American Society of Hematology 2014 Annual Meeting Highlights

Connie Cheng, PharmD
Hematology/Oncology Clinical Pharmacist
Cleveland Clinic
Cleveland, OH

The 56th American Society of Hematology Annual Meeting took place in San Francisco, CA, December 6–9, 2014. There were more than 20,000 attendees from across the world. In addition, more than 4,000 abstracts and six plenary sessions were presented. This report reviews key oral abstracts and plenary presentations regarding pharmacologic treatment of acute and chronic leukemia, myelodysplastic syndrome, and mantle cell lymphoma.

Myelodysplastic Syndrome

Abstract 0164: A Final Report: Phase I/ II Study of Sequential Azacitidine and Lenalidomide in Patients with Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Azacitidine is a hypomethylating agent used as first-line treatment of higher-risk myelodysplastic syndrome (MDS) and in patients with acute myeloid leukemia (AML) who are unfit to receive induction chemotherapy. Furthermore, lenalidomide is increasingly studied in combination with azacitidine in patients with MDS and AML. A phase 1/2 study evaluated sequential azacitidine (75 mg/m2 days 1–5) and lenalidomide in 88 patients with high-risk MDS and AML, including 23 patients with AML (>30% blasts). Lenalidomide was administered starting on day 6 per 28-day cycle. Following myelosuppression and infections observed with repeated cycles in the first 20 phase-2 subjects, the optimal lenalidomide dose was determined to be 25 mg on days 6–10. Rapid responses were obtained within median of two cycles. The overall response rate (ORR) was 35% with median overall survival (OS) of 33 weeks (range 1–172). Among the 40 patients ad- ministered the optimal lenalidomide dose, ORR was 55% with median OS duration of 75 weeks. Among 31 patients who responded to treatment, 42% of them proceeded to stem cell transplant. Therefore, this combination dose schedule was determined to be effective for patients with high-risk MDS and AML.

Acute Myeloid Leukemia

Abstract 0006: Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia (AML): Results from 267 Patients Treated in the Randomized Placebo- Controlled SAL-SORAML Trial

In vitro data and nonrandomized clinical studies have suggested that sorafenib as a multikinase inhibitor may be effective in the treatment of AML. This abstract was presented at the plenary session, which highlighted the results of the SORAML trial, a double-blind, placebo- controlled study that evaluated sorafenib in addition to standard induction and consolidation treatment in 267 AML patients who were 18–60 years old. All patients received two cycles of induction with daunorubicin 60 mg/m2 days 3–5 and cytarabine 100 mg/m2 days 1–7 followed by three cycles of consolidation with cytarabine 3 g/m2 twice daily on days 1, 3, 5. Allogeneic stem cell transplantation was scheduled for all intermediate and high-risk patients. Patients were randomized to receive either sorafenib (800 mg/day) or placebo in addition to standard treatment. The primary endpoint, median event-free survival (EFS), was 9.2 versus 20.5 months in favor of sorafenib. Further- more, there was a significant difference in 3-year relapse-free survival, which was 38% in the placebo arm and 56% with sorafenib. No differences in 3-year OS were reported, 56% in placebo arm and 63% with sorafenib, respectively. Similar EFS rates were observed among 46 FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD)- positive patients. Notably there was a higher incidence of fever, bleeding events, and hand-foot syndrome observed in sorafenib-treated patients.

Acute Promyelocytic Leukemia

Abstract 0012: Improved Outcome with ATRA-Arsenic Trioxide Compared to the ATRA-Chemotherapy in Non- High-Risk Acute Promyelocytic Leukemia (APL): Updated Results of the Italian-German APL0406 Trial on the Extended Final Series

Recently the randomized intergroup acute promyelocytic leukemia (APL) 0406 trial revealed the effectiveness of ATRA and arsenic tri- oxide (ATO) in combination compared with ATRA with chemotherapy for treatment of low-intermediate risk APL as defined by white blood cell count (WBC) <10x109/ L (Lo-CoCo et al., NEJM 2013). Patients in the ATRA-ATO arm received ATO 0.15 mg/ kg and ATRA 45 mg/m2/day until complete remission (CR), then ATO 5 days/week, 4 weeks on and 4 weeks off, for a total of four courses and ATRA 2 weeks on and 2 weeks off for a total of seven courses. The primary study objective was EFS at 2 years. Follow-up results of an extended cohort of 254 additional patients demonstrated the 2-year EFS was 98% versus 84.9% in favor of ATRA-ATO. Furthermore, the ATRA- ATO arm was associated with superior 2-year OS (99.1% versus 94.4%) and 2-year cumulative incidence of relapse rates (1.1% versus 9.4%), and CR was achieved in every patient who received ATRA-ATO. This data further confirm the survival benefit of ATRA with ATO versus chemotherapy in the non-high-risk setting.

