conference reporter

62nd ASH Annual Meeting and Exposition

Novel and Evolving Therapeutic Constructs in Aggressive B-Cell Lymphoma

by Jeremy S. Abramson, MD, MMSc

Overview

Several abstracts presented at the 62nd ASH Annual Meeting and Exposition focused on novel and emerging treatment approaches in aggressive B-cell lymphoma, including newer strategies for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). 

Our featured expert, Jeremy S. Abramson, MD, MMSc, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD, and Dr Abramson’s clinical perspectives on these emerging data are presented here. 

Jeremy S. Abramson, MD, MMSc

Director, Jon and JoAnn Hagler Center for Lymphoma
Jon and JoAnn Hagler Chair in Lymphoma
Massachusetts General Hospital Cancer Center
Associate Professor of Medicine
Harvard Medical School
Boston, MA

“This is an exciting time in DLBCL. We have made significant advances over the past decade, from R-CHOP, high-dose chemotherapy, and transplantation to newer strategies that include CD19-based CAR T-cell therapies and other novel therapies that are in development.”

Jeremy S. Abramson, MD, MMSc

This is an exciting time in DLBCL. We have made significant advances over the past decade, from R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone), high-dose chemotherapy, and transplantation to newer strategies that include CD19-based chimeric antigen receptor (CAR) T-cell therapies and other novel therapies that are in development. For instance, we are seeing that CAR T-cell therapies such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel produce durable responses in high-risk subsets such as those with double-hit lymphoma (ie, responses that are comparable to those of the overall population). This had not been the case with conventional therapy. 

Additionally, the recent completion of several early phase trials gives us confidence that this trend will continue to accelerate improvements in the treatment landscape for DLBCL. For instance, this year at ASH 2020, some data emerged for novel investigational anti–CD19-directed antibody-drug conjugates, such as loncastuximab tesirine (Lonca). 

In abstract 1183, Caimi and colleagues reported that the overall response rate (ORR) with Lonca as monotherapy was 48.3% and the complete response rate was 24.1%, with a median duration of response of 10.3 months among the 70 responders. In a subgroup analysis, the ORR was 33.3% for patients with double- or triple-hit DLBCL, and these appeared to be all or mostly all complete responses. Researchers reported that Lonca was also effective in those who had received prior CD19-directed CAR T-cell therapy (ORR, 46.2%). Patients who had received previous CD19-directed therapy were required to have persisting CD19 protein expression to enroll (NCT03589469); some patients who lose their response to CAR T cells do so owing to the loss of CD19 expression, so Lonca would not be expected to help in that scenario. 

Additional data, including long-term durability data, are needed to identify how Lonca might be sequenced in a relapsed/refractory DLBCL population. With existing CAR T-cell therapies, approximately 40% of patients appear to have sufficiently durable long-term remissions to suggest that cure is possible in this group. Are we going to see the same responses with something like Lonca? In my opinion, it may be wishful thinking to expect an antibody-drug conjugate to produce cures to the same degree as CAR T cells, but longer follow-up for durability will provide that answer. 

In abstract 2107, Linhares et al described the design for a phase 3, randomized, open-label study of Lonca plus rituximab (Lonca-R) vs rituximab plus gemcitabine and oxaliplatin (R-GemOx) in patients with relapsed/refractory DLBCL (NCT04384484). I do think that something like Lonca-R might be a reasonable combination for this population, given the limitations of the available standard of care. Lonca-R might also be an appealing treatment option for patients who do not respond to CAR T-cell therapy or who are not eligible for an autologous stem cell transplantation or CAR T-cell therapy based on poor performance status or medical comorbidities. 

Yet another strategy being studied involves CD47, a “do not eat me” checkpoint located on tumor cells that signals macrophages not to destroy that cell. In abstract 3016, Kim and colleagues evaluated the combination of the CD47 blocker ALX148 with rituximab in 33 patients with non-Hodgkin lymphoma, 11 of whom had DLBCL. By blocking CD47, ALX148 signals macrophages to “eat them.” The numbers in this study were small; however, ALX148 showed encouraging preliminary activity in combination with rituximab. These data, in concert with previously published data on the CD47 blocker Hu5F9-G4, help to validate this class of therapy for relapsed/refractory aggressive B-cell lymphomas for which new treatment options with novel mechanisms of action are still very much needed.

References

Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9-G4 and rituximab in non-Hodgkin’s lymphoma. N Engl J Med. 2018;379(18):1711-1721. doi:10.1056/NEJMoa1807315

Caimi PF, Ai WZ, Alderuccio JP, et al. Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large B-cell lymphoma [abstract 1183]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Chong EA, Chong ER, Landsburg DJ, et al. Anti-CD19 CAR-T for treatment of double expressor and double hit large B-cell lymphomas: a single institution real-world analysis [abstract 1213]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

ClinicalTrials.gov. Study to evaluate loncastuximab tesirine with rituximab versus immunochemotherapy in participants with relapsed or refractory diffuse large B-cell lymphoma (LOTIS 5). Accessed December 7, 2020. https://clinicaltrials.gov/ct2/show/NCT04384484

ClinicalTrials.gov. Study to evaluate the efficacy and safety of loncastuximab tesirine in patients with relapsed or refractory diffuse large B-cell lymphoma. Accessed December 7, 2020. https://clinicaltrials.gov/ct2/show/NCT03589469 

Kahl BS, Hamadani M, Radford J, et al. A phase I study of ADCT-402 (loncastuximab tesirine), a novel pyrrolobenzodiazepine-based antibody-drug conjugate, in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res. 2019;25(23):6986-6994. doi:10.1158/1078-0432.CCR-19-0711

Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511-e522. doi:10.1016/S2352-3026(20)30120-4

Kim TM, Lakhani N, Gainor J, et al. ALX148, a CD47 blocker, in combination with rituximab in patients with non-Hodgkin lymphoma [abstract 3016]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Linhares Y, Gandhi MD, Chung M, Adeleye J, Ungar D, Hamadani M. Safety and antitumor activity study evaluating loncastuximab tesirine and rituximab versus immunochemotherapy in diffuse large B-cell lymphoma [abstract 2107]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.

Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7

Oronsky B, Carter C, Reid T, Brinkhaus F, Knox SJ. Just eat it: a review of CD47 and SIRP-α  antagonism. Semin Oncol. 2020;47(2-3):117-124. doi:10.1053/j.seminoncol.2020.05.009

Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980


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