In last blog we discussed the definition, the clinical manifestations, the biology, and the first part of the management of myelofibrosis.

Let’s review the risk evaluation of myelofibrosis. According the Dynamic International Prognostic Scoring System (DIPSS) the risk grade can be divided into 5 groups.

  • No risk factors – low risk
  • 1 risk factor – intermediate 1
  • 2 or 3 risk factors – intermediate 2
  • ≥ 3 risk factors -high

These four risk groups are with respective median survivals of 15.4, 6.5, 2.9, and 1.3 years. Leukemic transformation was predicted by the presence of unfavorable karyotype or platelet count < 100 × 109/L.

For low- or intermediate 1-risk patients without symptoms, the strategy of “watch and wait” is preferred. For low- and intermediate 1-risk patients with symptoms, if clinical needed, it is reasonable to start with conventional drug therapy.

For patients with high- or intermediate 2-risk disease can be managed by conventional drug therapy, splenectomy, radiotherapy, allo-SCT, or experimental drug thearpy. We have talked about these approaches (except experimental drug therapy) in the first part. Today we focus on the experimental drug therapy or novel therapies.

Novel therapies

Pomalidomide

Pomalidomide is a thalidomide derivative classified with lenalidomide as an immunomodulatory drug. In vitro, immunomodulatory drugs antagonize angiogenesis and expression of tumor necrosis factor α and IL-6 while they facilitate production of IL-2 and interferon IFN-γ and enhance T-cell and nature killer-cell proliferation and activity;the precise mechanism of their action is not known but might include down-regulation cytokine signaling.

Due to the peripheral neuropathy or severe myelosuppression of thalidomide and lenalidomide, there was a room for improvement in both therapeutic activity and side effect profile. So pomalidomide was here.

In a phase 2 randomized study, ~ 25% of patients with anemia responded to pomalidomide alone (2mg/d) or pomalidomide (0.5 or 2 mg/d) combined with prednisone. In a subsequent phase 2 study of single-agent pomalidomide (0.5 mg/d), anemia response was documented only in the  presence of JAK2V617F (24% vs 0%) and predicted by the presence of pomalidomide-induced basophilia (38% vs 6%) or the absence of marked splenomegaly (38% vs 11%). Platelet response was seen in 58% of patients with baseline platelet count of 50-100 ×109/L, but the drug had limited activity in reducing spleen size. Unlike the case with thalidomide or lenalidomide, drug-associated neuropathy or myelosuppression was infrequent. However, higher doses of pomalidomide (> 2 mg/d) were myelosuppressive and not necessarily better in terms of efficacy.

JAK inhibitors

JAK2V617F (Janus kinase 2 mutation V617F) mutation plays an important role in the pathogenesis of myelofibrosis. JAK2V617F has been identified in approxmiately 60% of patients with myelofibrosis (half of patients with PMF and post-ET myelofibrosis and in nearly all of those with a secondary form following a previous PV).

On November 16, 2011 FDA approve ruxolitinib, a small-molecule inhibitor of JAK1 and JAK2, which is the first drug approved for the treatment of symptomatic intermediate- or high-risk myelofibrosis. For patient with symptomatic intermediate- or high-risk myelofibrosis who are not candidates for allogeneic hematopoietic stem cell transplantation, ruxolitinib is the first drug to demonstrate a significant and sustained improvement in splenomegaly and various other myelofibrosis-related symptoms. Quality-of-life measures are significantly improved with this agent, which may be its most dramatic benefit.

The recommended starting dose of ruxolitinib is based on platelet count. For patients with a platelet count of greater than 200 × 109/L, the recommended starting dose is 20 mg orally twice/day. For patients with a platelet count of 100-200 × 109/L, the recommended starting dose is 15 mg twice/day. Due to its hematologic adverse effects, interruption of treatment is warranted for patients with a platelet count less than 50 × 109/L. Once the platelet count has recovered, ruxolitinib should be restarted at the dosages in Table 1.

Table 1 Recommended Dosages for Restarting Ruxolitinib After Interruption of Therapy Due to Decreased Platelet Count

Platelet Count (× 109/L)Restarted Ruxolitinib Dosea
≥ 12520 mg twice/day
100-12415 mg twice/day
75-9910 mg twice/day
50-745 mg twice/day
< 50Withhold therapy

aRestart dose at least 5 mg twice/day less than dose before interruption.