How is indolent recurrent non-Hodgkin lymphoma (NHL) treated?

Updated: Feb 25, 2021
  • Author: Sanjay Vinjamaram, MD, MPH; Chief Editor: Emmanuel C Besa, MD  more...
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In general, treatment with standard agents rarely produces a cure in patients who have relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse usually ensues. Favorable survival after relapse has been associated with age younger than 60 years, prior complete remission rather than partial remission, and duration of response longer than 1 year. For relapse that remains low grade, the following are possible treatment options:

  • Single alkylating agents (chlorambucil or bendamustine)

  • Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, and temsirolimus [41]

  • Combination chemotherapy - CVP, CHOP, and others

  • Purine analogues - Fludarabine, 2-CDA

  • Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration

  • Radioimmunotherapy

131Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity. [42] Tositumomab (a murine IgG2a lambda monoclonal antibody directed against CD20 antigen) plus 131I (Bexxar) has been approved by the US Food and Drug Administration (FDA) for relapsed or refractory, low-grade, follicular, or transformed NHL. [43, 44]

Ibritumomab tiuxetan plus 90yttrium (Zevalin) also has been approved for use in relapsed indolent lymphoma. These radioimmunotherapy agents typically are used only in patients with less than 25% bone marrow involvement with lymphoma and in patients refractory to rituximab.

Local relapse can be treated with radiotherapy. High-dose chemotherapy plus stem cell transplantation is being investigated to determine whether it can produce significantly better survival rates compared with conventional chemotherapy. [45]

In 2019, the FDA approved lenalidomide in combination with a rituximab product for the treatment of previously treated follicular lymphoma or marginal zone lymphoma, the first nonchemotherapeutic regimen approved for those conditions. Approval was based on the AUGMENT study, in which patients were randomized to receive either lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The objective response was 80% in the lenalidomide plus rituximab arm compared with 55% in the control arm. Progression-free survival improved for lenalidomide plus rituximab arm versus control arm, with median duration of 39.4 months versus 14.1 months. [46]

Current NCCN guidelines recommend phosphoinositide 3-kinase (PI3K) inhibitors for relapsed or refractory indolent NHL that has failed to respond to 2 prior therapies. PI3K inhibitors include idelalisib, copanlisib, and duvelisib. [26]

Idelalisib (Zydelig) is the first PI3K inhibitor to receive accelerated approval from the FDA for relapsed follicular B-cell NHL and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. In this single-group, phase II, open-label study,  patients received idelalisib 150 mg PO BID until disease progression or study withdrawal. The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months.  [47]

Copanlisib and duvelisib were also FDA-approved for follicular lymphoma in patients who failed to respond to two prior therapies. For copanlisib, approval was based on a phase II trial that reported an objective response rate was 59%, with 12% complete responses. The median duration of response (DoR) was 22.6 months. The median progression-free survival was 11.2 months, with the median overall survival not yet reached. [48]

Duvelisib is a selective oral small molecule inhibitor of PI3K-delta and PI3K-gamma. The open label, global, phase II DYNAMO trial reported an overall response rate (ORR) of 47.3%. The estimated median DoR was 10 months, and the estimated median progression-free survival was 9.5 months. [49]

Although PI3K inhibitors provide therapeutic benefits, there have been concerns of severe adverse reactions, including severe infections (eg, Pneumocystis jirovecii pneumonia [PJP]) and long-term immune-related toxicities. Therefore, concomitant PJP prophylaxis is strongly recommended for patients receiving treatment with idelalisib and should be considered in those receiving copanlisib or duvelisib. 

Umbralisib is a dual inhibitor of PI3K-delta and casein kinase (CK1) 1-epsilon expressed on malignant B cells. It was granted accelerated approval for or refractory MZL who have received at least 1 prior anti-CD20-based regimen and for relapsed or FL who have received at least 3 prior lines of systemic therapy.

Approval was based on two single-arm cohorts of an open-label, multicenter trial, in patients with MZL who received at least 1 prior therapy and in patients with FL after at least 2 prior systemic therapies. Patients received umbralisib 800 mg PO once daily until disease progression or unacceptable toxicity. For patients with MZL, the overall response rate was 49% (95% CI: 37.0, 61.6) with 16% achieving complete responses. Median DOR was not reached (95% CI: 9.3, NE) in these patients. For patients with FL, the ORR was 43% (95% CI: 33.6, 52.2) with 3% achieving complete responses. Median DOR was 11.1 months (8.3, 16.4).  [50]


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