May 2013, Vol 2, No 3
Current Treatment of Myelofibrosis: How Far We Have Come and How Far We Have Yet to Go
At the 2012 conference of the Global Biomarkers Consortium, which took place March 9-11, 2012, in Orlando, Florida, Charles Schiffer, MD, from the Barbara Ann Karmanos Cancer Institute and Wayne State University in Detroit, Michigan, discussed the management of myeloproliferative neoplasms.
Major advances in understanding the biology of hematologic malignancies, such as the unraveling of the molecular pathophysiology of BCR-ABL and studies of the mechanisms of resistance in Philadelphia chromosome–positive chronic myeloid leukemia, have resulted in the rapid development of multiple selective BCR-ABL tyrosine kinase inhibitors (eg, imatinib, nilotinib, dasatinib), which improved 10-year survival from the historic experience of approximately 20% to an estimated rate of 85%.1
In the case study of a patient with myelofibrosis that follows, the role of inhibition of the JAK2-mutated signaling pathway is discussed.
The World Health Organization classification system for myeloid malignancies lists 8 disorders in the category of myeloproliferative neoplasms (MPNs), including the so-called “BCR-ABL1–negative MPN”: polycythemia vera, essential thrombocythemia, and primary myelofibrosis.2 The MPNs (previously referred to as myeloproliferative disorders) are clonal disorders arising in a pluripotent hematopoietic stem cell.3 The MPNs are rare diseases.4 The annual incidence of
myelofibrosis ranges from 0.2 to 1.5 cases per 100,000
The majority of patients with myelofibrosis experience splenomegaly, which can lead to portal hypertension or splenic infarcts,7 and cytopenias.8 In addition, progressive splenomegaly is associated with an increased risk of transformation to secondary acute myeloid leukemia,9 which has a poor prognosis (ie, median survival is 2.6 months after transforming to blast phase).10 Symptoms related to splenomegaly (ie, early satiety, abdominal pain) can also impair physical function, such as walking, bending, eating, or breathing.11 Anemia, which is prevalent among those with myelofibrosis, is prognostic of decreased survival.12 Myelofibrosis is also characterized by fatigue, night sweats, pruritus, bone and muscle pain, and unintentional weight loss – all of which impair quality of life.11,13,14 The median survival time for patients with myelofibrosis ranges from 2 to 11 years; high-risk patients show a rapid progression of the disease and a median survival time of 12 to 24 months.12,15
Traditional Therapies for Myelofibrosis
Most of the traditional therapies for myelofibrosis are palliative and have demonstrated limited efficacy in the management of splenomegaly, cytopenias, or the often debilitating symptoms associated with the disease.16,17 Hydroxyurea has generally been used as the first-line treatment of myelofibrosis-associated splenomegaly.13 Results from 1 study showed that approximately 30% of patients receiving hydroxyurea achieved a reduction in spleen size.18 However, the duration of response with hydroxyurea is only approximately 13 months, and hydroxyurea treatment is associated with the development and/or worsening of anemia.13 Splenectomy has also been used for the management of splenomegaly; however, in 1 study, splenectomy in patients with myelofibrosis was associated with 9% mortality and 31% morbidity.19 The only potentially curative therapy for myelofibrosis is alloSCT.20 However, the use of alloSCT is restricted to a small percentage of patients, since not all patients are appropriate candidates. Ideal candidates should be young, without comorbidities, with a performance status ?90%, and without peripheral blood blasts.13,21,22
In 2005, 4 research groups,23-26 using different approaches, independently discovered an acquired point mutation in the Janus kinase 2 (JAK2) gene at codon 617 within the JH2 domain, resulting in the substitution of a valine for a phenylalanine (Figure 3).27 Known as JAK2 V617F, this mutation is found in approximately 95% of patients with polycythemia vera, 50% to 60% of those with essential thrombocythemia, and 50% to 60% of those with myelofibrosis.28 The discovery of this mutation, a tyrosine kinase used by hematopoietic cell receptors for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor, provided an explanation for the shared clinical features of these 3 disorders.3 After the discovery of the JAK2 V617F mutation, hematologists and oncologists expected that specific JAK2 inhibitors could change the natural course of MPNs, as selective BCR-ABL tyrosine kinase inhibitors (eg, imatinib, nilotinib, dasatinib) had done in chronic myeloid leukemia. Therefore, a flurry of research and drug development activity took place in search of JAK2 inhibitors in the hope that the therapeutic paradigm would change from palliation to cure.29
Ruxolitinib (previously known as INCB018424), an orally administered JAK1 and JAK2 inhibitor approved by the FDA in 2011, is the first therapy approved for the targeted treatment of intermediate- and high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. The FDA approval of ruxolitinib was based on the results of 2 randomized phase 3 clinical studies: a placebo-controlled study in 309 patients with intermediate-2 or high-risk myelofibrosis and a study of ruxolitinib versus best available therapy in 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis.