Acute Lymphoblastic Leukemia

Abstract 0379: 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)

Minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) refers to the presence of leukemic cells below the threshold of detection by conventional morphologic methods despite achieving complete hematologic remission. Patients with persistent/recur- rent MRD following induction therapy are at a higher risk of relapse. A phase 2 study evaluated 116 adult patients with MRD-positive (> 10-3) B-precursor ALL who received blinatumomab after achieving hematologic complete remission, including 35% who were treated in second or later remission. The monoclonal antibody is a bispecific T cell engager that redirects CD3-positive T cells to CD19 target cells to ultimately cause lytic destruction of CD19-positive B cells.

Notably patients with Philadelphia chromosome, central nervous sys- tem (CNS) involvement or extramedullary disease, or previous allogeneic stem cell transplant were excluded. Blinatumomab 15 µg/m²/ day was intravenously administered as continuous infusion for 4 weeks per 6-week cycle. Responders received up to four cycles of treatment or underwent stem cell transplant after completion of at least one cycle. Patients with hematologic relapse discontinued treatment. The primary study endpoint was rate of complete MRD response, which was achieved in 78% of patients after one cycle of treatment and 80% across all cycles. The most common adverse events observed (≥20%) included pyrexia (88%), headache (38%), tremor (29%), chills (25%), fatigue (24%), nausea (22%), and vomiting (22%). Serious adverse events that occurred in ≥5% of patients included pyrexia (15%), tremors (7%), aphasia (5%), encephalopathy (5%), and overdose (5%). Therefore, blinatumomab has the potential to improve patient out- comes, especially in those with MRD-positive ALL following intensive therapy, including second-line treatment.

Chronic Myeloid Leukemia

Abstract 0152: Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia (CML-CP) Trial (DASISION)

The recent 3-year follow-up results of the DASISION trial, a randomized phase 3 study, demonstrated improved efficacy and faster response at 3 months with dasatinib 100 mg daily (n = 259) versus imatinib 400 mg daily (n = 260) in treatment-naïve chronic-phase chronic myeloid leukemia (CML-CP) patients (Jabbour et al., Blood. 2014). Since then, the final 5-year analysis of DASISION has been completed. The primary endpoint was confirmed complete cytogenetic response (cCCyR). At the end of the study period, 61% of dasatinibtreated patients and 63% of the imatinib group were still receiving therapy. The rate of cCCyR by 5 years was 83% with dasatinib versus 78% with imatinib and increased rates of major molecular response (BCR-ABL ≤ 0.1%) were observed with dasatinib (76% versus 64%) by 5 years. Time to cCCyR (HR = 1.46; 95% CI: 1.20–1.77) and major molecular response (HR = 1.54; 95% CI: 1.25–1.89) were faster with dasatinib. There were no differences in 5-year, progression-free survival (PFS) and OS rates between both treatment arms. Although no new or unexpected safety events were identified in either treatment arm at 5 years, the total incidence of pleural effusion increased each year among the dasatinib group (29% overall). A majority of pleural effusion events were grade 1–2 (91%), and the median time to first grade 1–2 pleural effusion was 114 weeks (range: 4–299 weeks). Only 20% of dasatinib-treated patients who experienced a pleural effusion discontinued treatment. At 5 years, dasatinib 100 mg once daily has demonstrated superior outcomes compared with imatinib 400 mg once daily as initial therapy for CML, and the 5-year follow-up data confirm dasatinib should remain the standard of care in this setting.

Chronic Lymphocytic Leukemia

Abstract 0019: 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 (CLL10 Study)

Among physically fit advanced chronic lymphocytic leukemia (CLL) patients with low comorbidity burden, fludarabine, cyclophosphamide, and rituximab (FCR) is considered the standard frontline regimen.

