SOHO Supplement 2014
Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera Haefaa Alchalby, Nicolaus Kröger Abstract Primary myelofibrosis is one of the Philadelphia chromosomeenegative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S36-41 ª 2014 Elsevier Inc. All rights reserved. Keywords: Allogeneic Stem Cell Transplantation, JAK inhibition, JAK2 V617F, Myeloproliferative neoplasms, Therapy related mortality
Introduction The term myelofibrosis (MF) alone usually refers to primary myelofibrosis (PMF), which is a stem cellederived hematologic disorder characterized by a clonal proliferation of multiple cell types, especially the megakaryocytes. PMF is one of the Philadelphia chromosomeenegative (Ph) myeloproliferative neoplasms (MPNs) and is the member of that group with the worst survival and the most significant limitations in quality of life. This proliferation is accompanied by an increased secretion of different cytokines with a secondary intramedullary fibrosis, osteosclerosis, angiogenesis, and University Medical Center Hamburg-Eppendorf, Hamburg, Germany Submitted: Feb 21, 2014; Revised: Apr 4, 2014; Accepted: Jun 4, 2014 Address for correspondence: Nicolaus Kröger, MD, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany E-mail contact: [email protected]
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extramedullary hematopoiesis.1 Additionally, MF may develop as a late evolution of 2 other MPNs: polycythemia vera (post-PV MF) and essential thrombocythemia (post-ET MF).2 The life expectancy of patients with PMF is variable, and the median survival is 69 months (95% CI, 61-76). Causes of death are transformation to acute leukemia (31%), progression without acute transformation (19%), thrombosis and cardiovascular complications (14%), infection (10%), bleeding (5%), portal hypertension (4%), and other causes (14%).3 That study3 established the International Prognostic Scoring System (IPSS) for PMF, which uses 5 prognostic variables: age > 65 years, constitutional symptoms, hemoglobin < 100 g/L, leukocyte count > 25 109 cells/L, and the presence of circulating blasts. Median survival in the low-risk category (no risk factors) was 135 months; in the intermediate-1 risk category (1 risk factor), 95 months; in the intermediate-2 risk category (2 risk factors), 48 months; and in the high-risk category (3 or more risk factors), 27 months. The IPSS is a
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.06.012
powerful risk stratification tool to estimate the life expectancy of patients with PMF at diagnosis. To track change of prognosis due to acquisition of new risk factors over time, the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) introduced the dynamic IPSS (DIPSS),4 which includes the same variables used in the IPSS but applies more weight on the acquisition of anemia. Recently, several other IPSS independent risk factors such as unfavorable cytogenetic status (þ8, 7/7q, i(17q), inv(3), 5/5q, 12p, or 11q23 rearrangement; median survival, approximately 40 months)5 and transfusion dependency (median survival, approximately 20 months)6 were identified and combined with DIPSS to result in the DIPSSplus stratification system.7 The systems are being increasingly implemented in daily practice to advise patients with PMF about their individualized risk status and to guide therapy decisions. More recently, molecular mutation can also be used as a prognostic model for survival.8 PMF can be cured with successful allogeneic stem cell transplant (allo-SCT),9 although the applicability of allo-SCT is limited owing to treatment-related mortality. Conventional therapies for PMF/MF include the use of growth factors such as erythropoietin, androgens, immunomodulatory drugs, interferon alfa, cytoreductive agents, and nonpharmacologic options such as blood transfusion, spleen irradiation, and splenectomy. None of these approaches have been found to prolong survival. The V617F mutation of JAK2 (Janus kinase 2) is an acquired point mutation in the pseudokinase domain of the gene that confers a constitutive JAK2 pathway activation with resulting growth factore independent proliferation of myeloid precursors.10,11 JAK inhibitors are compounds developed for the treatment of MPNs. Ruxolitinib is the first JAK inhibitor approved by the US Food and Drug Administration for use in patients with intermediate- or high-risk MF (primary MF, post-PV MF, post-ET MF) and in Europe for symptomatic patients with MF with splenomegaly, regardless of the IPSS risk classification. Ruxolitinib, a JAK1/JAK2 inhibitor, showed early and sustained clinical benefits in patients with intermediate-2 and high-risk MF, including spleen size reduction and improvement of constitutional symptoms in a phase I/II trial (INCB18424-251) and the phase III trials COMFORT-I and COMFORT-II (Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy).12-14 A survival benefit with ruxolitinib was found in the COMFORT-I analysis, in a 3-year follow-up of the COMFORT-II study,15,16 and (more recently) according to DIPSS.17
