World Lymphoma Awareness Day: More Drugs, Targets, and Hope in Non-Hodgkin Lymphoma

Lee Greenberger, PhD

As the chief scientific officer of The Leukemia & Lymphoma Society (LLS) since 2013, Lee Greenberger, PhD, is responsible for planning and executing the strategy for all LLS research programs. This effort includes a grant portfolio with more than 250 active research projects worldwide, as well as the Therapy Acceleration Program, a venture philanthropy initiative currently with 16 assets—3 of which have earned FDA approval in the past 2 years.

Prior to his tenure at LLS, Dr Greenberger held positions at Bristol Myers Squibb, Enzon Pharmaceuticals, Johnson & Johnson, and Wyeth Pharmaceuticals. Dr Greenberger holds a BA from the University of Rochester and a PhD from Emory University.

The non-Hodgkin lymphoma (NHL) landscape is evolving rapidly with the addition of new immunotherapies, including CAR (chimeric antigen receptor) T-cell therapies, monoclonal antibodies, and bispecific experimental antibodies in mid-stage clinical development. Additionally, allogeneic CD19 CAR T-cell therapy holds great promise as a potentially less expensive and more reliable treatment option that can be delivered to patients with NHL faster than autologous CAR T-cell therapeutics.

A deeper-than-ever scientific understanding of the underlying genetic and biological differences across, and even within NHL subtypes, underpins these and other advancements. Despite the foundational similarity that all NHL involves bone marrow and blood, NHL is better characterized as a diverse group of blood cancers. Today’s treatment and ongoing research are capitalizing not just on known similarities across NHL subtypes, but also delving into unique traits within subtypes to develop more targeted therapies for personalized care.

Immunotherapies, targeted therapies continue to improve lymphoma outcomes

By early 2021, we had the seventh CAR T-cell therapy approval since the first just 4 years ago. Up to that point, all were CD19-directed CAR T-therapies for a range of B-cell malignancies. These CAR Ts are providing substantial numbers of patients with complete response rates that can last for years and may even lead to cures. The seventh approved therapy, idecabtagene vicleucel (ide-cel; Abecma), targets BCMA and can be used for patients with relapsed/refractory multiple myeloma.

One of the most important and practice-changing drug approvals of the last year was brexucabtagene autoleucel (Tecartus), the first CAR T-cell therapy for adults with relapsed/refractory mantle cell lymphoma (MCL). MCL is rare, representing just 1 in 20 or fewer NHLs, and aggressive, with poor long-term survival. There is a clear need for additional treatments since all current treatments will fail eventually.¹

The ZUMA-2 trial (NCT02601313) enrolled patients with MCL who had relapsed/refractory disease after up to 5 previous therapies, one being a Bruton tyrosine kinase (BTK) inhibitor.² The objective response rate to the CAR T-cell therapy was 93% and the complete response rate was 67%. At a median follow-up of just over 1 year, 57% of the patients included in the primary efficacy analysis were still in remission. This provides a clear benefit over previous standard of care.

In another first this past year, axicabtagene ciloleucel (Yescarta) was the first CAR T approved for an indolent NHL, relapsed/refractory follicular lymphoma. New treatments are essential for these patients because the duration of response for relapsed/refractory follicular lymphoma decreases with each round of new therapy.³ The same trial that provided the data that the FDA used for this approval, ZUMA-5, included patients with relapsed/refractory marginal zone lymphoma (MZL). FDA is currently reviewing the supplemental Biologics License Application for this indication.

Despite being the second most common indolent NHL, MZL is understudied. Given its underlying disease heterogeneity, it has been challenging to define a single treatment approach for its subtypes. In the ZUMA-5 trial (NCT03105336), with a median follow-up of 17.5 months, the objective response rate was 85% with a 60% complete response rate among 20 evaluable patients with MZL and 2 MZL subtypes — extranodal and nodal.⁴

This year also saw approval of a targeted therapy for ALK-positive anaplastic large cell lymphoma (ALCL) in children. ALK, the molecular target for crizotinib, is altered in 85% of pediatric patients with ALCL. Targeted therapies are important across all ages, but even more so for children who could face a lifetime of negative effects of systemic, toxic chemotherapies.

The Leukemia & Lymphoma Society (LLS) Children’s Initiative is an unprecedented collaboration that is setting out to transform pediatric blood cancer treatment and care. Our goal is to shift the standard of care away from toxic chemotherapies and toward effective and safe treatments that target cancer cells with minimal impact on healthy cells.

