The world of hematologic malignancies continues to move forward at a robust pace despite the challenges of the COVID era. Although some areas of clinical trials and basic research suffered short-term stoppages or delays due to the pandemic, the studies presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition made it very clear that there continue to be significant breakthroughs in the risk assessment, prognosis, and treatment of patients with blood cancers.
Two of the primary areas of interest and excitement revolved around various aspects of immune therapy, as well as forays into precision medicine and targeted therapy. In the realm of immune therapy, the rise of not only chimeric antigen receptor (CAR) T cells but also bispecific antibodies or T-cell engagers against standard and new targets were areas of intense study. The overall response rates, complete remission rates, and measurable residual disease rates associated with these novel approaches were quite impressive, and it is clear they have opened up new directions of clinical and translational investigation in many diseases.
GUEST EDITORS
Sagar Lonial, MD, FACP
Ajay K. Nooka, MD, MPH, FACP
The second area of significant interest was in the precision medicine/targeted therapy realm. Nowhere has this been more impactful than in the diagnosis and treatment of acute myeloid leukemia (AML). At the 2020 ASH meeting, we began to see evidence of how molecular and genetic differences by race may impact outcomes, as well as promising results from targeted agents that will likely equal or supplant the role of standard chemotherapy for AML in the next few years. All of this is very exciting to see and brings hope to our patients, as we better understand the optimal way to approach treatment that will hopefully result in individualized care with fewer short- and long-term toxicities.
Are All Leukemias the Same?
An important study presented by Bhatnagar et al at the Plenary Scientific Session was aimed at the molecular characterization of adult patients with leukemia, evaluating the biologic and clinical race-related differences compared with the concurrently diagnosed Surveillance, Epidemiology, and End Results cohort over the past 3 decades.1 Targeted sequencing was performed on 81 genes in 1,339 patients treated on front-line CALGB/Alliance protocols for intense induction and consolidation therapies. Interestingly, Black patients had lower rates of normal cytogenetics and NPM1 mutations, which are favorable features in AML, and had a significantly higher frequency of IDH2 gene mutations, a finding that had not been reported before. Younger Black patients had inferior 3-year overall survival rates while receiving a similar access to care, highlighting the need for focused enrollment on trials and the use of precision-based, targeted mutation–driven therapeutics.
Immune Therapy: Making the Good Even Better
The prototype for T-cell engagers in hematologic malignancies is blinatumomab, which targets both CD19 and CD3. In a phase II study presented by Short et al, blinatumomab was combined with chemotherapy regimens for the first-line treatment of newly diagnosed Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia (ALL).2 In a disease where chemotherapy consolidation and maintenance already have clear benefits, the addition of immune therapy has the potential to further intensify induction therapy and increase the fraction of patients achieving measurable residual disease negativity. Of the 38 patients who received blinatumomab in addition to chemotherapy, a 2-year overall survival rate of 80% was seen along with high rate of measurable residual disease negativity. Although the number of patients treated was small, this study provides the proof of principle that adding immune therapy to traditional chemotherapy has the potential to further increase the fraction of patients who achieve measurable residual disease negativity—and, ultimately, cure. Although these findings need to be proven in larger studies, the results of this study are very encouraging, nonetheless.
Overcoming BTK Resistance
The BRUIN trial, reported by Mato et al and Wang et al, was an early-phase trial to determine the safety and efficacy of LOXO-305 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell non-Hodgkin lymphomas (NHLs).3,4 Despite most patients having received a prior Bruton’s tyrosine kinase (BTK) inhibitor and/or a BCL2 inhibitor, an overall response rate of 63% was observed, and the majority of responding patients remained on therapy, with a manageable adverse event profile. Though follow-up remains short, one has to recognize that patients with CLL that has progressed after treatment with both BTK and BCL2 inhibitors have an extremely poor prognosis, and LOXO-305 may be a good option alone or as a bridge to additional options.
CAR T-Cell Therapy Continues to Advance
The ZUMA-5 trial, presented by Jacobson et al, is a phase II trial that explored the use of axicabtagene ciloleucel among patients with relapsed or refractory indolent NHL.5 Of the 146 patients treated with axicabtagene ciloleucel (124 with follicular lymphoma and 22 with marginal zone lymphoma), the overall response rate was 94%, with 80% of patients with follicular lymphoma achieving a complete response. The median progression-free survival and overall survival were not reached at a median follow-up of 17.5 months. The safety profile included cytokine-release syndrome grade ≥ 3 in 7% of patients and grade ≥ 3 neurologic events in 19% of patients, highlighting the low rates of predictable, but manageable, toxicities associated with CAR T-cell therapies among patients with refractory indolent NHL.
In an era where CAR T-cell therapy is becoming the standard of care for both aggressive and indolent lymphomas, understanding the mechanisms of resistance to CAR T-cell therapies remains an area of unmet need. CD58 alterations or mutations have been implicated in resistance to CAR T-cell therapy. A study at the 2020 ASH meeting suggested that modifying CAR T-cell therapy by providing CD2 co-stimulation may restore the efficacy of therapy in patients with CD58 mutations.6 Analyzing genetic samples from 51 patients treated with axicabtagene ciloleucel, Majzner et al found that 25% of patients with diffuse large B-cell lymphoma lacked a fully functioning version of CD58; in all but one of these patients, axicabtagene ciloleucel was not effective. This study highlighted that the CD58-CD2 axis is an important therapeutic target for next-generation CAR T-cell strategies.