Allo-SCT for MF The published experience in allo-SCT for MF is summarized in Table 1. In the late 1980s and early 1990s, the feasibility of allo-SCT for MF was confirmed in small studies.18,19 One multicenter European-American report was published in the late 1990s and described a retrospective study with a larger cohort in which allo-SCT was performed using myeloablative conditioning (MAC) in relatively young patients (median age, 42 years). Nonrelapse mortality (NRM) was 27%, and the incidence of graft failure was 9%. The median overall survival (OS) and progressionfree survival (PFS) reached 47% and 39%, respectively, at 5 years.20 Another important study, from the Fred Hutchinson
Cancer Research Center (Seattle, WA), was first published in 2003 and was updated 5 years later to include 104 patients, most of whom received allo-SCT after MAC. In this study, NRM at 5 years of 34% and OS at 7 years of 61% were reported.9,21 A total-body irradiationebased study resulted in a high-risk NRM of 48% and a 2-year OS of 41%.22 Because MF is principally a disease of the elderly, the need was urgent to improve the tolerability of allo-SCT and enable more patients with advanced age to benefit from this treatment modality. The evidence of graft versus leukemia effect was already available through documented responses to donor lymphocyte infusion (DLI) after failure of allo-SCT.23,24 This justified the use of the reduced-intensity conditioning (RIC) in the setting of allo-SCT for MF. Small pilot reports could confirm that RIC can reduce NRM without jeopardizing engraftment.25-28 Larger clinical trials were published thereafter, but the only prospective study with a large sample size was conducted by the European Society for Blood and Marrow Transplantation (EBMT) and published in 2009 after including 103 patients. The median age was 55 years, and the NRM at 1 year was only 16%. The cumulative incidence of relapse was 22% at 3 years. PFS and OS at 5 years were 51% and 67%, respectively. Advanced age and HLA-mismatched donor were independent predictive factors for reduced OS.29 The study was updated recently after a median follow-up of 60 months and published in abstract form. The 8-year OS was 65%, with a stable plateau after 5.3 years of follow-up. The 5-year disease-free survival was 40%, and the 5-year cumulative incidence of relapse/progression was 28%, with 3-year NRM of 21%.30 Other studies using RIC or MAC confirmed the curative effect of allo-SCT irrespectively of the intensity of the conditioning regimen.31-41 It could be speculated that reduction of NRM achieved using RIC regimens may be offset by the theoretically increased risk of relapse. Unfortunately, there is no prospective comparison to date between MAC and RIC in PMF. However, a retrospective comparison found no statistically significant difference in outcome or relapse incidence.36 On the other hand, the efficacy of relapse prevention and treatment has improved in recent years owing to the use of minimal residual disease (MRD) monitoring strategies. Using sensitive assays to monitor JAK2 V617F mutation (detectable in 60% of patients with MPNs) after allo-SCT, MRD and molecular relapse could be treated early using DLIs in lower doses resulting in no or less severe graft-versus-host disease.42 Recently, more mutations and molecular markers such as MPL (myeloproliferative leukemia proto-oncogene, thrombopoietin receptor) W515L/K, TET2 (tet methylcytosine dioxygenase 2), ASXL1 (additional sex combs like transcriptional regulator 1), or CALR (calreticulin) could be discovered in Ph MPNs.43-45 The possibility to use those markers for MRD analysis in MF should be elucidated in future studies. According to the recently published recommendations of the European LeukemiaNet (ELN), it seems justified to offer allo-SCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS, as well as those with transfusion dependency or unfavorable cytogenetic status.46 Eligible patients with post-PV or post-ET MF are offered allo-SCT generally at the time of fibrotic transformation. Overall, there is an increase in the number of transplants in the United States and Europe, mainly
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Transplant in Myelofibrosis Table 1 Selected Trials of Allogeneic Stem Cell Transplant in Myelofibrosis No. of Patients
Conditioning Regimen
Median Age
Transplant-Related Mortality
Overall Survival
Guardiola et al (1999)20
55
TBI-based (n ¼ 35), various (n ¼ 20)
42
27% (at 1 year)
39% (at 5 years)
Deeg et al (2003)21
56
Busulfan-based (n ¼ 44), TBI-based (n ¼ 12)
43
20% (at 1 year)
31% (at 5 years)
Kerbauy et al 20079
104
TBI-based (n ¼ 15), busulfan-based (n ¼ 80), reduced-intensity (n ¼ 9)
49
34% (at 5 years)
61% (at 7 years)
Daly et al (2003)22
25
TBI-based
48% (at 1 year)
41% (at 2 years)
Reference MAC
RIC Hessling et al (2002)25
3
Busulfan/fludarabine
51
0% (at 1 year)
