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Abstract

Primary myelofibrosis (PMF) is a disease characterized by bone marrow fibrosis, extramedullary hematopoiesis, risk of transformation to acute myeloid leukemia, and a substantial symptom burden with diminished quality of life. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option; however, disease relapse and graft versus host disease (GVHD) are significant barriers to long-term survival. The discovery of the JAK2 V617F mutation, and subsequent development of JAK inhibitors, resulted in improved survival and significant improvements in spleen volumes and symptom scores. Though the effect of JAK inhibition on transplant outcome is poorly understood, using JAK inhibition to achieve maximal response prior to HCT is standard practice at major centers. After allogeneic HCT, a significant proportion of patients with steroid-refractory GVHD have clinical responses to JAK inhibition. Targeting this pathway is a key component in the management of patients with PMF before and after allogeneic HCT.

Keywords

myelofibrosis allogeneic transplantation relapse

Introduction

Primary myelofibrosis (PMF) is an uncommon disease that arises from clonal hematopoiesis and a relative excess of cytokines (i.e. basic fibroblast, platelet-derived and vascular endothelial growth factors) that promote the constitutional symptoms, fibrosis and angiogenesis frequently seen in the disease.^1–3 Clinically, these patients manifest with peripheral blood cytopenias, splenomegaly secondary to extramedullary hematopoiesis, and the transformation to acute myeloid leukemia (AML).⁴ PMF has an age- and sex-adjusted incidence of 1–1.46 per 100,000 persons annually, and median age at diagnosis of 67 years (range 43–84).^5–8 PMF is a heterogeneous disease with a complex pathobiology and often aggressive disease course with a median overall survival (OS) of approximately 5 years, ranging from 1 to 13 years.⁴ Although generally regarded as an acquired disorder, kindred with myeloproliferative neoplasms (MPNs) have been widely reported, suggesting a genetic predisposition for the disease may exist.^9,10

Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for patients with PMF. In recent years, post-HCT outcomes have improved as a result of better pre-HCT disease control, advances in supportive care, safer conditioning regimens, and enhanced long-term care.¹¹ Despite these improvements, relapse of the underlying disease and graft-versus-host disease (GVHD) are important barriers to long-term survival. Across all diseases, relapse leads to the death of 37–48% of patients and GVHD is the cause of death for 18–20% patients after allogeneic HCT. A prospective study of 103 patients with PMF, post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera-myelofibrosis (PPV-MF) that underwent allogeneic HCT demonstrated a 5-year event-free survival (EFS) of 51% and OS of 67%.¹² In PMF, the 3-year probability of survival with HCT is 38–58%; however, patients with high-risk features (hemoglobin ⩽10g/dl, grade 3 marrow fibrosis and/or >1% peripheral blasts) have an inferior anticipated 3-year survival of less than 20%.^13–15 Thus, reducing these risk factors pre-HCT is an important management strategy.

The discovery of the Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway, and the development of JAK inhibitors, are important advances in the care of patients with PMF and other MPNs. JAK inhibitors improve the symptom burden and OS of patients with PMF independent of allogeneic HCT.^16–18 In the pre-transplant setting, the use of these agents to achieve the best possible response prior to the start of conditioning is standard practice at many transplant programs; however, there are limited data to support this practice. After HCT, JAK inhibition has emerged as a new tool in the management of patients with acute and chronic GVHD, with response rates that exceed 80%.¹⁹ Further, a small but growing body of data suggests JAK inhibitors may also serve as steroid-sparing agents.²⁰ Both before and after HCT, JAK inhibition represents an important modality for improving the outcomes of patients with PMF.

Driver mutations in myeloproliferative neoplasms

The JAK-STAT signaling pathway facilitates a wide array of cytokines and growth factors in animals and humans that drive proliferation, differentiation and other cellular functions. In mammals, this pathway consists of four JAK proteins (JAK1, JAK2, JAK3 and Tyk2) and seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) which drive the signaling of >50 cytokines and growth factors.^21,22 JAK-STAT signaling is initiated when cytokines and the corresponding transmembrane receptors interact, leading to JAK activation, cytoplasmic tail phosphorylation, dimerization of STAT, and subsequent gene transcription.²³ In murine models, constitutive JAK-STAT phosphorylation drives cytokine hypersensitivity, inflammatory disease, peripheral blood abnormalities, and myeloproliferation, whereas JAK2 knockouts die during embryogenesis due to a failure to develop meaningful hematopoiesis.^24–27

