New Drugs for the Treatment of Myelofibrosis

Myelofibrosis (MF) includes primary MF and MF that has arisen from an antecedent polycythemia vera (PV) or essential thrombocythemia (ET) (post-PV/ET MF). MF can affect patients in various ways, including progressive splenomegaly, cytopenias (particularly anemia), and troublesome constitutional symptoms, including night sweats, fevers, unintentional weight loss, or debilitating fatigue. MF also can result in blastic transformation and death.

Splenomegaly in MF patients can be a major independent source of morbidity and a detriment to their quality of life. It is sometimes massive (>10 kg) and can lead to pain, early satiety, bloating, or even portal hypertension. The bulk of the spleen can result in areas of ischemia and painful episodes of splenic infarction, and splenic sequestration in splenomegaly can lead to the development or exacerbation of cytopenias.

Management of MF-associated splenomegaly can be difficult, and the questions that arise represent a microcosm of the management issues for MF in general. What are the treatment goals for an individual patient—cure or palliation? Who should receive an allogeneic stem cell transplant? What are the benefits of current medical therapies? How do I manage the myelosuppression brought about by medical therapy? Which patients should be considered for splenectomy or splenic radiation? What is the impact of experimental drugs (particularly the JAK2 inhibitors) on splenomegaly, and would my patient benefit from treatment with one of these agents? Each of these questions—the key challenges for hematologists involved in treating patients with MF—is addressed below.

New Drugs and Their Impact on Myelofibrosis Therapy

A key moment for the understanding—and potentially the treatment—of MF occurred in 2005 with the heavily publicized discovery of the JAK2V617F mutation. Subsequently, additional genetic mutations with potential pathogenetic implications for MF were found, including the c-MPLW515L/K (in 5% of primary MF and 1% of ET), and somatic mutations in TET2 were identified in about 15% of myeloid neoplasms (MPNs), an event preceding the JAK2 mutation in MPN patients. Additional insights recently gained through single nucleotide polymorphism analysis suggest that both variability in other genes, or perhaps even inherited haplotypes, may play a role in MPN pathogenesis. Although the past 5 years have seen significant advances in the understanding of MF pathophysiology, the therapies being investigated for the condition involve building on prior efficacious drug therapies (IMiDs), extrapolating from treatments for other chronic myeloid disorders such as MDS, or using targeted approaches (JAK2 inhibitors).

JAK2 Inhibitors
Various therapeutic strategies are being developed to try to block the proliferative stimulus associated with these MPN associated mutations. Current testing using these inhibitors can be divided into three groups: preclinical testing (based on in vitro activity against cells containing JAK2V617F), ongoing testing in murine models, and testing in clinical trials. Between 10 and 20 agents with reported in vitro or murine-model activity are in the pipeline, but we will focus on those agents in which clinical activity has already been reported in the public forum. JAK2 inhibition clinical results can be divided into two categories of agents: novel small molecules designed and tested for specificity and selectivity against JAK2 (INCB018424, XL019TG101348, SB1518, CYT387), and agents that inhibit a variety of kinases including JAK2 (ITF2357, CEP-701)

Current management of symptomatic splenomegaly in MF patients requires thoughtful consideration of prognosis and treatment goals. For those who are not candidates for transplantation, the palliative benefit of current therapies must be balanced against the potential risks and benefits of experimental therapies. The JAK2 inhibitors have created great excitement among those treating MF patients because of their targeted approach. Preliminary data indicate a meaningful response for MF patients in terms of symptomatic splenomegaly. However, although the JAK2 inhibitors have provided a valuable incremental benefit over previous options, particularly for symptoms and quality of life, they have not yet demonstrated a significant impact on anemia or more advanced disease features. Future advances for MF patients may require further vetting of current and future JAK2 inhibitors, trials of JAK2 inhibitors combined with other agents (such as an IMiD against anemia), or further advances in our understanding of the pathogenesis of the disorder, to open additional avenues for targeted therapies.



Ruben A. Mesa. Curr Hematol Malig Rep (2010) 5:15–21

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