In the first study, conducted by Verstovsek and colleagues, patients with intermediate-2 or high-risk myelofibrosis were randomized to receive twice-daily oral ruxolitinib (n=155) or placebo (n=153).30 As shown in Figure 4, 41.9% of patients in the ruxolitinib group versus 0.7% in the placebo group had a reduction in spleen volume, as assessed by MRI or CT scan, of ?35% at 24 weeks (P<.001). The response was durable and was observed not only in patients having the JAK2 V617F mutation but also in patients with wild-type JAK2.
A reduction in spleen volume was maintained in patients who received ruxolitinib; 67% of the patients with a response had the response for ?48 weeks (Figure 5).
An improvement of ?50% was seen in the total symptom score at 24 weeks in 46% of patients who received ruxolitinib versus 5% of patients who received placebo (P<.001). At the time of data cutoff, 10 deaths were reported in the ruxolitinib group (6.5%) versus 14 deaths in the placebo group (9.1%) (hazard ratio [HR] 0.67; 95% CI, 0.30-1.50; P=.33). Subsequently, a survival analysis based on a planned data cutoff with 4 additional months of follow-up (median follow-up, 51 weeks) revealed a significant survival advantage (Figure 6) for patients who received ruxolitinib, with 13 deaths in the ruxolitinib group (8.4%) and 24 deaths in the placebo group (15.6%) (HR 0.50; 95% CI, 0.25-0.98; P=.04). Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (1 patient in each group). Two patients experienced transformation to acute myeloid leukemia; both were in the ruxolitinib group.
In the second study, conducted by Harrison and colleagues, 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis were randomized to receive oral ruxolitinib (n=146) or best available therapy (n=73).31
Results showed that, at week 24, 32% of the patients in the ruxolitinib group had ?35% reduction in spleen volume, as assessed by MRI or CT, compared with no reduction in the patients receiving best available therapy (P<.001). At week 48, 28% of the patients in the ruxolitinib group had ?35% reduction in spleen volume compared with no reduction in the patients receiving best available therapy (P<.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. Figure 7 shows mean changes from baseline at week 48 in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life questionnaire core model (QLQ-C30) symptom scores. Improvement is represented by negative numbers (ie, reduction in symptoms). The most common hematologic abnormalities of grade ?3 in either group were thrombocytopenia and anemia, which were managed with dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment due to thrombocytopenia, and none discontinued due to anemia. Nonhematologic adverse events were rare and mostly grade 1/2. Two cases of acute myeloid leukemia were reported with best available therapy.
In addition, Verstovsek and colleagues analyzed the long-term outcomes of 107 patients with intermediate-2 or high-risk myelofibrosis receiving ruxolitinib in a phase 1/2 trial.32 After a median follow-up of 32 months, 58 patients (54%) were still receiving ruxolitinib, with an overall survival of 69%. The overall survival in these 107 patients with myelofibrosis was significantly better (P=.005) than that in 310 matched (based on trial enrollment criteria) historical control patients, primarily because of a highly significant difference in overall survival in the high-risk subgroup (P=.006). Furthermore, among the patients with myelofibrosis, those with high-risk myelofibrosis experienced the same overall survival as those with intermediate-2 risk. Patients with ?50% reduction in splenomegaly had significantly prolonged survival versus those with <25% reduction in splenomegaly (P<.0001).
However, in another long-term study, Tefferi and colleagues reported that among 51 patients with myelofibrosis treated long-term with ruxolitinib, 18 patients (35%) had died, and 5 patients (10%) experienced transformation to acute myeloid leukemia.33 No significant difference was seen in the survival rate for the 51 ruxolitinib-treated patients compared with a cohort of 410 patients with primary myelofibrosis who were treated with standard therapy (P=.43).