In 2005, the single base-pair substitution of phenylalanine for valine at residue 617 (V617F) within JAK2 was linked with clonal expansion in myeloproliferative neoplasms, and most dramatically, polycythemia vera (PV).^28–31 This gain-of-function mutation enhances JAK2 kinase activity and increases erythropoietin-induced cell signaling and the sensitivity of progenitor cells to growth factors and cytokines, all of which represent key biologic features of MPNs.²⁸ The incidence of the JAK2V617F mutation is highest in patients with PV (~90%), and occurs less frequently in essential thrombocythemia (ET) (~50%) or PMF (~50%).^29–31 Although JAK2V617F is the most common mutation, alternate driver mutations exist in the PMF. Gain-of-function mutations in exon 12 of JAK2 are observed in 4–13.7% of patients with MPNs, are associated with a PV phenotype, and tend to be younger at diagnosis than JAK2V617F-mutated patients.^32,33 Several studies, including a pooled analysis, report that 5% of PMF and 3–5% of ET patients carry MPL mutations and while usually mutually exclusive, a small percentage of patients have both JAK2V617F and MPLW515L mutations.^34,35 Mutations in calreticulin (CALR) are present in 17% of patients, most commonly in patients with ET and PMF.³⁶ More than 50 CALR mutations have been identified to date; however, the 52 base -pair deletion (type 1) and a five base-pair insertion (type 2) are the most common. Type 1 mutations are associated with a more aggressive phenotype and a higher risk of progression to myelofibrosis. Type 2 CALR mutations are more frequently associated with an ET phenotype and a more indolent clinical course.³⁷ Whereas PMF represents diagnosis made de novo, PET-MF and PPV-MF have nearly identical phenotypes, yet are defined by a progression from ET or PV, respectively.

JAK inhibition: a means to improve survival in myelofibrosis

Allogeneic HCT is the only known curative therapy for patients with PMF, yet long-term disease control and transplant related mortality (TRM) are persistent barriers to survival. Several poor-risk features such as high DIPSS score, adverse cytogenetic abnormalities, advanced age, and severe marrow fibrosis are independently associated with inferior outcomes, and are common in higher-risk PMF patients.^14,15,38 Aggressive pre- and post-HCT management may enhance long-term survival after HCT and improve outcomes, particularly in high-risk patients. Ruxolitinib, the first commercially available JAK2 inhibitor, has improved the outcomes of these patients, potentially increases the proportion of myelofibrosis patients eligible for HCT, and, thus increases the number of patients that may eventually be cured of their disease. Further advancements in regulating the JAK-STAT pathway and/or other novel therapies may enhance this effect.

Ruxolitinib, a selective and potent inhibitor of both JAK1 and JAK2, was one of the earliest JAK inhibitors evaluated in hematologic malignancies. In early studies, ruxolitinib was shown to be well-tolerated with rapid, widespread reduction of extramedullary hematopoiesis and vasoactive symptoms in most patients.^39,40 These findings were confirmed in the COMFORT-I study in which 41.9% of patients treated with ruxolitinib reached the primary endpoint of ⩾35% reduction in splenic volume and nearly half experienced a ⩾50% reduction in their symptom burden on the Total Symptom Score Symptom Assessment Form (TSS-SAF).^16,41 After 5 years of follow up, a limited number of patients maintained a durable reduction in their spleen size as well as improved OS.¹⁶ Similarly, in the COMFORT-II study, a higher percentage of ruxolitinib patients experienced a reduction in spleen volume compared to controls. Again, ruxolitinib was associated with a relative reduction in the risk of death and a trend toward improved OS.^17,42

The survival benefits seen in the COMFORT-I and COMFORT-II studies are thought to be secondary to reductions in splenomegaly, enhanced performance status and improvements in constitutional symptoms.^16,17 Consistent with this, health-related quality-of-life scores improved with ruxolitinib use, specifically improvements in physical and role functioning, fatigue and appetite loss.⁴³ Importantly, those patients who benefited most were those with higher-risk disease (i.e. intermediate-2 or high-risk disease).^18,44 Compared with other hematologic malignancies, patients with myelofibrosis are unique in that they begin conditioning chemotherapy with their primary disease intact, leading to potential delays in engraftment, and graft failure. Citing improvements in survival, quality of life, and MF-related symptoms in higher-risk patients, pre-HCT treatment with a JAK inhibitor should be considered, although data supporting this approach are limited, and peripheral blood cytopenias and/or intolerance may complicate the use of these agents. At many transplant centers, these patients are treated until maximum response prior to the start of conditioning chemotherapy. Patients who are not considered to be candidates for HCT may receive therapy indefinitely.

