Highlights from the 2016 American Society of Hematology Annual Meeting

Christina Howlett, PharmD BCOP
Assistant Clinical Professor
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey
New Brunswick, NJ
Oncology Pharmacy Specialist, Hackensack University Medical Center
Hackensack, NJ

With more than 3,000 scientific abstracts presented and more than 20,000 attendees from across the world, the American Society of Hematology (ASH) Annual Meeting is one of the largest forums for international ground-breaking research on blood cancer. The 58th ASH Annual Meeting took place in San Diego, CA, December 3–6, 2016, and focused on key topics such as immunotherapy, new targeted agents, and the genomic landscape of hematologic malignancies. The meeting provides a wide range of research sessions, including the renowned plenary scientific session, at which only six abstracts are selected for presentation. The following is a summary of five noteworthy abstracts presented at the 2016 meeting.

Reduced Intensity Delayed Intensification in Standard-Risk MRD-Negative Pediatric ALL
Martin Schrappe, MD, presented the results of a multicenter trial of 4,741 pediatric patients with minimal residual disease (MRD)-negative, standard-risk acute lymphoblastic leukemia (ALL), randomized to either a reduced intensity (RI, P-III) or standard delayed intensification protocol (P-II) following (AIEOP-BFM) ALL 2000 induction/consolidation. In comparison to P-II, the P-III protocol was shorter by 20 days, reduced the dexamethasone dose by 30%, and reduced the doses of vincristine, doxorubicin, and cyclophosphamide by 50%. Results demonstrated a 4-year disease-free survival (DFS) of 91.8% in P-III and 95.8% in the P-II arm (p = .04). Unfortunately, the attempt to reduce chemotherapy intensity resulted in a greater 4-year cumulate relapse rate with P-III (6.3% vs. 3.2%). Eight-year overall survival (OS) was 96.1% in P-III versus 98% in P-II (p = .06). These results validate the need for large prospective trials to further address RI treatment strategies in pediatric ALL.¹

Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma
Adam D. Cohen, MD, discussed preliminary results of an ongoing phase 1 dose-escalation study of chimeric antigen receptor T-cells (CART) targeting the B-cell maturation antigen (BCMA) in multiple myeloma. Patients with relapsed or refractory disease received CART-BCMA as split-dose infusions (10% on day 0, 30% on day 1, 60% on day 2). Results are available for patients in the initial cohort that received CART-BCMA cells alone, without chemotherapy. Future cohorts will assess the combination of CART-BCMA with cyclophosphamide.² Preliminary results of 6 patients demonstrated that CART-BCMA cells were detected by CAR-specific polymerase chain reaction (PCR) in all of the patients’ blood and bone marrow. Response to the therapy included 1 patient with stringent complete response, 1 with very good partial response, 1 with stable disease, 2 with minimal response, and 1 with progressive disease. Cytokine release syndrome (CRS) occurred in 5 patients, with 3 of these patients having grade 3 CRS requiring tocilizumab. Other grade 3/4 toxicities included electrolyte disturbances, cytopenias, hypofibrinogenemia, fatigue, pneumonia, urinary tract infection, elevated liver transaminases, hypertension, and pleural effusion. The authors concluded that depth of response was positively correlated to CART-BCMA cell expansion and the grade of CRS that developed following CART infusion.²

New Anti-CD26 Agent for Steroid-Refractory Graft-Versus-Host Disease
Andrea Bacigalupo, MD, presented results of two prospective trials evaluating begelomab, a murine IgG2B monoclonal antibody against CD26, in patients with steroid refractory acute graft-versus-host disease (GvHD). A total of 28 patients were enrolled in study 1 (pilot) and study 2 (dose finding). The study cohort was matched based on GvHD grading, age, disease phase, and donor type to a control arm of 82 patients grade 3–4 GvHD.³ No begelomab-related adverse events or infusion reactions were reported. At day 28, 75% of patients given begelomab responded to therapy versus 41% of controls (p = .004). Response rates in patients with grade 2–4 gut GvHD were 82% versus 34% (p = .001), and 1-year OS was 50% versus 31% (p = .06) for begelomab versus BAT, respectively. A multicenter prospective, randomized study is under way, comparing begelomab to BAT (NCT02411084).³