100% (at 1 year)
Devine et al (2002)26
4
Melphalan/fludarabine
56
0% (at 1 year)
100% (at 1 year)
Rondelli et al (2005)27
21
Various
54
10% (at 1 year)
85% (at 2.5 years)
Kröger et al (2005)28
21
Busulfan/fludarabine
53
16% (at 1 year)
84% (at 3 years)
Bacigalupo et al (2010)31
46
Thiotepa-based
51
24% (at 5 years)
45% (at 5 years)
Kröger et al (2009)29
103
Busulfan/fludarabine
55
16% (at 1 year)
67% (at 5 years)
Gupta et al (2014)32
233
Various
55
24% (at 5 years)
47% (at 5 years)
MAC þ RIC Stewart et al (2010)33
51
RIC þ STD
49
32% (at 1 year)
45% (at 5 years)
Ballen et al (2010)34
170 (sibling)
RIC þ STD
45
18% (at day 100)
100% (at 16 mo)
117 (MUD)
47
35% (at day 100)
67% (at 5 years)
33 (alternative related)
40
19% (at day 100)
44% (at 3 years)
53
16% (at 1 year)
37% (5 years)
Robin et al (2011)35
147
RIC þ STD
Patriarca et al (2008)
100
RIC þ STD
43% (at 3 years)
425 (at 3 years)
Gupta et al (2009)36
46
RIC þ STD
48% STD (at 1 year)
48% STD (at 3 years)
Abelsson et al (2012)37
92
RIC þ STD
32% STD (at 2 years) 24% RIC (at 2 years)
49% STD (at 5 years) 59% RIC (at 5 years)
Ditschkowsky et al (2012)38
76
RIC þ STD
36% (at 5 years)
53% (at 5 years)
Nivison-Smith et al (2012)40
57
RIC þ STD
25% (at 1 year)
58% (at 5 years)
Scott et al (2012)39
170
RIC þ STD
34% (at 5 years)
57% (at 5 years)
41
Abbreviations: MAC ¼ myeloablative conditioning; MUD ¼ matched unrelated donor; RIC ¼ reduced-intensity conditioning; STD ¼ standard; TBI ¼ total-body irradiation.
owing to RIC regimens, the more frequent use of unrelated donors, and the increasing use of allo-SCT in older patients.47
JAK Inhibition for MF JAK Inhibitor Development The discovery of MPN-associated molecular markers (especially JAK2 V617F) in the past 7 years has resulted in numerous efforts to develop efficient targeted therapies with the hope of altering the disease process. JAK2 inhibitors were developed, tested clinically, and found to alleviate some disease-related symptoms. The first JAK inhibitor with regulatory approval for the treatment of MF was the JAK1/2 inhibitor ruxolitinib (INCBO18424), which is approved in the United States and Europe.
Ruxolitinib (INCB018424)
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This drug is a JAK1 and JAK2 inhibitor that has already completed 2 phase III clinical trials. With a dose of 15 mg twice
Clinical Lymphoma, Myeloma & Leukemia September 2014
daily, significant reduction of splenomegaly and constitutional symptoms can be reached in about 50% of patients. Responses could be reached also in patients without JAK2 mutation and correlated well with reduction of serum inflammatory cytokines. Worsening of anemia or reversible thrombocytopenia are the main toxic effects. In the COMFORT-I trial, patients were randomized to start the drug at a dose of 15 mg or 20 mg orally 2 times daily depending on baseline platelet count against placebo. At week 24, the proportion of patients with 50% improvement in splenomegaly was 45.9%, versus 5.3%.48 The COMFORT-II trial, on the other hand, randomized ruxolitinib against best available therapy and included 219 patients. Again, reduction of the spleen volume of 35% from baseline at 48 weeks of therapy was reached in 28.5% of patients, compared with 0% in the control arm.49 A survival benefit was seen in the COMFORT-I and COMFORT-II studies. Long-term studies after the initial phase II study found that patients with intermediate-2 and high risk showed a survival benefit
Haefaa Alchalby, Nicolaus Kröger Figure 1 Potential Algorithm for Management
Abbreviations: IPSS ¼ International Prognostic Scoring System; JAK2 ¼ Janus kinase 2.
compared with a historical control and that the discontinuation rate at 1, 2, and 3 years was 24%, 36%, and 46%, respectively. Furthermore, patients with significant (> 50%) spleen size reduction had prolonged survival, whereas there was only moderate, if any, reduction in JAK2 allelic burden. Recent data reported some regression of bone marrow fibrosis after ruxolitinib treatment.50 Other JAK1 or JAK2 inhibitors are being tested in clinical trials and do not have regulatory approval yet.
SAR302503 SAR302503 is a selective JAK2 inhibitor with activity against JAK1, FLT3 (CD135), and RET (ret proto-oncogene). In a phase I/II trial,51 the dose-limiting toxicity was an asymptomatic and reversible increase in serum amylase. Gastrointestinal symptoms occurred in 70% of patients but were mostly mild and reversible with dose reduction. Bone marrow suppression manifested with worsening of anemia (35%), neutropenia (10%), and thrombocytopenia (24%) as the main toxic effects. Nearly all patients with thrombocytosis and the majority of those with leukocytosis achieved normalization of their counts. Reduction in spleen size of 50% of baseline was registered in about 59% of patients who completed 6 cycles of therapy. However, after completion of a phase III study, the further development of the drug was stopped owing to central nervous system toxicity.