The decision to move forward with allogeneic HCT is based on several factors, including disease burden and symptoms, the presence of high-risk mutations such as ASXL1 and SRSF2, quality of life, anticipated life expectancy, performance status, availability of a suitable donor, and others. Several scoring systems, including the Dynamic International Prognostic Scoring System (DIPPS) and DIPPS-plus are routinely used to gauge disease risk and expected survival, and to guide discussions regarding HCT.^45,46 Transplantation is not generally recommended for patients with low-risk disease due to a median survival of 15 years.^45,47 Individuals with intermediate-1 disease, especially younger patients and persons with high-risk myeloid mutations, should be considered for HCT since the majority will ultimately die from their disease or its complications.⁴⁷ Patients with intermediate-2 and higher-grade forms of the disease who are suitable candidates for HCT should be allografted.

In recent years, the use of JAK inhibitors have improved disease outcomes, but they also carry unique challenges. Abruptly stopping these agents may precipitate rebound splenomegaly, worsening of peripheral blood cytopenias and shock-like symptoms.⁴⁸ Because of this, and because of concerns associated with the use of myelosuppressive therapy during the period of stem-cell engraftment, JAK inhibitors should be tapered prior to the start of conditioning chemotherapy. There is no universally agreed-upon approach and clinical practice is heterogeneous. One recent study successfully tapered ruxolitinib over 2 weeks and discontinued after the initiation of conditioning chemotherapy and prior to stem-cell infusion (at day 4).⁴⁹

A small fraction of PV patients will progress to PPV-MF (approximately 6–14% at 15 years) and be considered for HCT.⁵⁰ Younger PV patients may develop PPV-MF later in their lifetime and may be evaluated for allogeneic HCT. Consequently, maximizing vascular fitness, minimizing proliferative complications and thromboembolic disease, and careful monitoring for progression are key elements of a comprehensive care plan for patients with PV and may improve their candidacy. Ruxolitinib is beneficial in PV patients who are refractory to, or intolerant of, hydroxyurea. In the RESPONSE study, 20.9% of ruxolitinib patients met the study’s primary endpoint of improved hematocrit and ⩾35% reduction in spleen volume versus <1% of controls.⁵¹ These responses were durable, with the majority of patients maintaining their response for ⩾80 weeks.⁵²

Whether the improvement in these patients’ outcomes are indicative of a more indolent disease biology or if these agents favorably alter the disease remains an area of investigation. Regardless, patients with PMF who are able to tolerate pre-HCT JAK inhibition should be treated to maximal response to maximize post-HCT engraftment and survival. Further studies are needed to more definitively describe the favorable post-HCT impact these agents have in PMF.

JAK inhibitors in development

Several JAK inhibitors are currently in clinical development, with a goal to improve upon the early success of ruxolitinib. In the PERSIST-1 study, pacritinib, a combined JAK2 and FLT3 inhibitor, led to significant reductions in splenomegaly by week 24 compared to the best available therapy (excluding other JAK2 inhibitors).⁵³ In the PERSIST-2 study, pacritinib reduced splenomegaly and improved total symptom scores when compared to the best available therapy (including ruxolitinib).⁵⁴ Importantly, pacritinib appears less myelosuppressive and may allow more aggressive therapy in patients with peripheral blood cytopenias. Momelotinib was compared to ruxolitinib in the SIMPLIFY-1 trial in patients with high-risk, treatment naïve PMF, PPV-MF or PET-MF. Momelotinib was non-inferior to ruxolitinib in reducing splenic volume and led to some improvements in hematologic parameters (specifically hemoglobin); however, it did not improve disease-associated symptoms.⁵⁵ Likewise, in the SIMPLIFY-2 study, momelotinib failed to improve spleen volumes but its use led to improvements in disease symptoms and transfusion dependence compared to the best available, second-line therapy (including ruxolitinib).⁵⁶ Development of momelotinib is stalled, but effective JAK inhibitors that can be safely given to anemic patients with MF are in considerable demand.

