Effective Very Long Term (6+ Years) Lenalidomide Therapy for Myelofibrosis

Background

Long term treatment options for symptomatic myelofibrosis (MF) are limited despite of rapid expansion in the knowledge of deranged pathways in myeloproliferative neoplasm (MPN) since the discovery of JAK2V617F mutation in 2005. MF is a biologically heterogeneous disorder ushering individualized intervention.

Aim

To describe the characteristics of patients who showed very long term response to lenalidomide therapy for MF.

Patients and Methods

From 40 patients who were treated with lenalidomide (21 days of 28 days cycle) and prednisone (in initial 3 cycles only) for MF, in a clinical study conducted at our center (Quintas-Cardama A. et al. J Clin Oncol 2009 Oct 1;27(28):4760-6), patients with continued response for more than 72 months on lenalidomide were reviewed retrospectively.

Results

Five patients (12.5%) showed clinical response for 72 months and longer on lenalidomide. The median treatment duration was 94 months. Median age was 55 (Table 1.).

Initial dose was 10mg/day and dose was reduced for toxicity or escalated to optimal response. Diarrhea (grade 1 and 2), neutropenia (grade 3) and peripheral neuropathy (grade 2) were reported as therapy-related toxicity and resolved with lowered dose level. Patient 1 died of sudden infection without neutropenia in 72 months of treatment. Patient 3 had increasing blasts with sudden splenomegaly and switched to other clinical trial at 83 months.

Major symptoms before therapy included fatigue, wasting and abdominal discomfort from splenomegaly; all improved on therapy. Including 2 patients who had required erythropoietin injection before lenalidomide therapy, all 4 patients with anemia had > 2g/dL improvement in hemoglobin. Splenomegaly started to improve as early as the completion of Cycle 1 and continued to improve as late as Cycle 20. Spleen size reduction at best response includes complete or near complete disappearance of palpable organomegaly (Patient 4 and 5). JAK2V617F mutation was present in 3 patients; Patient 3 had mutated myeloproliferative leukemia (MPL) gene. Bone marrow (BM) reticulin fibrosis has improved at its best response in all patients (Figure 1).

Conclusion

Lenalidomide has been used in MF with potential effect on tumor microenvironment, NK/T cell function and cell cycle with proapoptotic property. Retrospective review of the patients on lenalidomide single agent maintenance for longer than 6 years revealed a small group of patients with very durable response and low toxicity, with benefits on anemia, splenomegaly, symptoms and bone marrow fibrosis.

LEN, lenalidomide; NP, neuropathy; TKI, tyrosine kinase inhibitor; CI and PR, clinical improvement and partial remission by IWG-MRT 2013, ^a Not assessed by a questionnaire; ^b MPL mutation positive, ^c At progression, ^d requiring phlebotomy

Table 1

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Individual characteristics and clinical course in 5 patients with long term response to lenalidomide therapy.

Table 1

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Individual characteristics and clinical course in 5 patients with long term response to lenalidomide therapy.

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Figure 2

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Clinical laboratory values of Patient 4 during treatment. ▲, initiation of lenalidomide.

Figure 2

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Clinical laboratory values of Patient 4 during treatment. ▲, initiation of lenalidomide.

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