Pacritinib and CYT387 Pacritinib is another oral JAK2 inhibitor; it reduced spleen size > 50% in 24% of the patients studied and 35% in 41%. Myelosuppression was minimal, and the relevant side effect was diarrhea.52 CYT387 is a selective inhibitor of JAK1 and JAK2 that reduced spleen size 50% in 50% of the patients studied. In contrast to other JAK inhibitors, CYT387 improves anemia, resulting in transfusion independency for at least 12 weeks in 70% of the patients.53
Conclusion The management of patients with MF has improved in the past decade. A growing experience in allo-SCT as the only curative treatment accumulated over time, and promising novel therapies were developed for the palliative application. Through the improved understanding and prediction of the natural history of the disease, it is now possible to estimate the life expectancy of every patient individually and at every time point after diagnosis. Asymptomatic patients corresponding to low or intermediate-1 IPSS risk score should be offered a watch-and-wait strategy if there are no constitutional symptoms or splenomegaly. When symptoms warrant treatment, medical therapy can be initiated, and the approach should be problem-oriented. It should be kept in mind, however, that palliative therapy may change blood cell counts and reduce systemic complaints without altering the disease process. Those patients should be carefully monitored for acquisition of new risk factors and for disease acceleration. JAK inhibitor therapy can also be offered to symptomatic patients with poor prognosis who are not eligible for allo-SCT owing to advanced age or associated comorbidities, and the main goal of therapy should be alleviating symptoms and maintaining quality of life. Patients with limited life expectancy who are otherwise in good condition and have a suitable donor should be offered allo-SCT through an experienced transplant center. Some of those patients may already have exhausting symptoms and may be offered medical therapy before transplant. It may be possible that reduction of disease burden or improving the general condition before allo-SCT may positively influence its outcome. Early data on using ruxolitinib before transplant to reduce spleen size and constitutional symptoms have indicated that it is feasible and did not negatively affect the outcome of transplant.54,55 But on the other hand, it is still too early to exclude that some of those medications may negatively interfere with allo-SCT outcome, and cardiac toxicity and tumor lysis syndrome have been reported.56 This issue is the
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Transplant in Myelofibrosis subject of an ongoing clinical trial (NCT 01795677). A potential algorithm is given in Figure 1. Overall improvement in the management of allo-SCT for MF has increased the number of such procedures performed annually, and it remains the only curative treatment approach. By harnessing the major effects of JAK inhibitors (such as spleen size reduction and improvement of constitutional symptoms) before transplant, further reduction of treatment-related complications is likely, which will result in improved survival.
Disclosure Both authors state that they have no conflicts of interest.
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New mutations of myeloproliferative neoplasms. Blood 2011; 118:1723-35. 44. Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369:2379-90. 45. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391-405. 46. 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; 29:761-70. 47. Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012; 120:1367-79. 48. Verstovsek S, Mesa RA, Gotlib JR, et al. Results of COMFORT-I, a randomized double-blind phase III trial of JAK1/2 inhibitor INCB18424(424) versus placebo (PB) for patients with myelofibrosis (MF) (ASCO Annual Meeting Abstract). J Clin Oncol 2011; 29:6500.
Haefaa Alchalby, Nicolaus Kröger 49. Harrison CN, Kiladijan H, Al-Ali HK, et al. Results of a randomized study of the JAK inhibitor INC424 compared with best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera-myelofibrosis (PPV-MF) or postessential thrombocythemia myelofibrosis (PET-MF) (ASCO Annual Meeting Abstract). J Clin Oncol 2011; 29, LBA6501. 50. Kvasnicka HM, Thiele J, Bueso-Ramos CE, et al. Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis (ASCO Annual Meeting Abstract). J Clin Oncol 2013; 31:7030. 51. Pardanani A, Gotlib JR, Jamieson C, et al. Safety and efficacy of TG101348, a selective JAK2 inhibitor, in myelofibrosis. J Clin Oncol 2011; 29:789-96. 52. Verstovsek S, Odenike O, Scott B, et al. Phase I dose-escalation trial of SB1518, a novel JAK2/FLT3 inhibitor, in acute and chronic myeloid diseases, including primary or post-essential thrombocythemia/polycythemia vera myelofibrosis. Blood (ASH annual meeting abstracts) 2009; 114:3905.
53. Pardanani A, Gotlib J, Gupta V, et al. Phase I/II study of CYT387, a JAK1/JAK2 inhibitor for the treatment of myelofibrosis (ASH annual meeting abstracts). Blood 2012, abstract 3849. 54. Kröger N, Alchalby H, Ditschkowski M, et al. Ruxolitinib as pretreatment before allogeneic stem cell transplantation for myelofibrosis. Blood 2013; 122, abstract 392. 55. Jaekel N, Behre G, Behning A, et al. Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib [published online December 2, 2013]. Bone Marrow Transplant. http://dx.doi.org/10.1038/bmt.2013.173. 56. Robin M, Francois S, Huynh A, et al. Ruxolitinib before allogeneic hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis: a preliminary descriptive report of the JAK ALLO study, a phase II trial sponsored by GoelamsFIM in collaboration with the SFGM-TC. Blood 2013; 122, abstract 306.