Most patients with MPNs have elevated levels of JAK-dependent pro-inflammatory cytokines (e.g. IL-6) consistent with JAK1 hyperactivation. Itacitinib is a selective JAK1 inhibitor that was evaluated in patients with intermediate or high-risk MF regardless of JAK2 mutation status. Patients received benefit from the medication across three separate dose levels. Treated patients experienced reductions in their symptom scores (28.6–35.7%), splenomegaly (14.2–17.4%) and packed red blood cell (PRBC) transfusion needs (53.8%).⁵⁷ Recently, the preliminary results of two early studies were presented that stand to further improve upon the success of ruxolitinib. A phase I study of ruxolitinib and the PI3Kδ inhibitor TGR-1202 was undertaken based on the observation that PI3Kδ is highly expressed in patient samples with MF and its ex-vivo inhibition leads to favorable effects in MF and other diseases.^58,59 In this study, 83% of patients derived clinical benefit from the combination, with hematologic improvement, reduction in spleen size, and/or symptom improvement.⁶⁰ Second, the early results of a phase II study with sotatercept, an activin receptor type IIA (ActRIIA) ligand trap that binds and sequesters the ligands of transforming growth factor beta (TGF-B) superfamily, revealed 5 of 14 patients experiencing improvements in anemia, with reduced transfusion dependence.⁶¹

Inhibiting JAK-STAT signaling in GVHD

The JAK-STAT signaling cascade is involved in the regulation of several inflammatory pathways and plays an integral role in interferon-induced chemokine signaling – an important pathway in acute and chronic GVHD.^62–64 Ruxolitinib impairs the differentiation of CD4+ T cells into IFN-γ and IL-17A producing cells and promotes FoxP3+ regulatory T cells, both of which are key components of immune tolerance.⁶⁵ Murine studies of ruxolitinib prophylaxis during transplantation with major histocompatibility complex-mismatched grafts demonstrated reduced histologic evidence of GVHD and improved survival.^65,66 Some of the earliest clinical data came from six patients with refractory acute GVHD who responded to ruxolitinib. Serum levels of IL-6 and the soluble IL-2 receptor decreased with treatment in all analyzed patients, highlighting its role in controlling the disease.⁶⁵ Patients with GVHD treated with ruxolitinib appear to maintain the desirable graft versus leukemia (GVL) effects while controlling GVHD.⁶⁶ These findings have led to the recognition that the JAK-STAT signaling cascade is an attractive target in the post-HCT setting. Further retrospective analysis of ruxolitinib in acute and chronic GVHD for 95 patients treated with ruxolitinib salvage therapy for steroid-refractory GVHD from 19 HCT centers revealed an overall response rate (ORR) of 81.5% in acute GVHD (46.3% complete response [CR]) and 85.4% in chronic GVHD. The primary side effects were peripheral blood cytopenias and cytomegalovirus reactivation in both groups.¹⁹ Khoury and colleagues reported the results of 19 patients with severe steroid-dependent chronic GVHD treated with ruxolitinib salvage therapy. Responses were observed after a median of 14 days; 15/19 patients were able to discontinue prednisone and four remained on low doses.⁶⁷ In pediatric HCT, of 11 patients treated with ruxolitinib, 45% responded [1 CR, 4 partial response (PR)], and the most frequent toxicities were liver function abnormalities and peripheral blood cytopenias.⁶⁸

Ruxolitinib, itacitinib and the JAK1/2 inhibitor baricitinib are being explored in HCT. Preliminary results with itacitinib in patients with grade IIB-IVD acute GVHD revealed an ORR of 83.3% in first-line patients and 64.7% in steroid-refractory patients.⁶⁹ Several studies are being planned to evaluate the role of these agents in the maintenance setting after allogeneic HCT and active clinical trials involving JAK inhibitors are noted in Table 1.

Table 1.

Summary of active HCT clinical trials with JAK1/JAK2 inhibitors.