BCMA Emerges as a Key Target
The growing interest in novel targets of therapy has resulted in the identification of B-cell maturation antigen (BCMA) as a potential target, and several strategies are being explored. Among them is the recently approved antibody-drug conjugate belantamab mafodotin-blmf, and others such as bispecific T-cell engagers and CAR T-cell therapies are also in development. Belantamab mafodotin was approved by the U.S. Food and Drug Administration in August 2020 for the treatment of patients with relapsed or refractory multiple myeloma who have received four prior lines of therapy based on the results from DREAMM-2 trial, which showed an overall response rate of 31% at the recommended dose of 2.5 mg/kg.
Although several ongoing studies are evaluating belantamab mafodotin in combination with a variety of other antimyeloma drugs, two vital studies related to belantamab mafodotin were presented at this meeting. The first was a post hoc analysis of the DREAMM-2 trial by Lonial et al, showing single-agent belantamab mafodotin to be efficacious and tolerable in patients with relapsed or refractory multiple myeloma.7 Overall survival exceeded 13 months in each cohort (2.5 mg/kg and 3.4 mg/kg), responses were durable, and there were no long-term toxicity concerns for either cohort.
The second presentation by Trudel et al evaluated the combination of belantamab mafodotin with pomalidomide plus dexamethasone (B-Pd), with the goal of enhancing antibody-dependent cytotoxicity and thereby achieving clinical synergy.8 Among the 34 evaluable patients who had significant prior treatment exposure—half of whom had high-risk cytogenetics—significant depths of responses, including greater than very good partial response rates, were seen in two-thirds of patients treated at various doses. Notably, 72% of patients who were refractory to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies achieved a greater than very good partial response rate, with a median progression-free survival of 11.1 months, meeting or exceeding the benchmarks set up by the most effective salvage cellular strategies.
New Targets in Multiple Myeloma
Talquetamab is an IgG4 “duo body” that binds to G protein–coupled receptor family C group 5 member D (GPRC5D) and CD3, redirecting T cells to GPRC5D-expressing myeloma cells to mediate T-cell killing. When given as a single agent to heavily pretreated patients in the step-up dosing studies, the overall response rate was 69%, and the very good partial response rate was 39% at the recommended phase II dose of subcutaneous talquetamab at 405 µg/kg.9 The treatment was well tolerated, with manageable cytokine-release syndrome (usually seen within the first cycle). Although the initial activity is impressive, even more exciting is the possibility of having another new cell-surface target in our quest for achieving cure in multiple myeloma. As we seek to further reduce tumor burden and prevent the development of resistant clones, having multiple targets makes this goal far more achievable.
The 2020 ASH Annual Meeting & Exposition was an exciting conference (even though virtual) with significant advances featured across all hematologic malignancies. Taking early data from the lab or clinic and translating it to meaningful clinical benefit for all of our patients remains the goal, and we are now in a position to take these advances and accelerate the path for cure.
DISCLOSURE: Dr. Lonial has served as a consultant for Juno Therapeutics, Sanofi, Millennium, Genentech, Karyopharm, Novartis, Amgen, Takeda, Merck, AbbVie, GSK, Bristol Myers Squibb, and Janssen; has received honoraria from Onyx, Millennium, Novartis, Amgen, Merck, GSK, Bristol Myers Squibb, and Janssen; has received personal fees from Novartis, Amgen, Takeda, Merck, GSK, Bristol Myers Squibb, and Janssen; has received research funding from Takeda, Bristol Myers Squibb, and Janssen; and has served on a board of directors or advisory committee for TG Therapeutics. Dr. Nooka has received honoraria and served on advisory boards for Janssen, GlaxoSmithKline, Takeda, Oncopeptides, Sanofi Genzyme, Karyopharm, Bristol Myers Squibb, Adaptive Biotechnology, and Amgen.
REFERENCES
1. Bhatnagar B, Zhao Q, Fisher JL, et al: Poor treatment outcomes of young (< 60 years) African American patients diagnosed with acute myeloid leukemia (Alliance). 2020 ASH Annual Meeting & Exposition. Abstract 6. Presented December 6, 2020.
2. Short NJ, Kantarjian HM, Ravandi F, et al: Hyper-CVAD and sequential blinatumomab in adults with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia: Results from a phase II study. 2020 ASH Annual Meeting & Exposition. Abstract 464. Presented December 6, 2020.
3. Mato AR, Pagel JM, Coombs CC, et al: LOXO-305: A next generation, highly selective, non-covalent BTK inhibitor in previously pretreated CLL/SLL: Results from the phase 1/2 BRUIN study. 2020 ASH Annual Meeting & Exposition. Abstract 542. Presented December 7, 2020.
4. Wang M, Shah NN, Alencar AJ, et al: LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: Results from the phase 1/2 BRUIN Study. 2020 ASH Annual Meeting & Exposition. Abstract 117. Presented December 5, 2020.
5. Jacobson C, Chavez JC, Sehgal AR, et al: Primary analysis of ZUMA-5: A phase 2 study of axicabtagene ciloleucel in patients with relapsed/refractory indolent non-Hodgkin lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 700. Presented December 7, 2020.
6. Majzner RG, Frank MJ, Mount C, et al: CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. 2020 ASH Annual Meeting & Exposition. Abstract 556. Presented December 7, 2020.
7. Lonial S, Lee HC, Badros A, et al: DREAMM-2: Single-agent belantamab mafodotin in patients with relapsed/refractory multiple myeloma—1-year outcomes by prior therapies. 2020 ASH Annual Meeting & Exposition. Abstract 1417. Presented December 5, 2020.
8. Trudel S, McCurdy A, Sutherland HJ, et al: Part 1 results of a dose-finding study of belantamab mafodotin (GSK2857916) in combination with pomalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 725. Presented December 7, 2020.
9. Chari A, Berdeja JG, Oriol A, et al: A phase 1, first-inhuman study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 290. Presented December 5, 2020.