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Allogeneic Stem Cell Transplant vs. Janus Kinase Inhibition in the Treatment of Primary Myelofibrosis or Myelofibrosis After Essential Thrombocythemia or Polycythemia Vera Haefaa Alchalby, Nicolaus Kröger Abstract Primary myelofibrosis is one of the Philadelphia chromosomeenegative myeloproliferative neoplasms and is the member of that group with the worst survival and the most significant limitations in quality of life. Hepatosplenomegaly due to extramedullary hematopoiesis, constitutional symptoms, and cytopenias are the main manifestations. The natural history is highly variable, and up to 30% of patients can experience acceleration to acute myelogenous leukemia. Conventional therapy is only palliative and not always effective. However, huge advances have been achieved in the past 2 decades toward a better understanding of the pathogenesis of this disease, as well as improved management. Powerful risk stratification systems are now available and can reliably separate the patients into different prognostic categories to aid clinical management. Allogeneic stem cell transplant can offer cure but is still not universally applicable owing to the treatment-related mortality and toxicity. Nevertheless, outcomes of transplant are improving, owing to the introduction of reduced-intensity conditioning regimens and the optimization of remission monitoring techniques and relapse prevention strategies. The discovery of the V617F mutation of JAK2 (Janus kinase 2) and some other molecular aberrations has shed more light on the molecular pathogenesis of the disease and has led to the introduction of novel therapies such as JAK2 inhibitors. In fact, JAK inhibitors have shown promising symptomatic efficacy, and the JAK inhibitor ruxolitinib has also shown a potential survival benefit. Future effort should be made to combine allogeneic stem cell transplant with JAK inhibition. Clinical Lymphoma, Myeloma & Leukemia, Vol. 14, No. S3, S36-41 ª 2014 Elsevier Inc. All rights reserved. Keywords: Allogeneic Stem Cell Transplantation, JAK inhibition, JAK2 V617F, Myeloproliferative neoplasms, Therapy related mortality
Introduction The term myelofibrosis (MF) alone usually refers to primary myelofibrosis (PMF), which is a stem cellederived hematologic disorder characterized by a clonal proliferation of multiple cell types, especially the megakaryocytes. PMF is one of the Philadelphia chromosomeenegative (Ph) myeloproliferative neoplasms (MPNs) and is the member of that group with the worst survival and the most significant limitations in quality of life. This proliferation is accompanied by an increased secretion of different cytokines with a secondary intramedullary fibrosis, osteosclerosis, angiogenesis, and University Medical Center Hamburg-Eppendorf, Hamburg, Germany Submitted: Feb 21, 2014; Revised: Apr 4, 2014; Accepted: Jun 4, 2014 Address for correspondence: Nicolaus Kröger, MD, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany E-mail contact: [email protected]
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extramedullary hematopoiesis.1 Additionally, MF may develop as a late evolution of 2 other MPNs: polycythemia vera (post-PV MF) and essential thrombocythemia (post-ET MF).2 The life expectancy of patients with PMF is variable, and the median survival is 69 months (95% CI, 61-76). Causes of death are transformation to acute leukemia (31%), progression without acute transformation (19%), thrombosis and cardiovascular complications (14%), infection (10%), bleeding (5%), portal hypertension (4%), and other causes (14%).3 That study3 established the International Prognostic Scoring System (IPSS) for PMF, which uses 5 prognostic variables: age > 65 years, constitutional symptoms, hemoglobin < 100 g/L, leukocyte count > 25 109 cells/L, and the presence of circulating blasts. Median survival in the low-risk category (no risk factors) was 135 months; in the intermediate-1 risk category (1 risk factor), 95 months; in the intermediate-2 risk category (2 risk factors), 48 months; and in the high-risk category (3 or more risk factors), 27 months. The IPSS is a
2152-2650/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2014.06.012