Study name	Focus	Phase	ClinicalTrials.gov identifier	Status
A Phase 1/2 Study of Baricitinib, a JAK 1/2 Inhibitor, in Chronic Graft-Versus-Host Disease (cGVHD) After Allogeneic Hematopoietic Stem-Cell Transplantation (SCT)	Safety, efficacy	I/II	NCT02759731	Active
JAK Inhibitor Prior to Allogeneic Stem-Cell Transplant for Patients with Primary and Secondary Myelofibrosis: A Prospective Study	2-year OS	II	NCT02251821	Active
Treatment of Steroid-Refractory Acute and Chronic Graft-versus-host Disease with Inhibitor of Janus Kinases	ORR	II	NCT02997280	Active
A Single-Cohort, Phase 2 Study of Ruxolitinib in Combination with Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus Host Disease (REACH1)	ORR (day 28)	II	NCT02953678	Active
GRAVITAS-301: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Itacitinib or Placebo in Combination with Corticosteroids for the Treatment of First-Line Acute Graft-Versus Host Disease	ORR	III	NCT03139604	Active
A Phase III Randomized Open-label Multi-Center Study of Ruxolitinib Versus Best Available Therapy in Patients with Corticosteroid-refractory Acute Graft versus Host Disease after Allogeneic Stem-Cell Transplantation	ORR	III	NCT02913261	Active
JAK2 Inhibitors Ruxolitinib in Patients with High or Intermediate Risk Primary or Secondary Myelofibrosis Eligible for Allogeneic Stem-Cell Transplantation: A Prospective Multicenter Phase II Study	2-year DFS	II	NCT01795677	Not recruiting
Exploring the Potential of Dual JAK 1/2 Inhibitor Ruxolitinib (INC424) with Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis	100-day survival without graft failure	II	NCT01790295	Not recruiting

DFS, disease-free survival; ORR, overall response rate; OS, overall survival.

Conclusion

Allogeneic HCT remains the only available curative therapy for MF but is not widely available. The widespread use of JAK inhibitors may be increasing the number of eligible patients; however, post-HCT outcomes are historically poor. Both GVHD and disease relapse represent significant drivers of post-transplant mortality. The JAK-STAT signaling pathway has evolved into an attractive target both before and after transplant. In the pre-HCT setting, JAK inhibitors reduce symptoms and improve quality of life, as well as reduce spleen volumes. After HCT, JAK-STAT inhibition demonstrates significant response rates in both acute and chronic GVHD with preservation GVL-effects. Development of new JAK inhibitors and other novel treatments promises to further enhance the care of these patients.

Footnotes

Author contribution statement

Manuscript was written by MB, MRS and BS. All authors were responsible for reviewing the draft manuscript, and all authors provided approval of the final draft manuscript.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

Arber

Orazi

Hasserjian

et al . The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127: 2391–2405.

Ciurea

Merchant

Mahmud

et al . Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis. Blood 2007; 110: 986–993.

Tefferi

Pathogenesis of myelofibrosis with myeloid metaplasia. J Clin Oncol 2005; 23: 8520–8530.

Tefferi

Treatment approaches in myelofibrosis with myeloid metaplasia: the old and the new. Semin Hematol 2003; 40: 18–21.

Mesa

Silverstein

Jacobsen

et al . Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted County Study, 1976–1995. Am J Hematol 1999; 61: 10–15.

Mehta

Wang

Iqbal

et al . Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014; 55: 595–600.

Campbell

Green

AR.

The myeloproliferative disorders. N Engl J Med 2006; 355: 2452–2466.

Smith

Chelmowski

Szabo

EJ.

Myelofibrosis: a review of clinical and pathologic features and treatment. Crit Rev Oncol Hematol 1990; 10: 305–314.

Mallouh

Sa’di

AR.

Agnogenic myeloid metaplasia in children. Am J Dis Child 1992; 146: 965–967.

10.

Bonduel

Sciuccati

Torres

et al . Familial idiopathic myelofibrosis and multiple hemangiomas. Am J Hematol 1998; 59: 175–177.

11.

Hahn

McCarthy

Hassebroek

et al . Significant improvement in survival after allogeneic hematopoietic cell transplantation during a period of significantly increased use, older recipient age, and use of unrelated donors. J Clin Oncol 2013; 31: 2437–2449.

12.

