Myelofibrosis (Part Two)

May 7, 2013 Hematology, Pharmacotherapy, Therapeutics No comments , ,

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 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.

Top docs provide free online advice for rare leukemia

July 14, 2012 Hematology, Pharmacy Education No comments , ,

July 11, 2012 — Seven hematologists from leading cancer centers have volunteered to provide free medical advice to patients with myeloproliferative neoplasms (MPNs), a rare form of leukemia, and to their healthcare providers.

The physicians have signed on with the online MPNforum Magazine, which is published monthly by an MPN patient collective. They offer help to patients and caregivers on MPN Clinic, an online roundtable hosted by the publication.

The term MPN covers a rare set of disorders occurring in about 5 people per million, according to a press release from the publication, which operates on a shoestring budget. This rarity means that community-based clinicians may never see a case and if one comes along, help is needed.

The initial volunteers for the project are Richard Silver, MD (Weill-Cornell in New York City), Srdan Verstovsek, MD (M.D. Anderson in Houston, Texas), Ruben Mesa, MD (Mayo Clinic in Scottsdale, Arizona), Claire Harrison, DM (Guy’s and St. Thomas’ in London, United Kingdom), Jason Gotlib, MD (Stanford Medical Center in Palo Alto, California), Ross Levine, MD (Sloan-Kettering in New York City), and Attilio Orazi, MD (Weill-Cornell).

“It’s amazing that we have this group of doctors,” said Zhenya Senyak, the founder and editor of MPNforum, about the eminence of the participating experts. “They are really concerned about getting this information out,” he told Medscape Medical News in an interview. Senyak, who lives in Asheville, North Carolina, is a writer who has myelofibrosis.

I’ve never waited more than a day for a response.

The service is free. Patients, caregivers, and healthcare providers can email questions to, which are then forwarded to all members of the panel. One of the experts responds, and circulates that response among the other panel members for review and comment. The final response is then forwarded to the individual who submitted the question. “I’ve never waited more than a day for a response,” said Senyak. The volunteer experts have even responded while on vacation, he said, adding that the answers are highly detailed and “powerful.”

All the questions, answers, and comments will eventually be published in the monthly MPN Clinic section of MPNforum Magazine. The entries will be archived in a searchable, publicly available online database.

The first MPN Clinic report will be published on September 15. However, Senyak said that responses to 27 questions have already been received and forwarded to patients in the United States and England. He is delighted by the volunteer experts’ helpfulness. “They have nothing to gain. It is purely altruistic of them,” he said.

MPNforum is financed by small donations, which, to date, amount to about $2000.

More About MPNs

MPNs are caused by one or more mutations, usually acquired after middle age. However, increasing numbers of younger adults and children are being diagnosed with the disorder, according to an MPNforum press statement. In MPNs, an overproduction of blood cells disrupts normal hematopoiesis. The various MPNs are differentiated by what is overproduced, such as erythrocytes in polycythemia vera or platelets in essential thrombocythemia.

If treated properly, many patients can live a normal life span with minimal suffering, according to the organization; however, some forms, such as myelofibrosis, can be debilitating and even fatal.

Myelofibrosis is associated with the dysregulation of 2 enzymes — janus-associated kinase (JAK)1 and 2 — which are involved in regulating blood and immunologic functioning. As the disease progresses, bone marrow is replaced with scar tissue, leading to anemia and thrombocytopenia. However, the scarred bone marrow tissue accumulates in other organs, most notably the spleen and liver. This collagen fibrosis can also cause bone pain, intense fatigue, and loss of appetite.

The only cure for myelofibrosis has been stem cell transplantation. However, since the implication of a genetic mutation in this disease was discovered, there have been developments in drug treatment. In 2011, the first drug treatment ever for myelofibrosis, ruxolitinib (Jakafi, Incyte Corp.), was approved by the US Food and Drug Administration.

Ruxolitinib has shown results that are “unprecedented” in the treatment of this disorder, according to Dr. Harrison, who is one of the volunteers and one of the drug’s principal investigators.

While research continues, access to MPN specialists remains the surest means of securing optimal treatment, said Senyak.