Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis

Abstract

Purpose: To investigate the safety and efficacy of the combination of lenalidomide and prednisone in patients with myelofibrosis (MF).

Patients and methods: Forty patients with MF were treated. Therapy consisted of lenalidomide 10 mg/d (5 mg/d if baseline platelet count < 100 x 10(9)/L) on days 1 through 21 of a 28-day cycle for six cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d during cycle 2, and 15 mg/d every other day during cycle 3. Lenalidomide therapy was continued indefinitely in patients exhibiting clinical benefit.

Results: The median follow-up was 22 months (range, 6 to 27). Responses were recorded in 12 patients (30%) and are ongoing in 10 (25%). The median time to response was 12 weeks (range, 2 to 32). According to the International Working Group for Myelofibrosis Research and Treatment consensus criteria, three patients (7.5%) had partial response and nine patients (22.5%) had clinical improvement durable for a median of 18 months (range, 3.5 to 24+). Overall response rates were 30% for anemia and 42% for splenomegaly. Moreover, 10 of 11 assessable responders who started therapy with reticulin fibrosis grade 4 experienced reductions to at least a score of 2. All eight JAK2(V617F)-positive responders experienced a reduction of the baseline mutant allele burden, which was greater than 50% in four, including one of whom the mutation became undetectable. Grade 3 to 4 hematologic adverse events included neutropenia (58%), anemia (42%), and thrombocytopenia (13%).

Conclusion: The combination of lenalidomide and prednisone induces durable clinical, molecular, and pathologic responses in MF.

Trial registration: ClinicalTrials.gov NCT00352794.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Dynamics of JAK2V617F mutational burden during lenalidomide and prednisone therapy. JAK2V617F mutational burden was measured by a quantitative pyrosequencing assay in bone marrow specimens at the time points specified during lenalidomide and prednisone therapy in the (A) whole cohort of patients, in (B) responders, and in (C) nonresponders. A significant reduction in JAK2V617F allele burden was observed over the baseline median value after 18 months of therapy in responders (P = .03). In contrast, no reduction in JAK2V617F allele burden was observed among nonresponders during therapy with lenalidomide and prednisone. Minimum and maximum values at each time point are depicted; median values are depicted within each column.

Fig 2.

Effect of lenalidomide and prednisone therapy on cytokine levels, reticulin fibrosis and bone marrow cellularity in responders. (A) Levels of transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) were measured by enzyme-linked immunosorbent assays in peripheral blood before study entry and after 3 and 12 months of therapy in nine responders and 21 nonresponders to lenalidomide and prednisone. Control levels represent mean values in peripheral blood obtained from eight healthy volunteers. (B) Effects of lenalidomide and prednisone on the bone marrow of a responder carrying the JAK2V617F mutation. The upper panels (a, c, e) represent collagen trichrome stains and the lower panels (b, d, f) depict reticulin silver stains at baseline, and after 6 and 12 months of therapy. At baseline, the bone marrrow is markedly hypercellular (100%) with minimal increase in (a) collagen but with a diffuse, dense increase in reticulin fibers with (d) extensive intersections corresponding to a fibrosis score of 4. After 12 months of therapy, the bone marrow cellularity decreased to 70% with only a focal residual network of reticulin fibers in (f) perivascular areas corresponding to a fibrosis score of 1. (C) The dynamics of reticulin fibrosis are shown. All 11 assessable responders had a pretreatment reticulin fibrosis score of 4. This score was reduced to at least 2 in 10 of them during therapy (P = .007). (D) Changes in bone marrow cellularity among responders with respect to pretreatment values were not significant (P = .80).