Despite major advances in the understand- ing of the molecular pathogenesis of myelo- fibrosis and the development of Janus kinase. (JAK) 1/2 inhibitors as ...
Clinical Review
COMMENTARY
Allogeneic Hematopoietic Stem-Cell Transplantation in Myelofibrosis: Key Messages for Clinical Practice in the Era of Janus Kinase 1/2 Inhibitors Piyanuch Kongtim, MD, and Uday Popat, MD, MBA Thammasat University, Bangkok, Thailand, and The University of Texas MD Anderson Cancer Center, Houston, TX
ASSOCIATED CONTENT See accompanying article on page 611 DOI: 10.1200/JOP.2016.014308
Despite major advances in the understanding of the molecular pathogenesis of myelofibrosis and the development of Janus kinase (JAK) 1/2 inhibitors as targeted therapy for this disease, no curative drug treatment exists. Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative therapy. In this issue, Farhadfar et al1 summarize the current literature and provide recommendations on the role of and indications for HSCT in patients with myelofibrosis. Their article is comprehensive and can help practicing physicians to decide when and how to perform HSCT in these patients; however, several comments are in order. Who Should Be Considered for HSCT? HSCT entails significant risks of morbidity and mortality; therefore, transplantation should be done only when the potential benefits of the treatment justify the risks. Conversely, too long a delay in transplantation results in poor outcomes. Patients with high-risk disease have worse outcomes than those with intermediate-risk disease,2 and patients with poor performance status have worse outcomes. Thus, patients who have a poor prognosis but are currently in good health should be considered for HSCT. As recommended by Farhadfar et al1 and a consensus statement from the European Society for Blood and Marrow
Transplantation/European LeukemiaNet International Working Group,3 transplantation is a suitable option for patients with a good performance status; a suitably matched related or unrelated donor; and a poor prognosis, which is determined by the presence of one of the following presentations: 1. Intermediate-2–risk or high-risk disease or 2. Intermediate-1–risk disease and a. Refractory transfusion-dependent anemia; b. High peripheral blood blast count ($ 2%); c. Adverse cytogenetics; or d. Presence of adverse molecular markers such as ASXL1 mutation or triple-negative features (negative for JAK2, MPL, and CALR). Finally, patients with leukemic transformation have a dismal prognosis with standard therapy and should be considered for HSCT after appropriate cytoreduction because a minority of these patients can benefit from a transplant.4 Potential Complications of HSCT Unlike HSCT in patients with other hematologic malignancies, HSCT in patients with myelofibrosis entails unique challenges due to organ enlargement and dysfunction due to extramedullary hematopoiesis. In
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some studies, splenomegaly has been associated with prolonged cytopenia after transplantation and poor overall survival; however, splenectomy before transplantation remains controversial. Pretransplantation splenectomy has not improved overall survival and is associated with significant morbidity and mortality. Thus, if splenectomy is performed, it should be done only in patients with a truly massive spleen. Ruxolitinib, a selective JAK1/2 inhibitor that shrinks the spleen, may be particularly useful in patients with a large spleen. A recent retrospective study by Shanavas et al5 showed that survival was superior in patients who had clinical improvement with JAK1/2 inhibitors before HSCT. Prospective studies are under way to clarify the role of these agents before transplantation. In patients with myelofibrosis who undergo HSCT, hepatomegaly, portal hypertension, impaired hepatic function due to extramedullary hematopoiesis, and iron overload increase the risk of liver damage manifested by sinusoidal obstruction syndrome. Management of fluid balance after transplantation can be particularly challenging, and ascites may be a major problem. Thus, transplantation is best performed before the development of advanced disease that would increase the risk of these complications. In patients with myelofibrosis who undergo reducedintensity conditioning stem-cell transplantation, especially with a transplant from a matched unrelated donor,6 the other major challenge is high risk of primary graft failure and secondary graft failure with recurrence of the original abnormal clone. Use of peripheral blood as a stem cell source may be prudent because it reduces the risk of graft failure. An intensification of the conditioning regimen without an increase in the attendant toxicity may be the best way to further reduce the risk of graft failure and relapse. One way to achieve this objective is to deliver a higher exposure of busulfan on the basis of the pharmacokinetic profile.7 Encouraging data on this approach have recently been reported.8
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In summary, HSCT is a potentially curative therapy that should be considered in patients with advanced myelofibrosis. Authors’ Disclosures of Potential Conflicts of Interest Disclosures provided by the authors are available with this article at jop.ascopubs.org. Author Contributions Conception and design: All authors Collection and assembly of data: All authors Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors Corresponding author: Uday Popat, MD, MBA, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 423, Houston, TX; e-mail: upopat@ mdanderson.org.
References 1. Farhadfar N, Cerquozzi S, Patnaik MS, et al: Allogeneic hematopoietic stem-cell transplant for myelofibrosis: A practical review. J Oncol Pract 12:611-621, 2016 2. Scott BL, Gooley TA, Sorror ML, et al: The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 119:2657-2664, 2012 ¨ 3. Kr oger NM, Deeg JH, Olavarria E, et al: Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN International Working Group. Leukemia 29:2126-2133, 2015 4. Tam CS, Nussenzveig RM, Popat U, et al: The natural history and treatment outcome of blast phase BCR-ABL-myeloproliferative neoplasms. Blood 112: 1628-1637, 2008 5. Shanavas M, Popat U, Michaelis LC, et al: Outcomes of allogeneic hematopoietic cell transplantation in patients with myelofibrosis with prior exposure to Janus kinase 1/2 inhibitors. Biol Blood Marrow Transplant 22:432-440, 2016 6. Rondelli D, Barosi G, Bacigalupo A, et al: Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia. Blood 105:4115-4119, 2005 7. Kerbauy DM, Gooley TA, Sale GE, et al: Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant 13:355-365, 2007 8. Popat UR, Bassett RL, Chen J, et al: Allogeneic transplantation for myelofibrosis: Final analysis of a prospective study after a median follow up of 5 years. J Clin Oncol 33, 2015 (suppl; abstr 7008)
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Commentary
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Allogeneic Hematopoietic Stem-Cell Transplantation in Myelofibrosis: Key Messages for Clinical Practice in the Era of Janus Kinase 1/2 Inhibitors The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml. Piyanuch Kongtim No relationship to disclose
Uday Popat No relationship to disclose
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