powerful risk stratification tool to estimate the life expectancy of patients with PMF at diagnosis. To track change of prognosis due to acquisition of new risk factors over time, the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) introduced the dynamic IPSS (DIPSS),4 which includes the same variables used in the IPSS but applies more weight on the acquisition of anemia. Recently, several other IPSS independent risk factors such as unfavorable cytogenetic status (þ8, 7/7q, i(17q), inv(3), 5/5q, 12p, or 11q23 rearrangement; median survival, approximately 40 months)5 and transfusion dependency (median survival, approximately 20 months)6 were identified and combined with DIPSS to result in the DIPSSplus stratification system.7 The systems are being increasingly implemented in daily practice to advise patients with PMF about their individualized risk status and to guide therapy decisions. More recently, molecular mutation can also be used as a prognostic model for survival.8 PMF can be cured with successful allogeneic stem cell transplant (allo-SCT),9 although the applicability of allo-SCT is limited owing to treatment-related mortality. Conventional therapies for PMF/MF include the use of growth factors such as erythropoietin, androgens, immunomodulatory drugs, interferon alfa, cytoreductive agents, and nonpharmacologic options such as blood transfusion, spleen irradiation, and splenectomy. None of these approaches have been found to prolong survival. The V617F mutation of JAK2 (Janus kinase 2) is an acquired point mutation in the pseudokinase domain of the gene that confers a constitutive JAK2 pathway activation with resulting growth factore independent proliferation of myeloid precursors.10,11 JAK inhibitors are compounds developed for the treatment of MPNs. Ruxolitinib is the first JAK inhibitor approved by the US Food and Drug Administration for use in patients with intermediate- or high-risk MF (primary MF, post-PV MF, post-ET MF) and in Europe for symptomatic patients with MF with splenomegaly, regardless of the IPSS risk classification. Ruxolitinib, a JAK1/JAK2 inhibitor, showed early and sustained clinical benefits in patients with intermediate-2 and high-risk MF, including spleen size reduction and improvement of constitutional symptoms in a phase I/II trial (INCB18424-251) and the phase III trials COMFORT-I and COMFORT-II (Controlled Myelofibrosis Study with Oral JAK Inhibitor Therapy).12-14 A survival benefit with ruxolitinib was found in the COMFORT-I analysis, in a 3-year follow-up of the COMFORT-II study,15,16 and (more recently) according to DIPSS.17
Allo-SCT for MF The published experience in allo-SCT for MF is summarized in Table 1. In the late 1980s and early 1990s, the feasibility of allo-SCT for MF was confirmed in small studies.18,19 One multicenter European-American report was published in the late 1990s and described a retrospective study with a larger cohort in which allo-SCT was performed using myeloablative conditioning (MAC) in relatively young patients (median age, 42 years). Nonrelapse mortality (NRM) was 27%, and the incidence of graft failure was 9%. The median overall survival (OS) and progressionfree survival (PFS) reached 47% and 39%, respectively, at 5 years.20 Another important study, from the Fred Hutchinson
Cancer Research Center (Seattle, WA), was first published in 2003 and was updated 5 years later to include 104 patients, most of whom received allo-SCT after MAC. In this study, NRM at 5 years of 34% and OS at 7 years of 61% were reported.9,21 A total-body irradiationebased study resulted in a high-risk NRM of 48% and a 2-year OS of 41%.22 Because MF is principally a disease of the elderly, the need was urgent to improve the tolerability of allo-SCT and enable more patients with advanced age to benefit from this treatment modality. The evidence of graft versus leukemia effect was already available through documented responses to donor lymphocyte infusion (DLI) after failure of allo-SCT.23,24 This justified the use of the reduced-intensity conditioning (RIC) in the setting of allo-SCT for MF. Small pilot reports could confirm that RIC can reduce NRM without jeopardizing engraftment.25-28 Larger clinical trials were published thereafter, but the only prospective study with a large sample size was conducted by the European Society for Blood and Marrow Transplantation (EBMT) and published in 2009 after including 103 patients. The median age was 55 years, and the NRM at 1 year was only 16%. The cumulative incidence of relapse was 22% at 3 years. PFS and OS at 5 years were 51% and 67%, respectively. Advanced age and HLA-mismatched donor were independent predictive factors for reduced OS.29 The study was updated recently after a median follow-up of 60 months and published in abstract form. The 8-year OS was 65%, with a stable plateau after 5.3 years of follow-up. The 5-year disease-free survival was 40%, and the 5-year cumulative incidence of relapse/progression was 28%, with 3-year NRM of 21%.30 Other studies using RIC or MAC confirmed the curative effect of allo-SCT irrespectively