Katie S. Gatwood, PharmD BCOP
Stem Cell Transplant Clinical Pharmacist
Vanderbilt University Medical Center
The 59th American Society of Hematology (ASH) Annual Meeting—held in Atlanta, GA, December 9–12, 2017—was the largest yet, with 25,000 attendees and more than 3,000 abstracts presented in plenary and scientific research sessions covering a wide range of topics. Hot topics included chimeric antigen receptor (CAR)-T cells and other immunotherapies, novel targeted agents, and gene editing, genomics, and biomarkers. The following is a summary of the late-breaking abstracts and selected abstracts worthy of special note.
Late Breaking Abstracts
Results of the Randomized, Double-Blind, Placebo-Controlled, Phase 3 HERCULES Study of Caplacizumab in Patients with Acquired Thrombotic Thrombocytopenic Purpura1
Marie Scully, MD, presented the results of this phase 3 trial of 145 patients with newly diagnosed acquired thrombotic thrombocytopenic purpura (aTTP) who received either placebo (n = 73) or caplacizumab, an anti-vWF nanobody, (n =72) with plasma exchange (PE) and corticosteroids. Caplacizumab 10 mg intravenous (IV) was given before the first PE session and then dosed at 10 mg subcutaneous (SC) daily for the duration of PE and 30 days thereafter. For the primary end point of platelet response, patients in the caplacizumab group were >50% more likely to achieve a platelet response (platelet count normalization rate: 1.55, p <.01) and less likely to have TTP recurrence (9 patients with caplacizumab vs. 28 with placebo, p < .001). Caplacizumab also resulted in a 74% reduction in TTP-related death, recurrence, or a major thromboembolic event (p > .0001). The most common adverse events (AEs) with caplacizumab were epistaxis, gingival bleeding, and bruising. The authors concluded that caplacizumab represents a novel treatment option for patients with aTTP and is associated with faster aTTP resolution and decreased risk of recurrence or death as compared with PE and corticosteroids with an acceptable toxicity profile.
Venetoclax Plus Rituximab Is Superior to Bendamustine Plus Rituximab in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)—Results from Pre-Planned Interim Analysis of the Randomized Phase 3 MURANO Study2
Data from the primary analysis of the first multinational phase 3 trial of venetoclax plus rituximab (VR) in R/R CLL were presented by John Seymour, PhD MBBS. A total of 389 patients with R/R CLL were enrolled, 194 received VR, and 195 received bendamustine plus rituximab (BR). Venetoclax was given as a 4- or 5-week dose ramp-up from 20 mg to 400 mg by mouth (PO) daily. At week 6, rituximab was given IV once monthly for 6 cycles in combination with daily venetoclax for a maximum of 2 years or until disease progression. The primary end point of investigator-assessed progression-free survival (PFS) was superior for VR versus BR (hazard ratio [HR] 0.17; 95% confidence interval [CI] 0.11–0.25, p < .0001) with 24-month PFS estimated at 84.9% and 36.3%, respectively. PFS benefit was consistent across all risk subgroups analyzed, including those with del(17p). Higher minimal residual disease (MRD) negativity rates were also observed and were more durable with VR versus BR. Grade 3 neutropenia and tumor lysis syndrome (TLS) rates were higher with VR, and rates of Richter transformation and death were similar between the groups. Improved disease control with an acceptable safety profile demonstrates that VR has superior outcomes compared to BR for R/R CLL.
Phase 3 Randomized Study of Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM) Patients Ineligible for Transplant (ALCYONE)3
Maria-Victoria Mateos, MD PhD, presented the results from this phase 3 trial in 706 NDMM patients ≥65 years or otherwise ineligible for autologous stem cell transplant (autoSCT) that were randomized to receive up to 9 cycles of D-VMP (n = 350) or VMP (n = 356). Daratumumab was given at 16 mg/kg IV weekly for cycle 1, every 3 weeks for cycles 2–9, and every 4 weeks for cycles 10 and beyond until disease progression. At the time point of the prespecified analysis, patients had received a median of 12 cycles of D-VMP and 9 cycles of VMP. At a median follow-up of 16.5 months, median PFS was not reached versus 18.1 months for D-VMP and VMP, respectively (HR 0.5; 95% CI 0.38–0.65, p < .0001), which was the study’s primary end point. The benefit was observed across all prespecified subgroups (age, stage, and cytogenetics). Overall response rate (ORR) for D-VMP was 90.9% versus 73.9% for VMP, and more patients achieved better than a very good partial response (VGPR; 71.1% vs. 49.7%) and complete response (CR; 42.6% vs. 24.4%) with D-VMP. The most common AEs were myelosuppression, peripheral neuropathy, and upper respiratory infection, with similar rates between groups. Rates of secondary malignancy were also similar. Adding D to the VMP regimen has shown consistent doubling of PFS in this and other combination trials as well as increased MRD negativity without increased AEs, supporting the use of this combination in transplant-ineligible NDMM patients.4,5
A Randomized, Open-Label, Blinded Outcome Assessment Trial Evaluating the Efficacy and Safety of LMWH/Edoxaban versus Dalteparin for Venous Thromboembolism Associated with Cancer: Hokusai VTE-Cancer Study6
