CAR-T therapy isn’t the only new product on the NHL shelf. Twenty years after the rituximab transformed the care of B-cell lymphomas, bispecific antibodies — which bind 2 target antigens — are now attracting attention. Blinatumomab, for example, binds to CD19 on tumor cells and to CD3 on T cells. This drug, approved by the U.S. Food and Drug Administration (FDA) for relapsed/refractory B-cell precursor acute lymphoblastic leukemia, has shown encouraging results in early clinical trials for relapsed/refractory B-cell NHL. Neurologic side effects limited the treatment in this setting. But this is just 1 bispecific antibody being studied for NHL — several others are in development, including mosunetuzumab, GEN3013, REGN1979, and RO7082859. These drugs can be distributed through pharmacies (an advantage over CAR-T), but the authors point out that studies have not yet determined whether they will achieve lasting remissions.

Antibody-drug conjugates (ADCs) are another branch in the evolutionary tree that monoclonal antibodies began. Two of these agents — brentuximab vedotin and polatuzumab vedotin — are FDA-approved for NHL, and more are currently under evaluation. “By harnessing the antibody-antigen interactions to deliver cytotoxins preferentially to tumor cells, ADCs can maximize efficacy and minimize toxicity,” the authors wrote.

For some NHL histologies, including follicular lymphoma (FL) and mantle cell lymphoma (MCL), chemotherapy-free treatment is on the rise. Such approaches have the obvious advantage of avoiding the toxicity associated with chemotherapy. But that leaves doctors facing what may be an unfamiliar list of side effects. “The toxicity profiles are distinct and warrant education and experiencing,” noted Dr Abramson. The variant of MCL that is similar to chronic lymphocytic leukemia has benefit from chemotherapy-free approaches more than other MCL subtypes, although no such regimens are currently approved for first-line treatment for this disease. A multicenter phase 2 study of lenalidomide plus rituximab in 38 patients with newly diagnosed MCL demonstrated an overall response rate of 92%.10 A later update reported a 5-year overall survival rate of 77%.11 

The targeted therapy revolution is also carrying FL into a better future. The immunomodulatory drug lenalidomide has shown overall response rates exceeding 90% in clinical trials. And in the recently published RELEVANCE study (ClinicalTrials.gov Identifier: NCT01476787) — in which more than 1000 patients were randomly assigned to receive chemoimmunotherapy plus maintenance rituximab or lenolidomide plus rituximab (LR) — remission rates and 3-year progression free survival were nearly identical, and the toxicity profiles also showed little difference.12 These results are leading to more experimental investigations, such as replacing rituximab with obinutuzumab or adding a third agent to the LR combination. Other studies are looking at PI3K inhibitors as frontline therapy. Similar approaches are being tested for relapsed FL. The authors also highlight EZH2 inhibitors as particularly promising.


Continue Reading

In short, optimism surrounding the future of NHL is warranted in light of these gains. These treatments may offer powerful results “without the burden of chemotherapy-induced second malignancies and other long-term effects,” points out Dr. Edward Copelan, MD, FACP, who chairs the Department of Hematologic Oncology and Blood Disorders at Carolinas Healthcare System, and who was not an author of the review.

The coronavirus disease 2019 (COVID-19) pandemic, however, is affecting the pace of research. “Many foundations no longer have funds to support research,” noted Dr Heslop. Study participants are hesitant to engage. “Patients are wary about traveling for treatment and trials,” he said. However, Dr Abramson notes that research is slowly picking back up. “Progress is again being made,” he said.

References

  1. Key Statistics for Non-Hodgkin Lymphoma. American Cancer Society website. https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html. Updated January 8, 2020. Accessed July 1, 2020.
  2. Survival Rates and Factors That Affect Prognosis (Outlook) for Non-Hodgkin Lymphoma. American Cancer Society website. https://www.cancer.org/cancer/non-hodgkin-lymphoma/detection-diagnosis-staging/factors-prognosis.html. Updated January 8, 2020. Accessed September 3, 2020.
  3. Davis CP, Stoppler MC (ed). Mantle Cell Lymphoma (MCL). Medicine Net website. https://www.medicinenet.com/mantle_cell_lymphoma_mcl/article.htm#what_is_the_prognosis_of_mantle_cell_lymphoma. Accessed September 3, 2020.
  4. Abramson JS, Ghosh N, Smith SM. ADCs, BiTEs, CARs, and small molecules: a new era of targeted therapy in non-Hodgkin lymphoma. Am Soc Clin Oncol Educ Book. 2020:302-313. doi:10.1200/EDBK_279043
  5. Pollack A. Setting the Body’s ‘Serial Killers’ Loose on Cancer. New York Times website. https://www.nytimes.com/2016/08/02/health/cancer-cell-therapy-immune-system.html. Published August 1, 2016. Accessed September 3, 2020.
  6. 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;20:31-42. doi:10.1016/S1470-2045(18)30864-7
  7. 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;380:45-56. doi:10.1056/NEJMoa1804980
  8. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134lauren(Supplement_1):241. doi:10.1182/blood-2019-127508
  9. Landsburg DJ, Falkiewicz MK, Maly J, et al. Outcomes of patients with double-hit lymphoma who achieve first complete remission. J Clin Oncol. 2017;35(20):2260-2267. doi:10.1200/JCO.2017.72.2157
  10. Ruan J, Leonard JP. Lenalidomide plus rituximab for mantle-cell lymphoma. N Engl J Med. 2016;374:793. doi:10.1056/NEJMc1515465
  11. Ruan J, Martin P, Christos P, et al. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018;132:2016-2025. doi:10.1182/blood-2018-07-859769
  12. Morschhauser F, Fowler NH, Feugier P, et al. RELEVANCE Trial Investigators. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379:934-947. doi:10.1056/NEJMoa1805104