of the intensity of the conditioning regimen.31-41 It could be speculated that reduction of NRM achieved using RIC regimens may be offset by the theoretically increased risk of relapse. Unfortunately, there is no prospective comparison to date between MAC and RIC in PMF. However, a retrospective comparison found no statistically significant difference in outcome or relapse incidence.36 On the other hand, the efficacy of relapse prevention and treatment has improved in recent years owing to the use of minimal residual disease (MRD) monitoring strategies. Using sensitive assays to monitor JAK2 V617F mutation (detectable in 60% of patients with MPNs) after allo-SCT, MRD and molecular relapse could be treated early using DLIs in lower doses resulting in no or less severe graft-versus-host disease.42 Recently, more mutations and molecular markers such as MPL (myeloproliferative leukemia proto-oncogene, thrombopoietin receptor) W515L/K, TET2 (tet methylcytosine dioxygenase 2), ASXL1 (additional sex combs like transcriptional regulator 1), or CALR (calreticulin) could be discovered in Ph MPNs.43-45 The possibility to use those markers for MRD analysis in MF should be elucidated in future studies. According to the recently published recommendations of the European LeukemiaNet (ELN), it seems justified to offer allo-SCT to eligible patients with PMF whose median survival is expected to be less than 5 years. This includes patients with intermediate-2 and high risk according to IPSS, as well as those with transfusion dependency or unfavorable cytogenetic status.46 Eligible patients with post-PV or post-ET MF are offered allo-SCT generally at the time of fibrotic transformation. Overall, there is an increase in the number of transplants in the United States and Europe, mainly
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Transplant in Myelofibrosis Table 1 Selected Trials of Allogeneic Stem Cell Transplant in Myelofibrosis No. of Patients
Conditioning Regimen
Median Age
Transplant-Related Mortality
Overall Survival
Guardiola et al (1999)20
55
TBI-based (n ¼ 35), various (n ¼ 20)
42
27% (at 1 year)
39% (at 5 years)
Deeg et al (2003)21
56
Busulfan-based (n ¼ 44), TBI-based (n ¼ 12)
43
20% (at 1 year)
31% (at 5 years)
Kerbauy et al 20079
104
TBI-based (n ¼ 15), busulfan-based (n ¼ 80), reduced-intensity (n ¼ 9)
49
34% (at 5 years)
61% (at 7 years)
Daly et al (2003)22
25
TBI-based
48% (at 1 year)
41% (at 2 years)
Reference MAC
RIC Hessling et al (2002)25
3
Busulfan/fludarabine
51
0% (at 1 year)
100% (at 1 year)
Devine et al (2002)26
4
Melphalan/fludarabine
56
0% (at 1 year)
100% (at 1 year)
Rondelli et al (2005)27
21
Various
54
10% (at 1 year)
85% (at 2.5 years)
Kröger et al (2005)28
21
Busulfan/fludarabine
53
16% (at 1 year)
84% (at 3 years)
Bacigalupo et al (2010)31
46
Thiotepa-based
51
24% (at 5 years)
45% (at 5 years)
Kröger et al (2009)29
103
Busulfan/fludarabine
55
16% (at 1 year)
67% (at 5 years)
Gupta et al (2014)32
233
Various
55
24% (at 5 years)
47% (at 5 years)
MAC þ RIC Stewart et al (2010)33
51
RIC þ STD
49
32% (at 1 year)
45% (at 5 years)
Ballen et al (2010)34
170 (sibling)
RIC þ STD
45
18% (at day 100)
100% (at 16 mo)
117 (MUD)
47
35% (at day 100)
67% (at 5 years)
33 (alternative related)
40
19% (at day 100)
44% (at 3 years)
53
16% (at 1 year)
37% (5 years)
Robin et al (2011)35
147
RIC þ STD
Patriarca et al (2008)
100
RIC þ STD
43% (at 3 years)
425 (at 3 years)
Gupta et al (2009)36
46
RIC þ STD
48% STD (at 1 year)
48% STD (at 3 years)
Abelsson et al (2012)37
92
RIC þ STD
32% STD (at 2 years) 24% RIC (at 2 years)
49% STD (at 5 years) 59% RIC (at 5 years)
Ditschkowsky et al (2012)38
76
RIC þ STD
36% (at 5 years)
53% (at 5 years)
Nivison-Smith et al (2012)40
57
RIC þ STD
25% (at 1 year)
58% (at 5 years)
Scott et al (2012)39
170
RIC þ STD
34% (at 5 years)
57% (at 5 years)
41
Abbreviations: MAC ¼ myeloablative conditioning; MUD ¼ matched unrelated donor; RIC ¼ reduced-intensity conditioning; STD ¼ standard; TBI ¼ total-body irradiation.
owing to RIC regimens, the more frequent use of unrelated donors, and the increasing use of allo-SCT in older patients.47
JAK Inhibition for MF JAK Inhibitor Development The discovery of MPN-associated molecular markers (especially JAK2 V617F) in the past 7 years has resulted in numerous efforts to develop efficient targeted therapies with the hope of altering the disease process. JAK2 inhibitors were developed, tested clinically, and found to alleviate some disease-related symptoms. The first JAK inhibitor with regulatory approval for the treatment of MF was the JAK1/2 inhibitor ruxolitinib (INCBO18424), which is approved in the United States and Europe.