The CLL10 study is a phase 3 study that compared bendamustine and rituximab (BR) with FCR in the frontline setting among 547 evaluable fit patients without del(17p) and who had a cumulative illness rating scale (CIRS) score <6 and creatinine clearance >70 ml/min. Patients were randomized to receive six courses of FCR (n = 274; fludarabine 25 mg/m2 days 1–3, cyclophosphamide 250 mg/m2 days 1–3, rituximab 375 mg/m2 day 0 at first cycle and 500 mg/m2 day 1 all subsequent cycles every 28 days) or BR (n =273; bendamustine 90 mg/m² days 1–2, rituximab 375 mg/m2 day 0 at first cycle and 500 mg/m2 day 1 all sub- sequent cycles every 28 days). The median CIRS score was 2 and a significantly higher proportion of patients 70 years or older was included in the BR arm (22% versus 14%, p = .020). The ORR in both arms was 97.8%. The CR rate was 40.7% in favor of FCR compared to 31.5% with BR. Median PFS was 53.7 months in the FCR arm, which was significantly higher than 43.2 months in the BR arm (HR = 1.589; 95% CI:1.25–2.079). Interestingly, among patients with unmutated IGHV status, median time to progression was 43.9 months after FCR compared with 34.0 months after BR (p = .015). Physically fit subgroups (CIRS max 3, only one CIRS item, age <65 years) benefited most from FCR therapy. On the other hand, no differences in PFS were observed be- tween both treatment arms in patients 65 years or older, CIRS 4–6 or >1 CIRS item. No difference in 3-year OS was observed between the two treatment groups (90.6% for FCR versus 92.2% for BR). There was a higher incidence of severe neutropenia observed in the FCR arm (87.7% versus 67.8%, p < .001), but no significant difference in the incidence of anemia (14.2% versus 12.0%; p = .46) or thrombocytopenia (22.4% versus 16.5%; p = .096) was found. Severe infections occurred more frequently (39.8% versus 25.4%, p = .001) in the FCR arm, especially in older patients (48.4% versus 26.8%; p = .001). Treatment-related mortality was 3.9% (FCR) and 2.1% (BR), respectively. The final analysis of the CLL10 study demonstrates that FCR results in higher CR rates and longer PFS, especially in very fit CLL patients. How- ever, BR should be considered as an alternative regimen in elderly fit patients or those with previous infections because increased toxicities were seen in older patients, which may have led to similar efficacy results between both arms.

Mantle Cell Lymphoma

Abstract 0149: Phase II Trial of R-CHOP Plus Bortezomib Induction Therapy Followed by Bortezomib Maintenance for Previously Untreated Mantle Cell Lymphoma: SWOG 0601

Currently there is no optimal induction regimen established for treat- ment of mantle cell lymphoma (MCL). Bortezomib, which is a 26S proteasome inhibitor, has been demonstrated to be active as mono- therapy for treatment of MCL, and preclinical data suggest that synergism may be exerted by combination with other cytotoxic agents. Given that maintenance rituximab administration following rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was associated with a survival benefit, the SWOG cancer re- search cooperative group conducted a phase 2 study (S0601) to evaluate the safety and efficacy of combining bortezomib with R-CHOP for induction, followed by bortezomib maintenance for 2 years among 65 treatment-naïve adult patients with stage 3, 4, or bulky stage 2 MCL. Induction therapy included six cycles of R-CHOP (375 mg/m2 rituximab, 750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine on day 1 and 100 mg prednisone daily for 5 days) plus bortezomib 1.3 mg/m2 on days 1 and 4 of every 21 day cycle. Patients achieving at least stable disease after induction were eligible for bortezomib maintenance therapy 1.3 mg/m2 days on 1, 4, 8, and 11 every 3 months for eight cycles. The primary endpoint was 2-year PFS rate. The 2-year PFS was 62% and 2-year OS was 85%. At 5 years the PFS was 28% and OS was 66%. Based on prior studies, the historical 2-year PFS rate for R-CHOP alone in this population is 30%. The Mantle Cell Lymphoma International Prognostic Index (MIPI) scores were significantly associated with outcome, with a 2-year PFS of 72%, 61%, and 25% for low-, intermediate-, and high-risk MIPI groups, respectively. Forty-eight percent of patients experienced grade 4 hematologic toxicities during induction therapy and 38.5% grade 3 nonhematologic and 6% grade 4 nonhematologic toxicities. During maintenance therapy, 13% of patients experienced grade 3 nonhematologic toxicities. Grade 3 peripheral neuropathy was experienced by 8% of patients during induction and 2% of patients during maintenance bortezomib, but grade 4 neuropathy was not reported. Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared with historical data of R-CHOP alone, which suggests the addition of bortezomib to induction chemotherapy or maintenance should be further evaluated in a larger prospective study.