Rapid Progress in Aggressive Hematologic Malignancies Highlighted at ASH 2018
San Diego, CA—The 60th Annual Meeting of the American Society of Hematology drew more than 25,000 attendees from across the globe who were seeking information on the rapid pace of progress in hematology. Updates on the panoply of immunotherapies for B-cell malignancies, including chimeric antigen receptor (CAR) T-cell therapy, and the impressive progress made in the management of multiple myeloma and chronic lymphocytic leukemia (CLL) were highlighted in the scientific sessions.
The Ham-Wasserman lecture was delivered by Michael Hallek, MD, Professor and Chairman, Center for Integrated Oncology, University Hospital of Cologne, Germany. Dr Hallek discussed the impressive progress made in our understanding of the biology of CLL, the use of minimum residual disease (MRD) as a highly important clinical end point in CLL, and advances in therapeutic strategies. He highlighted the importance of using clinical and genetic information for optimal management of CLL, and emphasized new data presented at the meeting pointing to different strategies for older and younger patients with CLL, as discussed in this issue.
Nitin Jain, MD, Associate Professor, Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, noted the dramatic changes in the treatment landscape of CLL based on the better understanding of the disease biology, and pointed to recent approvals of B-cell receptor inhibitors, such as ibrutinib (Imbruvica) and idelalisib (Zydelig), and B-cell lymphoma-2 inhibitors, such as venetoclax (Venclexta).
Improved Options in CLL
New data presented at the meeting demonstrated that ibrutinib-based therapy may become a new treatment standard in many patients with CLL. Ibrutinib combined with rituximab (Rituxan) significantly improved progression-free survival (PFS) compared with a standard chemoimmunotherapy regimen as first-line treatment in younger patients with CLL, with the combination prolonging PFS by 65% compared with chemotherapy plus rituximab.
“The most important take-home message is that this late-breaking study demonstrates a paradigm shift away from chemotherapy to targeted therapy to improve outcomes for our patients,” said Aaron Gerds, MD, MS, of Cleveland Clinic Taussig Cancer Institute, OH.
In a study of older patients aged ≥65 years with newly diagnosed CLL, ibrutinib alone improved PFS compared with standard-of-care chemoimmunotherapy with bendamustine (Bendeka) plus rituximab. The 2-year estimates of PFS were 87% among patients randomized to ibrutinib alone and 88% among those randomized to ibrutinib plus rituximab compared with 74% in patients randomized to chemotherapy plus rituximab (see First-Line Ibrutinib Improves Outcomes Compared with Current Standard of Care in Older Patients with Chronic Lymphocytic Leukemia).
Furthermore, results of the MURANO study in patients with relapsed or refractory CLL showed that the use of a fixed-dose immunotherapy combination with venetoclax plus rituximab for 2 years achieved MRD-negativity in 78% of the patients. Perhaps not surprising, the immunotherapy combination had better outcomes than chemotherapy with venetoclax and chemotherapy. The estimated overall survival was 87.9% with the immunotherapy combination versus 79.5% with chemoimmunotherapy (see MURANO: Venetoclax-Rituximab at Fixed Duration Beats Chemoimmunotherapy in Relapsed/Refractory CLL).
Enhanced Responses to CAR T-Cell Therapy
CAR T-cell therapies have shifted the treatment paradigm for many patients with aggressive hematologic cancer in whom treatment options have been limited. Several studies spotlighted the long-term efficacy of CAR T-cell therapies, analyzed how combination therapies may affect treatment responses, and examined if a transplant after CAR T-cell therapy improved remission rates.
“These are transformative therapies and we’re seeing their expanding value in terms of giving patients who essentially ran out of options an opportunity to live,” said Joseph Alvarnas, MD, Vice President, Government Affairs; and Senior Medical Director, Employer Strategy, City of Hope, Duarte, CA, who moderated a press briefing on CAR T-cell therapy.
“At the same time, we’re identifying the limitations of these therapies. For example, CAR T-cells may stop working in some patients for various reasons, which has prompted researchers to ask what combination therapies could be used to extend the benefits of treatment,” Dr Alvarnas added.
Long-term analyses of the ELIANA clinical trial in patients with relapsed or treatment-resistant acute lymphocytic leukemia (ALL) and the JULIET clinical trial in adults with relapsed and refractory diffuse large B-cell lymphoma demonstrated sustained responses to the CAR T-cell therapy tisagenlecleucel (Kymriah), which targets the CD-19 protein often expressed on lymphoma cells (see Durable Responses to CAR T-Cell Therapy in B-Cell Lymphomas).
In another study, combining a CAR T-cell therapy with ibrutinib was shown to have the potential to improve outcomes and reduce the toxicity of CAR T-cell therapy in patients with difficult-to-treat CLL. “To our knowledge, these are the most encouraging results that have been seen to date in humans with a combination of CAR T-cells and a targeted agent,” said Jordan Gauthier, MD, Fred Hutchinson Cancer Research Center, Seattle, WA. “While the CAR T-cells expanded robustly in both groups and led to high rates of response, we did not observe a single case of severe cytokine release syndrome in patients receiving ibrutinib during CAR T therapy.”
And another study showed that anti-CD19–directed CAR T-cell therapy combined with an immune checkpoint inhibitor—pembrolizumab (Keytruda) or nivolumab (Opdivo)—prolonged the effect of CAR T-cell therapy in children with relapsed B-cell ALL (see Checkpoint Inhibitor a New Approach to Jump-Start a Waning Response to CAR T-Cell Therapy).
Finally, undergoing a first stem-cell transplant after CAR T-cell therapy was shown to reduce the rate of disease relapse in patients with ALL.
Taking a BiTE Out of Multiple Myeloma
A wealth of B-cell maturation antigen (BCMA) therapies are being investigated for patients with multiple myeloma. A next-generation BCMA-targeted CAR T-cell therapy was associated with an objective response rate of 83.3% in patients with heavily treated, relapsed or refractory multiple myeloma, according to the results from phase 1 data presented at the meeting (see Explosive Development of BCMA CAR T-Cell Therapies for Multiple Myeloma).
In addition to CAR T-cell therapy, the bispecific T-cell engager (BiTE) AMG 420 induced responses in 7 of 10 patients with heavily pretreated multiple myeloma and manageable toxicity. The finding earned AMG 420 a fast-track designation from the FDA (see AMG 420, a Novel BiTE, Shows Impressive Responses in Heavily Treated Patients with Multiple Myeloma).
In transplant-ineligible patients with multiple myeloma, the combination of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone is a new treatment standard based on data from a phase 3 clinical trial presented at the meeting (see Daratumumab Enhances Remissions When Added to Lenalidomide and Dexamethasone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma).
Finally, in a phase 2 clinical trial of patients with high-risk smoldering multiple myeloma, 84% responded to treatment with elotuzumab (Empliciti), lenalidomide, and dexamethasone, and no patients progressed to overt multiple myeloma during the 3-year follow-up period (see Elotuzumab, Lenalidomide, and Dexamethasone Combination Demonstrates High Response Rate in High-Risk Smoldering Multiple Myeloma).