Next generation CAR T, new monoclonal and bispecific antibodies on the way

While revolutionary, CAR T is not without its limitations. It does not work for everyone, and it is expensive, can cause life-threatening toxicities, and cumbersome to produce. LLS directs substantial funding to CAR T and other immunotherapy research because there is so much promise in it.

Our current focus is on making CAR T available for more types of blood cancers by expanding the proteins targeted, and on making it less costly, quicker to administer and more reliable than current treatments where manufacturing issues are possible. LLS-funded researchers are working on “off the shelf” allogeneic CAR T-cell therapies that may provide a solution to all these challenges.

Researchers are also looking at ways to express CAR on natural killer cells and macrophages. These cells hold promise for providing longer lasting anti-tumor activity against more types of cancer, including solid tumors, than traditional CAR T-cell therapies.

Monoclonal antibodies also continue to advance, providing new and better NHL treatment options. While CD20 is the most common target, today we have antibodies that target CD19, CD52, CD30 and CD79b. We also have promising bispecific experimental antibodies in clinical phase testing that may be used as an alternative to CAR T therapy.

Results reported at the December 2020 Annual Meeting of the American Society of Hematology showed response rates for odronextamab and epcoritamab surpassed 90% in early trials. Odronextamab is a CD3xCD20 bispecific antibody that has shown preliminary efficacy, safety, and tolerability in patients with highly refractory indolent NHL.⁵

Epcoritamab is also a CD3xCD20 bispecific antibody that is distinguished from others in development by its subcutaneous administration route, which investigators believe will lead to more gradual increases and lower peak plasma cytokine levels.⁶ This may improve drug tolerability while still providing sufficient drug potency. These exciting new treatments could provide off-the-shelf, outpatient treatment options that engage T cells with compelling antitumor activity in heavily pretreated patients with NHL.

Potential NHL drug approvals coming soon

In addition to the anticipated approval of axicabtagene ciloleucel this year for treatment of relapsed/refractory MZL, BTK inhibitor zanubrutinib is likely to receive FDA approval for the treatment of MZL and Waldenström macroglobulinemia (WM). BTK inhibitors have already transformed treatment of WM, but their effectiveness is not uniform across all subtypes and some BTK inhibitors have significant adverse events that can lead to discontinuation of the therapy. We are learning more about the impact of CXCR4 mutations, which occur in up to 40% of patients with WM on top of the very common alterations in the MYD88 gene seen in more than 90% of patients.⁷

LLS is the largest funder of cutting-edge research to advance cures for NHL and all other blood cancers. On this World Lymphoma Day, we should be proud of what we’ve accomplished and optimistic about what’s to come thanks to a wider range of drug types and targets than ever before. But there is still much work to be done for the more than 80,000 Americans and hundreds of thousands of people worldwide who are diagnosed with NHL each year.

_References

_{1. Ladha A, Zhao J, Epner EM, Pu JJ. Mantle cell lymphoma and its management: where are we now? Exp Hematol Oncol. Published online 2019 Jan 30. doi:10.1186/s40164-019-0126-0}

_{2. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382:1331-1342. doi:10.1056/NEJMoa1914347}

_{3. Rivas-Delgado A, Magnano L, Moreno-Velázquez M, et al. Response duration and survival shorten after each relapse in patients with follicular lymphoma treated in the rituximab era. Br J Heamatol. 2019;184(5):753-759. doi:10.1111/bjh.15708}

_{4. Jacobson C, Chavez JC, Sehgal AR, et al. Primary analysis of Zuma-5: a phase 2 study of axi-cel in patients with R/R iNHL. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 700.}

_{5. Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a human CD20xCd3 bispecific antibody, induces durable, complete responses in patients with highly refractory B-cell non-Hodgkin lymphoma, including patients refractory to CAR T therapy. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 400.}

_{6. Bankhead C. Non-Hodgkin lymphoma: bispecific antibodies impress in refractory disease. MedPageToday. December 11, 2020. https://bit.ly/3DN5QNt}

_{7. Kaiser LM, Hunter ZR, Treon SP, Buske C. CXCR4 in Waldenstrom’s macroglobulinemia: chances and challenges. Leukemia. 2021;35:333-345. https://doi.org/10.1038/s41375-020-01102-3}