Kröger

Zabelina

de Wreede

et al . Allogeneic stem cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia 2013; 27: 604–609.

13.

Ditschkowski

Beelen

Trenschel

et al . Outcome of allogeneic stem cell transplantation in patients with myelofibrosis. Bone Marrow Transplant 2004; 34: 807–813.

14.

Deeg

Gooley

Flowers

et al . Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912–3918.

15.

Lussana

Rambaldi

Finazzi

et al . Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2014; 99: 916–921.

16.

Verstovsek

Mesa

Gotlib

et al . A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 2012; 366: 799–807.

17.

Harrison

Kiladjian

Al-Ali

et al . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 2012; 366: 787–798.

18.

Vannucchi

Kantarjian

Kiladjian

et al . A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase III trials of ruxolitinib for the treatment of myelofibrosis. Haematologica 2015; 100: 1139–1145.

19.

Zeiser

Burchert

Lengerke

et al . Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey. Leukemia 2015; 29: 2062–2068.

20.

Khoury

Kota

Arellano

et al . Ruxolitinib as sparing agent for steroid-dependent chronic Graft-Versus-Host Disease (cGVHD). Presented at the American Society of Hematology 57th Annual Meeting & Exposition, 2015, Orlando, FL.

21.

Yamaoka

Saharinen

Pesu

et al . The Janus kinases (Jaks). Genome Biol 2004; 5: 253.

22.

Villarino

Kanno

Ferdinand

et al . Mechanisms of Jak/STAT signaling in immunity and disease. J Immunol 2015; 194: 21–27.

23.

Villarino

Kanno

O’Shea

JJ.

Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol 2017; 18: 374–384.

24.

Neubauer

Cumano

Müller

et al . Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397–409.

25.

Parganas

Wang

Stravopodis

et al . Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 385–395.

26.

James

Ugo

Le Couédic

et al . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 2005; 434: 1144–1148.

27.

Rawlings

Rosler

Harrison

DA.

The JAK/STAT signaling pathway. J Cell Sci 2004; 117: 1281–1283.

28.

Zhao

Xing

et al . Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005; 280: 22788–22792.

29.

Baxter

Scott

Campbell

et al . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005; 365: 1054–1061.

30.

Kralovics

Passamonti

Buser

et al . A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005; 352: 1779–1790.

31.

Levine

Wadleigh

Cools

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.

32.

Scott

Tong

Levine

et al . JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007; 356: 459–468.

33.

Passamonti

Rumi

Pietra

et al . A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 2010; 24: 1574–1579.

34.

Pardanani

Levine

Lasho

et al . MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 2006; 108: 3472–3476.

35.

Cabagnols

Favale

Pasquier

et al . Presence of atypical thrombopoietin receptor (MPL) mutations in triple-negative essential thrombocythemia patients. Blood 2016; 127: 333–342.

36.

Klampfl

Gisslinger

Harutyunyan

et al . Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379–2390.

37.

Pietra

Rumi

Ferretti

et al . Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms. Leukemia 2016; 30: 431–438.

38.

Kröger

Giorgino

Scott

et al . Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood 2015; 125: 3347–3350; quiz 64.

39.

Verstovsek

Kantarjian

Mesa

et al . Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363: 1117–1127.

40.

Quintás-Cardama

Vaddi

Liu

et al . Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 2010; 115: 3109–3117.

41.

Mesa

Schwager

Radia

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.

42.

Harrison

Vannucchi

Kiladjian

et al . Long-term findings from COMFORT-II, a phase 3 study of ruxolitinib vs best available therapy for myelofibrosis. Leukemia 2016; 30: 1701–1707.

43.

Harrison

Mesa

Kiladjian

et al . Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol 2013; 162: 229–239.

44.

Cervantes

Pereira

Does ruxolitinib prolong the survival of patients with myelofibrosis?

Blood 2017; 129: 832–837.

45.

Gangat

Caramazza

Vaidya

et al . DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29: 392–397.

46.

Passamonti

Cervantes

Vannucchi

et al . A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115: 1703–1708.

47.

Ballen

How to manage the transplant question in myelofibrosis. Blood Cancer J 2012; 2: e59.

48.

Tefferi

Pardanani

Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis. Mayo Clin Proc 2011; 86: 1188–1191.

49.

