Advertisement

Lenalidomide for Previously Treated Follicular and Marginal Zone Lymphomas


Advertisement
Get Permission

On May 28, 2019, lenalidomide was approved for use in combination with a rituximab product for previously treated follicular lymphoma and previously treated marginal zone lymphoma.1,2

Supporting Efficacy Data

Approval was based on the findings of two clinical trials: AUGMENT (ClinicalTrials.gov identifier NCT01938001) and MAGNIFY (NCT01996865).2,3 In the AUGMENT trial, 358 patients with relapsed or refractory follicular lymphoma or marginal zone lymphoma were randomly assigned to receive lenalidomide and rituximab (n = 178) or rituximab and placebo (n = 180). The primary endpoint was progression-free survival in the intent-to-treat population assessed by independent review committee.

OF NOTE

Lenalidomide carries boxed warnings for embryofetal toxicity, hematologic toxicity, and venous and arterial thromboembolism.

Median progression-free survival was 39.4 months in the lenalidomide group vs 14.1 months in the placebo group (hazard ratio [HR] = 0.46, P < .0001). Objective response rates were 80% vs 55% among 295 patients with follicular lymphoma and 65% vs 44% among 63 patients with marginal zone lymphoma.

In the single-arm component of the MAGNIFY trial, 232 patients with relapsed or refractory follicular lymphoma, marginal zone lymphoma, or mantle cell lymphoma received 12 induction cycles of lenalidomide and rituximab. Objective response rates on investigator assessment were 59% in 177 patients with follicular lymphoma (median response duration not reached with median follow-up of 7.9 months) and 51% in 45 patients with marginal zone lymphoma (median response duration not reached with median follow-up of 11.5 months).

How It Works

Lenalidomide is an analog of thalidomide with immunomodulatory, antiangiogenic, and antineoplastic properties. Cellular activities of lenalidomide are mediated through its target cereblon, a component of a cullin ring E3 ubiquitin ligase enzyme complex. In vitro, in the presence of drug, substrate proteins are targeted for ubiquitination and subsequent degradation leading to direct cytotoxic and immunomodulatory effects.

Lenalidomide inhibits proliferation and induces apoptosis of certain hematopoietic tumor cells including multiple myeloma, mantle cell lymphoma, del(5q) myelodysplastic syndromes, follicular lymphoma, and marginal zone lymphoma in vitro. Lenalidomide causes a delay in tumor growth in some in vivo nonclinical hematopoietic tumor models including multiple myeloma. Immunomodulatory properties of lenalidomide include increased number and activation of T cells and natural killer (NK) cells, leading to direct and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via increased secretion of interleukin 2 and interferon-gamma, increased numbers of NK T cells, and inhibition of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin 6) by monocytes. In multiple myeloma cells, the combination of lenalidomide and dexamethasone synergizes the inhibition of cell proliferation and the induction of apoptosis. The combination of lenalidomide and rituximab increases ADCC and direct tumor apoptosis in follicular lymphoma cells and increases ADCC in marginal zone lymphoma cells compared with rituximab alone in vitro.

How It Is Used

The recommended starting dose of lenalidomide in follicular lymphoma and marginal zone lymphoma is 20 mg once daily on days 1 to 21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab product. In the AUGMENT trial, rituximab was given at 375 mg/m2 every week in cycle 1 (days 1, 8, 15, and 22) and on day 1 of every 28-day cycle from cycles 2 through 5. Full prescribing information for rituximab should be consulted for dose adjustments for rituximab toxicity.

Prescribing information for lenalidomide provides instructions on dose adjustment for thrombocytopenia, neutropenia, and other grade 3 or 4 toxicities. Instructions on starting doses based on renal function in patients with follicular lymphoma or marginal zone lymphoma are also provided in the prescribing information.

LENALIDOMIDE WITH RITUXIMAB PRODUCT FOR LYMPHOMAS

  • Lenalidomide was approved for use in combination with a rituximab product for previously treated follicular lymphoma and previously treated marginal zone lymphoma.
  • The recommended starting dose of lenalidomide in follicular lymphoma and marginal zone lymphoma is 20 mg once daily on days 1 to 21 of repeated 28-day cycles for up to 12 cycles of treatment in combination with a rituximab product.

Concomitant use of lenalidomide with digoxin requires periodic monitoring of digoxin plasma levels due to increased exposure with lenalidomide treatment. Concomitant use with erythropoietin-stimulating agents or estrogen-containing therapies may increase the risk of thrombosis.

Safety Profile

Across the AUGMENT and MAGNIFY trials, the most common adverse events of any grade occurring in at least 20% of patients receiving lenalidomide and rituximab were neutropenia (48%), fatigue (37%), diarrhea (32%), constipation (27%), nausea (21%), and cough (20%). In the AUGMENT trial, the most common grade 3 or 4 adverse events in the lenalidomide/rituximab group were neutropenia (50%), leukopenia (7%), and anemia (4.5%).

In both trials, fatal adverse reactions occurred in six patients (1.5%) receiving lenalidomide plus rituximab, consisting of cardiorespiratory arrest, arrhythmia, cardiopulmonary failure, multiple organ dysfunction syndrome, sepsis, and acute kidney injury. Serious adverse reactions occurred in 26% of the lenalidomide group in the AUGMENT trial and 29% in the MAGNIFY trial, with the most common being febrile neutropenia (3%). Adverse events led to permanent discontinuation of lenalidomide or rituximab in 14.6% of patients, with the most common cause being neutropenia (4.8%).

Lenalidomide carries boxed warnings for embryofetal toxicity, hematologic toxicity, and venous and arterial thromboembolism. To avoid embryofetal exposure, lenalidomide is available only through a restricted distribution program. Pregnancy must be excluded before the start of treatment and should be prevented during treatment by the use of two reliable methods of contraception.

Lenalidomide also carries warnings/precautions for serious and fatal cardiac adverse events (observed in patients with chronic lymphocytic leukemia); second primary malignancies; hepatic failure including fatalities; cutaneous reactions (hypersensitivity, angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia, and systemic symptoms), including fatalities; tumor-lysis syndrome, including fatalities; tumor flare reactions (observed in chronic lymphocytic leukemia and lymphoma); impaired stem cell mobilization; and early mortality in mantle cell lymphoma. Patients should be advised not to breastfeed during treatment with lenalidomide. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves lenalidomide for follicular and marginal zone lymphoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenalidomide-follicular-and-marginal-zone-lymphoma. Accessed August 26, 2019.

2. Revlimid (lenalidomide) capsules prescribing information, Celgene Corporation, May 2019. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021880s057lbl.pdf. Accessed August 26, 2019.

3. Leonard JP, Trneny M, Izutsu K, et al: AUGMENT: A phase III study of lenalidomide plus rituximab versus placebo plus rituximab in relapsed or refractory indolent lymphoma. J Clin Oncol 37:1188-1199, 2019.


Advertisement

Advertisement



Advertisement