Targeted Therapies in Indolent Lymphoma: Challenging the Current Paradigm

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Jeremy S. Abramson, MD

The treatment landscape is rapidly evolving, relying less on traditional chemotherapy. The future for indolent NHL patients is increasingly bright and chemotherapy-free.

—Jeremy S. Abramson, MD

The use of targeted therapies in indolent non-Hodgkin lymphoma (NHL) is a burgeoning area. New targeted therapies directed at the cell surface, intracellular pathways, and the microenvironment are being studied for relapsed indolent NHL. These treatments, if validated in large randomized trials, may make it possible to avoid traditional chemotherapeutic agents in some patients.

“Ongoing clinical trials are studying these newer agents as initial therapy, in combination with, or in lieu of, traditional chemotherapy. Further study is needed to refine toxicity prevention and management and to identify optimal sequencing, novel-novel combinations, and predictors of response with targeted agents. The treatment landscape is rapidly evolving, relying less on traditional chemotherapy. The future for indolent NHL patients is increasingly bright and chemotherapy-free,” said Jeremy S. Abramson, MD, Assistant Professor at Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, during a presentation at the 8th Annual National Comprehensive Cancer Network (NCCN) Congress on Hematologic Oncology.1

Rituximab (Rituxan) was the first targeted therapy to advance treatment of lymphomas. Novel targets that have been identified for study include the cell surface, intracellular pathways, and the microenvironment.

Targeting the Cell Surface

Mechanisms for targeting the cell surface include naked antibodies, radioimmunoconjugates, and antibody-drug conjugates, Dr. Abramson explained.

Obinutuzumab (Gazyva) has been approved in untreated chronic lymphocytic leukemia, but studies have shown this agent has less activity in indolent lymphomas, he noted. On the other hand, radioimmuotherapy with yttrium-90 ibritumomab tiuxetan (Zevalin) has shown potential in relapsed/refractory indolent NHL.

“[Ibritumomab tiuxetan] doesn’t replace rituximab as a treatment option, but rituximab-refractory patients may respond to this agent. It was also evaluated as maintenance therapy following initial chemoimmunotherapy but was inferior to rituximab in that setting,” Dr. Abramson told listeners.

A third strategy is an antibody-drug conjugate (anti-CD79b conjugated to monomethyl auristatin E). Encouraging antitumor responses to this conjugate have been observed within lymphoma subtypes, including follicular lymphoma and mantle cell lymphoma.

“These are early data. This is an appealing compound, and we will be hearing more about this,” Dr. Abramson stated.

Targeting Intracellular Pathways

Idelalisib (Zydelig) targets the PI3K pathway. Idelalisib was studied in relapsed/refractory indolent NHL in a phase II trial that included 125 patients refractory to both rituximab and an alkylator, with a median of four prior therapies.2 Excellent responses were observed.

“This represents an unmet need—high-risk patients who are double-refractory. The caveat is that the drug has relatively uncommon toxicities including diarrhea, colitis, pneumonia, and infection, and oncologists should keep an eye out for them,” he continued.

Ibrutinib (Imbruvica) is an inhibitor of Bruton’s tyrosine kinase approved for relapsed/refractory chronic lymphocytic leukemia and studied in a phase I trial in relapsed B-cell NHL.3 Thus far, results are encouraging, with an overall response rate greater than 50% and tumor volume reductions in 55% of patients. This drug is being investigated in multiple ongoing studies in lymphomas, including combinations with lenalidomide (Revlimid), rituximab, and both lenalidomide and rituximab.

“Ibrutinib is experimental outside of chronic lymphocytic leukemia, small lymphocytic lymphoma, and mantle cell lymphoma. These encouraging results in refractory lymphoma patients make us expect that we will see even better results in lower-risk patients,” he said.

ABT-199 (GDC-0199) targets BCL2 in indolent NHL and has been investigated in a phase I trial in relapsed/refractory NHL.4 Experience has taught investigators that the drug should be given in a slower dosing scheme than originally used to avoid tumor lysis syndrome. This drug produces grade 3/4 myelosuppression in 7% to 19% of patients. Results in mantle cell lymphoma are so far the best, with some responses in follicular lymphoma, diffuse large B-cell lymphoma, Waldenström’s macroglobulinemia, and marginal zone lymphoma.

“Many of the responses with ABT-199 occur at higher dose levels, but there are too few patients in these groups to validate this. We need more data at higher doses and in combinations with other drugs. We will be hearing a lot more about ABT-199,” Dr. Abramson predicted.

Targeting the Microenvironment

The third strategy of targeting the microenviroment is exemplified by lenalidomide. The Cancer and Leukemia Group B (CALGB) 50401 trial compared rituximab plus lenalidomide vs lenalidomide alone in patients with recurrent follicular lymphoma.5 A third arm, rituximab alone, was closed early. The combination proved highly active, with an overall response rate of 72.7% compared to 51.1% with lenalidomide alone. At a median follow-up of 1.7 years, complete response rates were 36.4% vs 13.3%, respectively. The 2-year event-free survival rate was 44% vs 27%.

Two additional trials evaluated lenalidomide plus rituximab in untreated indolent NHL.6,7 Both trials used a chemotherapy-sparing approach up front. In the first trial (from The University of Texas MD Anderson Cancer Center), overall response rate was 85%, complete response rate was 60%, and 3-year progression-free survival rate was 78%. In the second trial (from the Alliance/CALGB), overall response rate was 96%, complete repsonse rate was 71%, and 2-year progression-free survival was 89%.

These encouraging results led to the RELEVANCE study, which will enroll about 1,000 patients and compare rituximab/lenalidomide for induction and maintenance vs rituximab and chemotherapy of the investigator’s choice followed by rituximab maintenance as first-line treatment for NHL.

“Two ongoing trials are looking at PD-1 blockade in indolent NHL. Both pidilizumab and nivolumab have had interesting activity in relapsed rituximab-sensitive follicular lymphoma and relapsed follicular lymphoma, respectively,” he said. Further study is needed. ■

Disclosure: Dr. Abramson is a consultant for Millennium, Gilead, and Janssen.


1. Abramson JS: Targeted therapy in indolent lymphoma. NCCN Annual Congress on Hematologic Malignancies. Presented September 20, 2014.

2. Gopal AK, Kahl BS, deVos S, et al: PI3K delta inhibition by idelalisib in patients with relapsed/refractory indolent lymphoma. N Engl J Med 370:1008-1018, 2014.

3. Advani RH, Buggy JJ, Sharman JP, et al: Bruton’s kinase inhibitor (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31:88-94, 2013.

4. Seymour JF, Davids MS, Pagel JM, et al: ABT-199 (GDC-0199) in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia: High response rates about patients with high risk disease features including unmutated IGHV. European Hematology Association Annual Congress. Abstract 5375. Presented June 14, 2014.

5. Leonard J, Jung S-H, Johnson JL, et al: CALGB 50401: A randomized trial of
lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma. J Clin Oncol 30(suppl):Abstract 8000, 2012.

6. Fowler NH, Neelapu SS, Hagemeister FB, et al: Lenalidomide and rituximab for untreated indolent lymphoma: Final results of a phase II study. American Society of Hematology Annual Meeting. Abstract 901. Presented December 11, 2012.

7. Martin P, Jung S-H, Johnson JL, et al: CALGB 50803 (Alliance): A phase II trial of lenalidomide plus rituximab in patients with previously untreated follicular lymphoma. ASCO Annual Meeting. Abstract 8521. Presented May 30, 2014.

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