Salit

Stevens

Baker

et al . JAK inhibitors prior to allogeneic stem cell transplant for patients with myelofibrosis: a prospective study. Presented at the BMT Tandem Meetings, 2018, Salt Lake City, UT.

50.

Cerquozzi

Tefferi

Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J 2015; 5: e366.

51.

Vannucchi

Kiladjian

Griesshammer

et al . Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 2015; 372: 426–435.

52.

Verstovsek

Vannucchi

Griesshammer

et al . Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial. Haematologica 2016; 101: 821–829.

53.

Mesa

Vannucchi

Mead

et al . Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): an international, randomised, phase 3 trial. Lancet Haematol 2017; 4: e225–e236.

54.

Mascarenhas

Hoffman

Talpaz

et al . Results of the Persist-2 Phase 3 Study of Pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (Rux), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/ul. Presented at the American Society of Hematology Annual Meeting & Exposition, 2016, San Diego, CA.

55.

Mesa

Kiladjian

Catalano

Phase 3 trial of momelotinib (MMB) vs ruxolitinib (RUX) in JAK inhibitor (JAKi) naive patients with myelofibrosis (MF). Presented at the ASCO Annual Meeting, 2017, Chicago, IL.

56.

Harrison

Vannucchi

Platzbecker

Phase 3 randomized trial of momelotinib (MMB) versus best available therapy (BAT) in patients with myelofibrosis (MF) previously treated with ruxolitinib (RUX). Presented at the ASCO Annual Meeting, 2017, Chicago, IL.

57.

Mascarenhas

Talpaz

Gupta

et al . Primary analysis of a phase II open-label trial of INCB039110, a selective JAK1 inhibitor, in patients with myelofibrosis. Haematologica 2017; 102: 327–335.

58.

Choong

Pecquet

Pendharkar

et al . Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors. J Cell Mol Med 2013; 17: 1397–1409.

59.

Meadows

Vega

Kashishian

et al . PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 2012; 119: 1897–1900.

60.

Moyo

Sochacki

Ayers

et al . Preliminary results from a phase I dose escalation trial of ruxolitinib and the PI3Kd inhibitor TGR-1202 in myelofibrosis. Presented at the American Society of Hematology Annual Meeting & Exposition, 2016, San Diego, CA.

61.

Bose

Daver

Jabbour

et al . Phase-2 study of sotatercept (ACE-011) in myeloproliferative neoplasm-associated myelofibrosis and anemia. Presented at the American Society of Hematology Annual Meeting & Exposition, 2016, San Diego, CA.

62.

Ghoreschi

Laurence

O’Shea

JJ.

Janus kinases in immune cell signaling. Immunol Rev 2009; 228: 273–287.

63.

O’Shea

Holland

Staudt

LM.

JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 2013; 368: 161–170.

64.

Hakim

Memon

Jin

et al . Upregulation of IFN-inducible and damage–response pathways in chronic graft-versus-host disease. J Immunol 2016; 197: 3490–3503.

65.

Spoerl

Mathew

Bscheider

et al . Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood 2014; 123: 3832–3842.

66.

Choi

Cooper

Alahmari

et al . Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect. PLoS One 2014; 9: e109799.

67.

Khoury

Kota

Arellano

et al . Ruxolitinib as sparing agent for steroid-dependent chronic graft-versus-host disease (cGVHD). Presented at the BMT Tandem Meetings, 2017, Orlando, FL.

68.

Khandelwal

Teusink-Cross

Davies

et al . Ruxolitinib as salvage therapy in steroid-refractory acute graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Biol Blood Marrow Transplant 2017; 23: 1122–1127.

69.

Schroeder

Khoury

Jagasia

et al . A phase I trial of Janus kinase (JAK) inhibition with INCB039110 in acute graft-versus-host disease (aGVHD). Presented at the American Society of Hematology Annual Meeting & Exposition, 2016, San Diego, CA.

Leveraging JAK-STAT regulation in myelofibrosis to improve outcomes with allogeneic hematopoietic stem-cell transplant

Abstract

Keywords

Introduction

Driver mutations in myeloproliferative neoplasms

JAK inhibition: a means to improve survival in myelofibrosis

JAK inhibitors in development

Inhibiting JAK-STAT signaling in GVHD

Conclusion

Footnotes

Author contribution statement

Funding

Conflict of interest statement

References