Lenalidomide Maintenance Extends Progression-Free Survival in CLL


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Lenalidomide (Revlimid), a cornerstone of therapy for multiple myeloma in the modern era, is making headway as maintenance therapy in chronic lymphocytic leukemia (CLL). Separate phase III studies presented at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition showed prolonged progression-free survival with lenalidomide maintenance as part of treatment.

Interim results of the CLL M1 study by the German CLL Study Group showed that lenalidomide maintenance following front-line chemotherapy led to an 80% reduction in the risk of disease progression in high-risk CLL.1 The phase III CONTINUUM study found that lenalidomide maintenance reduced the risk of disease progression by 60% when given to patients with at least a partial response to second-line therapy.2 The results of both studies were so robust that their respective data safety and monitoring boards recommended unblinding and continuing patients on maintenance lenalidomide.

CLL M1 Study

Anna Fink, MD

Anna Fink, MD

“Lenalidomide maintenance therapy substantially prolonged progression-free survival. We saw conversion to minimal residual disease–negative status in the lenalidomide group. Thus far, there is no difference in survival at this interim analysis. The study confirms the prognostic significance of achieving minimal residual disease,” stated lead author Anna Fink, MD, of the University of Cologne, Germany.

CLL M1 enrolled 468 physically fit, previously untreated patients with CLL. They received investigator’s choice of chemotherapy: fludarabine/cyclophosphamide/rituximab (Rituxan; FCR), fludarabine and rituximab, fludarabine and cyclophosphamide, or bendamustine and rituximab. Most patients received bendamustine and rituximab, with FCR coming in second.

After 4 cycles of chemotherapy, 89 of 468 patients were deemed at high risk for disease progression because they had minimal residual disease levels of at least 10-2 cells or levels greater than or equal to 10-4 to less than 10-2 combined with either unmutated IGHV gene status, del (17p), or mutated TP53 at baseline. “Seventy-eight percent of all patients reached [minimal residual disease] negativity and were not eligible for the trial,” she said.

High-risk patients were randomized in a 2:1 ratio to lenalidomide maintenance (5 mg/d orally for cycle 1, escalated to a targeted dose of 15 mg/d by cycle 7) or placebo. Minimal residual disease was assessed every 6 months, and the dose of lenalidomide could be adjusted accordingly. Treatment was continued until disease progression or unacceptable toxicity. Patients received anticoagulation according to their level of risk for thromboembolic events.

Treatment was given to 56 patients in the lenalidomide arm and 29 patients in the placebo arm. According to an independent review, at a median follow-up of 17.5 months, median progression-free survival for lenalidomide was not yet reached vs 13.3 months for placebo—representing a relative risk reduction for disease progression of 80%, which was highly statistically significant (P < .00001).

A linear correlation was observed between minimal residual disease level at baseline and progression-free survival. No difference in overall survival was reported. Final survival data are expected in 2021.

Most adverse events were mild or moderate. Reasons for treatment discontinuation differed between the two treatment arms. Discontinuations due to adverse events occurred in 32.1% of patients on lenalidomide, whereas 44.8% of patients on placebo discontinued treatment due to disease progression. There was one fatality in each arm.

CONTINUUM Trial

Anna Schuh, MD, PhD, of the University of Oxford, United Kingdom, presented the results of the CONTINUUM trial. This trial enrolled patients with at least a partial response to second-line therapy and an Eastern Cooperative Oncology Group (ECOG) performance score of between 0 and 2.

Patients (n = 314) were randomized in a 1:1 ratio to receive lenalidomide or placebo. Lenalidomide was given at a starting dose of 2.5 mg/d for the first 28-day cycle, 5 mg/d from cycle 2, and esclated up to 10 mg/d from cycle 7 on based on tolerability.

At a median follow-up of 31.5 months, median progression-free survival was 33.9 months in the lenalidomide arm vs 9.2 months for placebo—representing a significant 60% difference favoring lenalidomide (P < .001).

The advantage of lenalidomide was maintained in all subgroups, regardless of age, prior response to chemotherapy, and the number of poor prognostic factors.

Role of Lenalidomide Maintenance in CLL

  • Lenalidomide maintenance therapy following either first-line or second-line chemoimmunotherapy prolonged progression-free survival in CLL in phase III trials.
  • The robust results of these two phase III trials are only applicable to patients who receive chemotherapy as upfront treatment of CLL.
  • In the United States, CLL treatment strategies appear to be moving toward upfront ibrutinib or other chemotherapy-free regimens.

Although there was a numerical trend toward improved survival in the lenalidomide arm, the difference was not statistically significant.

Subsequent therapy was given to 36% of the lenalidomide-treated patients vs 58% of placebo patients. Of these patients, 16% and 20%, respectively, were treated with a Bruton’s tyrosine kinase or phosphatidylinositol 3-kinase inhibitor.

“The subsequent therapies may explain the lack of a survival difference,” Dr. Schuh commented.

Lenalidomide treatment led to more frequent grade 3 or higher adverse events (neutropenia, thrombocytopenia, diarrhea, pneumonia, fatigue, hypokalemia, pulmonary embolism, and sepsis). The incidence of second primary malignancies was not increased in the lenalidomide arm.

“No clinically meaningful difference was reported in quality of life between the two arms,” she said. ■

Disclosure: Both studies were sponsored by Celgene. Dr. Fink has received travel grants from Mundipharma, Roche, and AbbVie; honoraria from Roche; and research funding from Celgene. Dr. Schuh has served as a consultant and received honoraria from Gilead, Roche, Janssen, Novartis, Celgene, and AbbVie.

References

1. Fink AM, et al: Lenalidomide maintenance after front line therapy substantially prolongs progression free survival in high risk CLL. 2016 ASH Annual Meeting. Abstract 229. Presented December 3, 2016.

2. Foà R, et al: Results of the phase 3 study of lenalidomide versus placebo as maintenance therapy following second-line treatment for patients with chronic lymphocytic leukemia. 2016 ASH Annual Meeting. Abstract 230. Presented December 3, 2016.


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