Lenalidomide as maintenance therapy in patients with relapsed DLBCL not eligible for transplantation — Phase II final results

There is an unmet clinical need for patients with diffuse large B-cell lymphoma (DLBCL) who are not eligible for autologous stem cell transplantation (auto-HSCT) or relapse after it. This specific poor prognosis population, with chemosensitive relapse, are usually good candidates for clinical trials. However, not all of them have access to large referral hospitals or meet the selection criteria.

 Andrés J.M. Ferreri and colleagues designed a phase II trial (NCT00799513) to evaluate the approved and available therapy, lenalidomide, as maintenance therapy in relapsed DLBCL for those patients who cannot or refuse to participate in a clinical trial. Preliminary results of this study were previously reported on the Lymphoma Hub. Recently, the investigators published in Hematological Oncology the final study results, with all patients having completed treatment with lenalidomide and with a median follow-up of more than 5 years.¹

 Study design and patient characteristics

 This is an open-label, single-arm, multicenter, phase II trial that included patients with chemosensitive relapse of DLBCL:

• Patients must have had histological diagnosis of de novo or transformed DLBCL at first or second relapse after treatment with anthracycline- and rituximab-based regimens, including auto-HSCT with ≥ 3 months from last treatment to progression
• Patients must have achieved a partial or complete response to second- or third-line salvage treatment

 Patients were treated with lenalidomide 25 mg once daily for 21 days every 28 days until progression or unacceptable toxicity. This maintenance therapy could be discontinued as per physician’s choice 2 years after trial registration.

 The investigators included 46 patients with centrally confirmed de novo or transformed DLBCL at first (72%) or second (28%) relapse following anthracycline- and/or rituximab-based therapy. Other patient characteristics are summarized in Table 1, including the salvage chemoimmunotherapy regimens administered before starting lenalidomide maintenance.

 Table 1. Patient characteristics at trial registration¹

 Results

 After a median follow-up of 65 (range, 39–124) months, Ferreri et al. report a 5-year progression-free survival (PFS) of 48% ± 7%. The PFS curve reached a plateau after 2 years of treatment with lenalidomide, with 22 patients remaining progression-free, demonstrating a beneficial effect of lenalidomide even after maintenance completion. Moreover, the 5-year overall survival rate was 62% ± 7%, meaning that 26 patients were alive by the time of the analysis.

 Other highlighted findings at the median follow-up of 65 months were:

• Ten out of the 20 patients (50%) who started lenalidomide with a partial response achieved a complete remission during maintenance; 75% of patients in complete remission did not relapse
• Patients who had a time to progression since their last pre-enrollment treatment of ³ 12 months presented with a significantly longer PFS following lenalidomide maintenance (5-year PFS: 62% ± 9%)
• In total, 29 (63%) patients reached a duration of response to lenalidomide longer than that to prior treatment

 Safety

 Lenalidomide courses were administered a total of 849 times, with an average of 19 courses per patient (range, 3–82). Treatment discontinuation before 2 years was related to progressive disease in 17 patients, toxicity in eight patients, and patient request in five cases. However, 17 patients received lenalidomide for ≥ 2 years.

 As registered in Table 2, frequent adverse events were Grade 1–2, and Grade 3–4 adverse events only occurred in £ 3% of delivered courses, except for neutropenia.

• Neutropenia was the most frequently reported adverse event and the leading cause of dose reduction, but ultimately, patients treated with or without lenalidomide dose reduction had the same 5-year PFS (48%; 95% CI, 38–58)
• There were 13 serious adverse events reported in 12 patients due to febrile neutropenia (n = 5), diarrhea (n = 2), melena, stroke, vomiting, ocular infection of herpes zoster virus, intestinal infarction, and infective meningitis. All but two patients recovered, and nine continued with lenalidomide treatment
• In this trial, four (9%) patients developed five other cancers, but the investigators consider this rate consistent with previous reports in a similar population

 Table 2. Toxicity of lenalidomide maintenance¹

Adverse event, n (%)	Grade 1–2	Grade 3	Grade 4	Grade 5*
Neutropenia	135 (16)	113 (13)	30 (4)	—
Anemia	204 (24)	25 (3)	—	—
Thrombocytopenia	139 (16)	15 (2)	4 (< 1)	—
Febrile neutropenia/infections	13 (2)	1 (< 1)	—	1 (< 1)
Diarrhea	39 (5)	27 (3)	1 (< 1)	—
Nausea/vomiting	13 (2)	2 (< 1)	—	—
Hepatotoxicity	41 (5)	4 (< 1)	—	—
Constipation	9 (1)	5 (1)	—	—
Neurotoxicity	53 (6)	1 (< 1)	—	—
Rash	18 (2)	6 (1)	2 (< 1)	—
Nephrotoxicity	19 (2)	3 (< 1)	—	—
Thrombotic/ischemic events	1 (< 1)	1 (< 1)	—	2 (< 1)
Adverse events of Grade 1 or 2 occurring in ≥ 10% of patients and all Grade 3–5 events are reported. *Toxic deaths were due to septic meningitis, intestinal infarction, and sudden death (probably a thromboembolic event) Denominator for the different forms of toxicity is the number of delivered courses (n = 849)

 Conclusion

 Based on previous publications about patients with relapsed DLBCL, the expected 1-year PFS is nearly 30%.² Upon adding lenalidomide maintenance, the 1-year PFS improved to 68% ± 7%, above the investigator’s expectations. In this update with longer follow-up, the benefit of lenalidomide is further confirmed and extended beyond maintenance treatment duration, with a 5-year PFS of 48% ± 7% and 5-year overall survival of 60% ± 7%.

Of note, in 50% of patients, response to lenalidomide was twice as long as response duration to the prior treatment line, even when 61% of this cohort were > 70 years, and previously exposed to rituximab, which are features associated with poorer outcomes. Nevertheless, the study cohort does not represent the global population in this setting, since patients with refractory disease were excluded, and 72% were enrolled at first relapse.

 In conclusion, the authors state that lenalidomide demonstrated its efficacy in this setting and its positive safety-benefit balance with appropriate and timely dose reductions. It should also be further studied as maintenance therapy for patients with chemosensitive relapsed DLBCL in a randomized controlled trial.