The results from this open-label noninferiority trial of low-molecular-weight heparin (LMWH) versus the oral factor Xa inhibitor edoxaban, in cancer patients with acute symptomatic or incidental venous thromboembolism (VTE) were presented by Gary Raskob, PhD. A total of 1,050 patients (525 per arm) were randomized to a minimum of 5 days of LMWH followed by edoxaban 60 mg PO daily or dalteparin 200 units/kg SC daily for 1 month and 150 units/kg SC daily thereafter for up to 12 months. The primary end point was a composite of first recurrent VTE or a major bleeding event in the next 12 months. Among the entire study group, 67% of patients had symptomatic VTE, pulmonary embolism was present in 63%, and 97% had active cancer at the time of study entry. The primary outcome occurred in 12.8% of patients in the edoxaban group, compared with 13.5% in the dalteparin group (HR 0.97; 95% CI 0.7–1.36, p = .0056 for noninferiority). The difference in risk for recurrent VTE was -3.8% (95% CI, -7.1 to -0.4), and the corresponding difference in risk of major bleeding was 3.1% (95% CI, 0.5–5.7) with edoxaban. The frequency of severe major bleeding events was similar in each group (12 patients), and survival at 12 months free of recurrent VTE or major bleeding was also similar (55% and 56.5% for edoxaban and dalteparin, respectively). The results of this study suggest that edoxaban is noninferior to dalteparin for the treatment of cancer-associated VTE.
Other Oral Abstracts
Primary Analysis of JULIET: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma7
Stephen Schuster, MD, presented results from this international phase 2 trial that enrolled 147 patients with relapsed or refractory (RR) diffuse large B-cell lymphoma (DLBCL) who had failed 2 or more lines of therapy to receive tisagenlecleucel (CTL019). Ninety-nine patients were infused by the data cutoff of 5.8 months postinfusion. The ORR was 53% (95% CI, 42%–64%, p < .0001), with 39.5% of patients achieving a complete response (CR). Response rates were consistent across subgroups, including those who failed prior autoSCT and double-hit lymphoma. The 6-month probability of being relapse free was 73.5% (95% CI, 52.0%–86.6%), and the 6-month probability of overall survival (OS) was 64.5% (95% CI, 51.5%–74.8%). Grade 3 or 4 adverse events (AEs) occurred in 86% of patients, with cytokine-release syndrome (CRS) observed in 58% (15% grade 3, 8% grade 4, 15% requiring tocilizumab). Neurologic AEs were observed in 12% and were managed with supportive care. No deaths attributable to CTL019 occurred. Overall, this trial demonstrated higher response rates to CTL019 than previous studies in DLBCL, with encouraging tolerability. Of note, several patients received CTL019 infusion as outpatients.
Long-Term Follow-up ZUMA-1: A Pivotal Trial of Axicabtagene Ciloleucel (Axi-Cel; KTE-C19) in Patients with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)8
Sattva Neelapu, MD, presented the 1-year follow-up data from the phase 2 ZUMA-1 study of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in patients who either had no response to immediate prior chemotherapy or relapsed within 12 months after autologous stem cell transplant (autoSCT). This analysis had a longer follow-up period than many studies presented to date. The ORR in the 108 infused patients at median follow-up of 15.4 months was 82%, with 58% of patients achieving complete response (CR), both of which are similar to the prior 8.7 month primary analysis rates of 82% and 54%, respectively.9 Median duration of response is 11.1 months for all patients, and 42.8% of patients from the original phase 1 trial continue to have a CR at 24 months. Of patients who achieved a CR, 60% remained in remission for 12 months or longer. No new late-onset CRS, neurologic toxicities, or grade 5 toxicities were observed, and most serious AEs occurring after 6 months postinfusion were infection related and resolved by data cutoff. Most patients experienced B-cell aplasia, with 8% requiring intravenous immunoglobulin support at some point. The long-term data from this trial suggest responses to axi-cel can be durable, particularly for those who are in remission at 6 months, without additional significant toxicity.
Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy10
The CLARITY trial evaluated the combination of ibrutinib and venetoclax in patients with relapsed, refractory (R/R) chronic lymphocytic leukemia (CLL), and Peter Hillmen, PhD, presented the trial’s initial results. Fifty patients who relapsed within 3 years of receiving fludarabine, cyclophosphamide and rituximab (FCR) or BR or patients with (del)17p who had failed 1 or more prior therapies received ibrutinib 420 mg PO daily as monotherapy for 8 weeks and then had an add-in weekly ramp-up of venetoclax (10-400 mg PO daily) which continued for the duration of treatment (6 months at the time of planned analysis). The primary end point of MRD negativity was 28% at 8 months among the 25 patients with adequate follow-up. The ORR was 100%, and 60% have achieved a complete response (CR) or CR with incomplete count recovery (CRi). Toxicities were primarily hematopoietic, with 19 episodes of grade 3 or 4 neutropenia. Tumor lysis syndrome was uncommon, occurring in only 2 patients, and the condition resolved after a temporary interruption of venetoclax. All patients were able to remain on therapy without fatal adverse events. The authors concluded that the novel combination of ibrutinib and venetoclax seems well tolerated with potent synergy and may be a good option for patients who are not otherwise candidates for more intensive regimens. This trial also serves as a proof-of-concept of using MRD to develop new therapeutic strategies in CLL.