Ruxolitinib (INCB018424)
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This drug is a JAK1 and JAK2 inhibitor that has already completed 2 phase III clinical trials. With a dose of 15 mg twice
Clinical Lymphoma, Myeloma & Leukemia September 2014
daily, significant reduction of splenomegaly and constitutional symptoms can be reached in about 50% of patients. Responses could be reached also in patients without JAK2 mutation and correlated well with reduction of serum inflammatory cytokines. Worsening of anemia or reversible thrombocytopenia are the main toxic effects. In the COMFORT-I trial, patients were randomized to start the drug at a dose of 15 mg or 20 mg orally 2 times daily depending on baseline platelet count against placebo. At week 24, the proportion of patients with 50% improvement in splenomegaly was 45.9%, versus 5.3%.48 The COMFORT-II trial, on the other hand, randomized ruxolitinib against best available therapy and included 219 patients. Again, reduction of the spleen volume of 35% from baseline at 48 weeks of therapy was reached in 28.5% of patients, compared with 0% in the control arm.49 A survival benefit was seen in the COMFORT-I and COMFORT-II studies. Long-term studies after the initial phase II study found that patients with intermediate-2 and high risk showed a survival benefit
Haefaa Alchalby, Nicolaus Kröger Figure 1 Potential Algorithm for Management
Abbreviations: IPSS ¼ International Prognostic Scoring System; JAK2 ¼ Janus kinase 2.
compared with a historical control and that the discontinuation rate at 1, 2, and 3 years was 24%, 36%, and 46%, respectively. Furthermore, patients with significant (> 50%) spleen size reduction had prolonged survival, whereas there was only moderate, if any, reduction in JAK2 allelic burden. Recent data reported some regression of bone marrow fibrosis after ruxolitinib treatment.50 Other JAK1 or JAK2 inhibitors are being tested in clinical trials and do not have regulatory approval yet.
SAR302503 SAR302503 is a selective JAK2 inhibitor with activity against JAK1, FLT3 (CD135), and RET (ret proto-oncogene). In a phase I/II trial,51 the dose-limiting toxicity was an asymptomatic and reversible increase in serum amylase. Gastrointestinal symptoms occurred in 70% of patients but were mostly mild and reversible with dose reduction. Bone marrow suppression manifested with worsening of anemia (35%), neutropenia (10%), and thrombocytopenia (24%) as the main toxic effects. Nearly all patients with thrombocytosis and the majority of those with leukocytosis achieved normalization of their counts. Reduction in spleen size of 50% of baseline was registered in about 59% of patients who completed 6 cycles of therapy. However, after completion of a phase III study, the further development of the drug was stopped owing to central nervous system toxicity.
Pacritinib and CYT387 Pacritinib is another oral JAK2 inhibitor; it reduced spleen size > 50% in 24% of the patients studied and 35% in 41%. Myelosuppression was minimal, and the relevant side effect was diarrhea.52 CYT387 is a selective inhibitor of JAK1 and JAK2 that reduced spleen size 50% in 50% of the patients studied. In contrast to other JAK inhibitors, CYT387 improves anemia, resulting in transfusion independency for at least 12 weeks in 70% of the patients.53
Conclusion The management of patients with MF has improved in the past decade. A growing experience in allo-SCT as the only curative treatment accumulated over time, and promising novel therapies were developed for the palliative application. Through the improved understanding and prediction of the natural history of the disease, it is now possible to estimate the life expectancy of every patient individually and at every time point after diagnosis. Asymptomatic patients corresponding to low or intermediate-1 IPSS risk score should be offered a watch-and-wait strategy if there are no constitutional symptoms or splenomegaly. When symptoms warrant treatment, medical therapy can be initiated, and the approach should be problem-oriented. It should be kept in mind, however, that palliative therapy may change blood cell counts and reduce systemic complaints without altering the disease process. Those patients should be carefully monitored for acquisition of new risk factors and for disease acceleration. JAK inhibitor therapy can also be offered to symptomatic patients with poor prognosis who are not eligible for allo-SCT owing to advanced age or associated comorbidities, and the main goal of therapy should be alleviating symptoms and maintaining quality of life. Patients with limited life expectancy who are otherwise in good condition and have a suitable donor should be offered allo-SCT through an experienced transplant center. Some of those patients may already have exhausting symptoms and may be offered medical therapy before transplant. It may be possible that reduction of disease burden or improving the general condition before allo-SCT may positively influence its outcome. Early data on using ruxolitinib before transplant to reduce spleen size and constitutional symptoms have indicated that it is feasible and did not negatively affect the outcome of transplant.54,55 But on the other hand, it is still too early to exclude that some of those medications may negatively interfere with allo-SCT outcome, and cardiac toxicity and tumor lysis syndrome have been reported.56 This issue is the
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Transplant in Myelofibrosis subject of an ongoing clinical trial (NCT 01795677). A potential algorithm is given in Figure 1. Overall improvement in the management of allo-SCT for MF has increased the number of such procedures performed annually, and it remains the only curative treatment approach. By harnessing the major effects of JAK inhibitors (such as spleen size reduction and improvement of constitutional symptoms) before transplant, further reduction of treatment-related complications is likely, which will result in improved survival.
Disclosure Both authors state that they have no conflicts of interest.
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