separate patients into distinct prognostic groups with significantly different overall survival rates. According to an analysis of relative goodness of fit, the MDAPSS and FPSS prognostic systems were superior to the IPSS, IPSS-R, and WPSS systems for predicting overall survival. The MDAPSS scheme separated patients into four risk groups with the following median overall survival durations: not reached, 32.5 months, 20.8 months, and 14.1 months, respectively (p = 5.7 x ). The FPSS separated patients into three risk groups with median overall survival durations of 37.2 months, 17.5 months, and 10.4 months, respectively (p = 4.0 x 10-9 ). Despite the success of these tools in predicting overall survival in higher-risk MDS, no risk-stratification tool was able to predict best response to treatment with HMA therapy: IPSS (p =.55), IPSS-4 (p =.14), FPSS (p =.21), MDAPSS (p =.39), and WPSS (p =.88). In summary, these findings suggest that patients with high-risk MDS and poor projected survival should be considered for alternate treatment approaches, including upfront HCT or investigational therapy in the clinical trial setting. In the future, the development and validation of better riskstratification models to predict treatment response may guide the selection of frontline therapy in MDS. Source: Zeidan AM, Sekeres MA, Garcia-Manero G, et al. The prognostic utility of the current risk models in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with hypomethylating agents. American Society of Hematology (ASH) Annual Meeting. December 6-9, 2014; San Francisco, CA. Abstract Related Video Interview with Amer M. Zeidan, MBBS, MHS