Anti-CCR4 Monoclonal Antibody, Mogamulizumab, Demonstrates Significant Improvement in PFS Compared to Vorinostat in Patients with Previously Treated Cutaneous T-Cell Lymphoma (CTCL): Results from the Phase III MAVORIC Study11
Youn Kim, MD, presented results from the largest phase 3 trial to date in patients with previously treated cutaneous T-cell lymphoma (CTCL) and was based on earlier-phase data that showed a response rate of 30%–40% using mogamulizumab, a chemokine receptor 4 (CCR4) monoclonal antibody, in relapsed or refractory (R/R) CTCL.12 It is also the first pivotal trial to use progression-free survival (PFS) as a primary end point in CTCL. The international multicenter study included 372 patients with stage IB–IVB confirmed mycosis fungoides or Sézary syndrome, with at least one prior course of systemic therapy. Patients were randomized to either mogamulizumab 1 mg/kg IV weekly for 4 weeks and then every 2 weeks thereafter or vorinostat 400 mg PO daily, and crossover was allowed if patients’ disease progressed or they were intolerant of vorinostat. The median age was 63 years (range: 25–101), and most patients had stage IVA disease. The study showed a significant improvement in PFS with mogamulizumab (7.7 months vs. 3.1 months with vorinostat, p < .0001). There was also a higher ORR in the mogamulizumab arm: 28% compared with 4.8% in the vorinostat arm (p < .0001), and an ORR of 30.1% was observed in mogamulizumab-treated patients who crossed over from the vorinostat arm. Mogamulizumab showed significantly greater symptom reduction and improved functional status in early cycles and throughout treatment as compared to vorinostat (p < .05). The most common adverse events (AEs) in the mogamulizumab arm were infusion-related reactions (33.2%) and skin eruptions due to the drug (23.9%), and the majority of AEs were mild to moderate in severity. In comparison, patients in the vorinostat group had higher rates of diarrhea (61.8% vs. 23.4%), nausea (42.5% vs. 15.2%), thrombocytopenia (30.6% vs. 11.4%), and dysgeusia (29.0% vs. 3.3%), and increased serum creatinine (28.0% vs. 3.3%). The MAVORIC study presented mogamulizumab as a new treatment option for patients with R/R CTCL, having fewer AEs than vorinostat and better patient-reported outcomes, and has resulted in a recent breakthrough therapy designation from the U.S. Food and Drug Administration.
The above review briefly highlights only a selection of the key research presented at the meeting. To view all the abstracts, visit: http://www.bloodjournal.org/content/130/suppl_1. The 60th ASH Annual Meeting will take place December 1-4, 2018, in San Diego, CA.
- Scully M, Cataland SR, Peyvandi F, et al. Results of the randomized, double-blind, placebo-controlled, phase 3 HERCULES study of caplacizumab in patients with acquired thrombotic thrombocytopenic purpura. Blood. 2017;130 (suppl 1): LBA-1.
- Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia—results from pre-planned interim analysis of the randomized phase 3 MURANO Study. Blood. 2017;130(suppl 1):LBA-2.
- Mateos MV, Dimopoulos MA, Cavo M, et al. Phase 3 randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) patients ineligible for transplant (ALCYONE). Blood. 2017;130(suppl 1):LBA-4.
- Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754-766.
- Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:1319-1331.
- Raskob GE, Van Es N, Verhamme P, et al. A randomized, open-label, blinded outcome assessment trial evaluating the efficacy and safety of LMWH/edoxaban versus dalteparin for venous thromboembolism associated with cancer: Hokusai VTE-Cancer Study. Blood. 2017;130(suppl 1):LBA-6.
- Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of JULIET: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood. 2017;130(suppl 1):577.
- Neelapu SS, Locke FL, Bartlett NL, et al. Long-term follow-up ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-Cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). Blood. 2017;130(suppl 1):578.
- Neelapu SS, Locke FL, Bartlett NL. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. New Engl J Med. 2017;377(26):2531-2544.
- Hillmen P, Munir T, Rawstron A, et al. Initial results of ibrutinib plus venetoclax in relapsed, refractory CLL (Bloodwise TAP CLARITY Study): high rates of overall response, complete remission and MRD eradication after 6 months of combination therapy. Blood. 2017;130(suppl 1):428.
- Kim YH, Bagot M, Pinter-Brown L, et al. Anti-CCR4 monoclonal antibody, mogamulizumab, demonstrates significant improvement in PFS compared to vorinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL): results from the phase III MAVORIC study. Blood. 2017;130(suppl 1):817.
- Ogura M, Ishida T, Hatake K, et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-CC chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma. J Clin Oncol. 2014;32:1157–1163.