Conclusions and Future Directions
This first JAK inhibitor therapy for myelofibrosis had been long anticipated; however, the value of this treatment is not yet known. Ruxolitinib has been unable to significantly decrease peripheral blood blast count, reverse marrow fibrosis, induce cytogenetic remission, or reduce JAK2 V617F allele burden.15 Other limitations of the drug include hematologic toxicities, especially anemia and thrombocytopenia, and the rapid return of splenomegaly and other myelofibrosis-related symptoms upon the discontinuation of therapy.15 Thus, although ruxolitinib may improve patients’ quality of life by significantly reducing splenomegaly and disease-related symptoms, it is not curative for myelofibrosis. Therefore, ruxolitinib may play a definite but limited role in the management of patients with myelofibrosis who are not eligible for alloSCT.15
Several new JAK inhibitors are under clinical development for patients with myelofibrosis. For example, SAR302503, formerly known as TG101348, is a JAK2 and FLT3 inhibitor currently under evaluation in a phase 3 placebo-controlled study (JAKARTA). Pacritinib (SB1518) is a JAK2 and FLT3 inhibitor under investigation in a phase 3 study versus best available therapy. CYT387, a JAK1 and JAK2 inhibitor, is undergoing evaluation in phase 2 studies, including a long-term extension study. LY2784544, which has been described as a JAK2 V617F (mutation)-selective inhibitor, is in phase 1/2 studies.13
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5. National Institutes of Health (NIH). Office of Rare Diseases Research. Genetic and Rare Diseases Information Center (GARD). Myelofibrosis. http://rarediseases.info.nih.gov/GARD/Condition/8618/QnA/22942/My elofibrosis.aspx#1496. Accessed February 27, 2013.
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10. Mesa RA, Li CY, Ketterling RP, et al. Leukemic transformation in myelofibrosis with myeloid metaplasia: a single-institution experience with 91 cases. Blood. 2005;105:973-977.
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12. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
13. Komrokji R, Verstovsek S. Assessing efficacy in myelofibrosis treatment: a focus on JAK inhibition. Expert Rev Hematol. 2012;5:631-641.
14. Mesa RA, Schwager S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.
15. Jung CW. Will JAK1/2 inhibitors change the standard of care for myelofibrosis? Korean J Hematol. 2012;47:241-242.
16. Verstovsek S. Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clin Cancer Res. 2010;16:1988-1996.
17. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008;83:491-497.
18. Martínez-Trillos A, Gaya A, Maffioli M, et al. Efficacy and tolerability of hydroxyurea in the treatment of the hyperproliferative manifestations of myelofibrosis: results in 40 patients. Ann Hematol. 2010;89:1233-1237.
19. Tefferi A, Mesa RA, Nagorney DM, et al. Splenectomy in myelofibrosis with myeloid metaplasia: a single-institution experience with 223 patients. Blood. 2000;95:2226-2233.
20. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29:761-770.
21. Alchalby H, Kröger N. Reduced-intensity conditioning followed by allogeneic hematopoietic stem cell transplantation in myelofibrosis. Curr Hematol Malig Rep. 2010;5:53-61.
22. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010;16:358-367.
23. Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365:1054-1061.
24. James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144-1148.
25. Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. 2005; 352:1779-1790.
26. Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387-397.
27. Goldman JM. A unifying mutation in chronic myeloproliferative disorders. N Engl J Med. 2005;352:1744-1746.
28. Lippert E, Boissinot M, Kralovics R, et al. The JAK2-V617F mutation is frequently present at diagnosis in patients with essential thrombocythemia and polycythemia vera. Blood. 2006;108:1865-1867.
29. Harrison C, Verstovsek S, McMullin MF, et al. Janus kinase inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure? Br J Haematol. 2012;157:426-437.
30. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
31. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366:787-798.
32. Verstovsek S, Kantarjian HM, Estrov Z, et al. Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls. Blood. 2012;120:1202-1209.
33. Tefferi A, Litzow MR, Pardanani A. Long-term outcome of treatment with ruxolitinib in myelofibrosis. N Engl J Med. 2011;365:1455-1457.
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