Combined Therapy with Lenalidomide and Prednisone Renders Durable Clinical, Histopathological, and Molecular Responses in Patients with Myelofibrosis

Prompted by the activity of single-agent oral lenalidomide (LEN) in primary or secondary (post-essential thrombocythemia or post-polycythemia vera) myelofibrosis (MF), we sought to evaluate the safety and efficacy of the combination of LEN and prednisone (LEN+PRD) in a phase II study for patients with MF. The rationale is that the potent antiangiogenic and cytokine-modulating activity of LEN may be enhanced by PRD to reduce marrow fibrosis and improve hematopoiesis in MF. Therapy consisted of LEN 10mg/d PO (dose level [DL] 0) on days 1–21 of a 28-day cycle in combination with PRD 30mg/d PO during cycle 1, 15mg/d during cycle 2, and 15 mg/d every other day during cycle 3. LEN was to be given for a minimum of 6 cycles and continued indefinitely in responders. LEN dose could be reduced to 5 mg/d (DL −1) or to 5 mg/d every other day (DL −2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) according to toxicity or lack of response. Forty patients (23 male) have been treated. Median age was 62 years (range, 41–86), time from MF diagnosis to LEN+PRD therapy 10 months (range, 0–122), WBC count 87×10⁹/L (range, 1.1–89), hemoglobin 9.8 g/dL (range, 7.8–17.3), and palpable splenomegaly 10cm (range, 0–25). Patients had received a median of 1 prior therapy (range 0–4), including hydroxyurea (n=14), azacitidine (n=6), thalidomide (n=4), and IFN-α (n=3). Ten (25%) patients were treatment-naïve. The JAK2^V617F mutation was detected in 18 (50%) of 36 tested patients and 20 (50%) of 40 had abnormal cytogenetics. Thus far, 341 cycles have been administered. Patients have received therapy for a median of 18 months (range, 6–24.5). According to the International Working Group for Myelofibrosis Research and Therapy (IWG-MRT) criteria, 12 (30%) patients responded, including 8 JAK2^V617F-positive, 3 previously untreated, and 2 who had failed prior thalidomide-based therapy. Three (7.5%) partial response (PR), and 9 (22.5%) clinical improvement (CI) were seen. Anemia improved in 7 (30%; 3 PR and 4 CI) of 23 patients with pretreatment Hb <10g/dL or transfusion dependency. Splenomegaly significantly decreased in 10 (42%; 2 PR and 8 CI) of 24 patients. Responses occurred after a median of 12 weeks (range, 2–32), have been sustained for a median of 15 months (range, 4.1–20), and are ongoing in 10 of 12 responders still receiving LEN. After 12 months of therapy, a significant decrease was observed in the JAK2^V617F allele burden among the 8 JAK2^V617F positive responders (p=0.03). Four of the 8 JAK2^V617F-positive responders had >50% reduction of the mutant allele burden, becoming undetectable in 1. Serial histopathology analyses revealed significant reductions in bone marrow cellularity (p=0.01) and reticulin fibrosis (p=0.02) after 12 months of therapy in 8 assessable responders. After 3 cycles of LEN+PRD, no significant changes were observed in the peripheral blood levels of bFGF, PDGF, TGF-β1, TNF-α, or osteonectin in responders with respect to healthy volunteers, as assessed by ELISA. The most frequent grade 3–4 toxicities were neutropenia (65%), anemia (50%), fatigue (30%), and thrombocytopenia (20%). Twenty-four (60%) patients required one dose level reduction (5 required further reduction to dose level -2), 1 (2.5%) had the dose escalated, and 15 (25%) remained at the initial dose level. Thirty (75%) patients discontinued therapy due to lack of response (n=15), pt’s decision (n=3), grade 3–4 toxicity (n=9), allogeneic stem cell transplant (n=1), loss of response (n=1), and poor compliance (n=1). No transformation to acute myeloid leukemia has been observed. In summary, prolonged administration of LEN is generally well-tolerated, and yields long-lasting clinical, histopathological, and molecular responses in patients with MF when administered in a continuous manner.