Chapter 30 Primary Myelofibrosis
Figure 30-1 Survival of patients with myelofibrosis after reduced-intensity allogeneic stem cell transplantation according to age (A), donor (B), and Lille risk profile (C).
Algorithm for Selection of Appropriate Patients for Stem Cell Transplantation Stratified According to Risk Status
How Should PMF Patients with Thrombocytopenia Be Treated?
Platelet Count 50 to 100 × 109/L:
It is important to ensure that vitamin B12 or folate deficiency is not contributing to the low platelet count as well as suppression from prior chemotherapeutic agents. Chemotherapeutic agents such as hydroxyurea can be used in patients with marked splenomegaly because initially this can result in an improvement in platelet count as the spleen is reduced in volume. Patients can also be treated with thalidomide or lenalidomide in combination with prednisone. These first-generation IMiDs can sometimes improve cytopenias and reduce splenomegaly in PMF patients, and in some cases, this response can persist even after drug discontinuation. Lenalidomide can induce cytopenias to a greater extent than thalidomide, and this needs to be taken into consideration before the use of this agent in this setting. In a phase II trial, pomalidomide was reported to have a response rate of 58% in increasing the baseline platelet count by greater than 50% in patients with baseline platelets above 50 × 109/L. This second-generation IMiD will need to be evaluated in patients with platelet counts below 50 × 109/L. The use of JAK2 inhibitors in patients with reduced platelets counts remains a subject of research because these agents are associated with thrombocytopenia. For patients with symptoms related to splenomegaly and constitutional symptoms, a recently FDA-approved JAK1/2 inhibitor, ruxolitinib, is being evaluated in a clinical trial in MF patients with this platelet range. Patients can also be enrolled in other JAK2 inhibitor clinical trials in which reduced platelet counts are acceptable or in clinical trials with other agents in development. If thrombocytopenia worsens with the current treatment plan, then proceed with the strategy outlined below.
Platelet Count 20 to 50 × 109/L:
Thalidomide or lenalidomide in combination with prednisone can be attempted to correct anemia in these PMF patients but rarely improve the platelet count in a clinically meaningful way. Most clinical trials involving a variety of therapeutic agents including JAK2 inhibitors will require baseline platelets above 50 × 109/L. In patients who are experiencing life-threatening bleeding, in addition to aggressive immediate platelet transfusions, splenectomy is a reasonable therapeutic option.
Platelet Count Below 20 × 109/L
The treatment choices are truly limited for these patients. Intervention is also dependent on the clinical picture with emphasis on addressing bleeding. Supportive therapy with frequent platelet transfusions is a possibility, but it is likely not sustainable in the long term. It is our practice to transfuse if platelets are below 10 × 109/L unless there is no evidence of mucosal bleeding or life-threatening hemorrhage. Occasionally, patients may have an improvement in the degree of thrombocytopenia with steroids; however, this has not been systematically evaluated. About 20% to 30% of patients with severe thrombocytopenia will have significant improvement in platelet counts after a splenectomy. Aggressive platelet transfusional support is necessary before, during, and after splenectomy in many cases. However, splenectomy in patients with PMF is associated with a postoperative morbidity rate of 15% to 30% and mortality rate of close to 10%. These numbers, however, are highly dependent on the institutional experience and the operating surgeon. Splenectomy can also result in EMH in the liver, causing hepatomegaly, which may require the administration of judicious amount of chemotherapeutic agents (hydroxyurea, busulfan, cladribine). Severe thrombocytopenia is an adverse prognostic feature. Such patients who are eligible for stem cell transplant and have available donors should be considered for transplantation. TPO mimetics have been associated with increased BM fibrosis when used for the treatment of ITP and have not been evaluated in the setting of PMF-associated thrombocytopenia. Additionally, patients with extreme thrombocytopenia and signs of leukemic transformation can be considered for therapy with decitabine or azacytidine with aggressive platelet transfusional support and then should proceed on to allogeneic SCT if a donor is available and the patient’s performance status is appropriate.