Frontline Ibrutinib-Rituximab Followed by Shortened Chemoimmunotherapy Consolidation in Mantle Cell Lymphoma
A single-center phase 2 trial of chemotherapy-free induction with ibrutinib-rituximab in mantle cell lymphoma (MCL) was presented by Michael Wang, MD. Initial therapy (part 1) consisted of ibrutinib 560 mg orally daily with rituximab 375 mg/m² intravenously (IV) weekly x 4 during cycle 1 (28-day cycle), and then rituximab day 1 only during cycles 3–12. Treatment then continued in part 2 with a shortened course of chemoimmunotherapy (rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone [hyperCVAD], alternating every 28 days with rituximab plus high-dose methotrexate and high-dose cytarabine).⁴ Preliminary findings of the study were available for 36 of the total 50 patients enrolled. Overall response rate to part 1 (ibrutinib-rituximab) was 100%: partial response in 28% and complete response (CR) in 72%. All 19 patients that completed both parts 1 and 2 achieved a CR, an unprecedented response rate in MCL. Compared to historic controls, adverse events were reduced in shortened chemoimmunotherapy cycles. Decreasing chemotherapy exposure may also prove to reduce the risk of therapy-related myeloid malignancy seen after the conventional 6 cycles of hyperCVAD. Wang and colleagues do note that longer follow-up is needed to further elucidate safety results.⁴

Nivolumab for Relapsed or Refractory Primary CNS Lymphoma and Primary Testicular Lymphoma
Lakshmi Nayak, MD, discussed the role of programmed cell death-1 (PD-1) inhibition in primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). This phase 1 study was generated on the basis of identification of genetic alterations in PCNSL and PTL that have been associated with increased expression of PD-1 ligands. A total of 4 relapsed or refractory PCNSL patients and 1 PTL patient were treated with nivolumab 3 mg/kg IV every 2 weeks.⁵ Evaluation of objective radiographic response determined that 4 patients had a CR and 1 had a PR after a median of 3 doses of nivolumab, with a median progression-free survival of 9 months. This pilot study was the clinical foundation for a phase 2 open-label trial of nivolumab in relapsed or refractory PCNSL and PTL patients that is actively recruiting participants.⁵

The above account briefly highlights the research presented at the meeting. To view all the abstracts, visit www.bloodjournal.org/content/128/22. Next year’s meeting is scheduled for December 9–12, 2017, in Atlanta, GA.

References

1. Schrappe M, Zimmerman M, Mӧricke A, et al. Reduced intensity delayed intensification in standard-risk patients defined by minimal residual disease in childhood acute lymphoblastic leukemia: results of an international randomized trial in 1164 patients (Trial AIEOP-BFM ALL 2000). Blood. 2016;128(22):4.
2. Cohen AD, Garfall AL, Stadtmauer EA, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood. 2016;128(22):1147.
3. Bacigalupo A, Deeg HJ, Caballero D, et al. Treatment of patients with steroid refractory acute graft vs host disease (SR-GvHD): a matched paired analysis of anti-CD26 (begelomab) compared to other treatment. Blood. 2016;128(22):671.
4. Wang M, Lee HJ, Thirumurthi S, et al. Chemotherapy-free induction with ibrutinib-rituximab followed by shortened cycles of chemo-immunotherapy consolidation in young, newly diagnosed mantle cell lymphoma patients: a phase II clinical trial. Blood. 2016;128(22):147.
5. Nayak L, Iwamoto F, LaCasce AS, et al. Nivolumab (anti-PD1) therapy for relapsed/ refractory primary central nervous system lymphoma and primary testicular lymphoma. Blood. 2016;128(22):930.