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D.P. McLornan et al.
Figure 1. Factors determining outcomes following allogeneic stem cell transplantation in myelofibrosis. The determinants of outcomes following allogeneic stem cell transplantation can be divided into: pre-transplantation, transplant-specific, and post-transplant strategies and relapse management. IPSS: International Prognostic Scoring System; DIPSS: dynamic IPSS; IST: immunosuppressive therapy; DLI: donor lymphocyte infusion; MRD: minimal residual disease; Sib: sibling; MUD: matched unrelated donor; MMUD: mismatched unrelated donor; MAC: myeloablative conditioning; RIC: reduced Intensity conditioning; CMV: cytomegalovirus
aid engraftment and perhaps be associated with improved post-transplant outcome.30 However, this procedure is not without risk. Over a decade ago, the Mayo clinic group reported on 314 myelofibrosis patients, albeit not transplant candidates, undergoing elective splenectomy: the interven- tion was associated with significant perioperative compli- cations in nearly 28% of cases.31 Despite major improve- ments with minimally invasive approaches, there are still potential risks of both thrombosis and hemorrhage. Although a prospective study of 103 patients undergoing allogeneic SCT coordinated by the Chronic Malignancies Working Party of the EBMT suggested more rapid neu- trophil engraftment in those who had undergone splenecto- my (n=14) compared to those who had not, both univariate and multivariate analyses suggested a significantly higher rate of relapse at 3 years for the former.32 Moreover, effects on immune reconstitution and GvHD modulation are unclear. In contrast, a French group retrospectively reported on 85 myelofibrosis allogeneic SCT patients from a single center, 39 of whom had undergone pre-transplant splenec- tomy.33 Of note, one half of those patients undergoing splenectomy had surgical or post-surgical complications, most frequently of a thrombotic or hemorrhagic nature. Following Cox adjustment analyses, there was no associa- tion between pre-transplant splenectomy and either non- relapse mortality (NRM) or relapse risk, in fact there was a suggestion towards improved overall survival and event- free survival. This evidently requires evaluation in a larger cohort and ideally in a controlled study as suggested by the authors. In contrast to these findings, initial analyses by
McLornan et al. found no significant effect of splenectomy on overall survival or NRM in a large cohort of splenec- tomized patients undergoing allogeneic SCT with either reduced intensity conditioning (RIC) or MAC (n=180) reg- istered in the EBMT registry database and nor did the retro- spective Center for International Blood and Marrow Transplant Research (CIBMTR) study.34,35 Moreover, given the potential splenic effects of JAK inhibitor therapy, alter- native methods of reducing bulky splenomegaly are possi- ble. Lastly, it is unknown what effect pre-transplant spleen removal will have on immune reconstitution. In general, it is the view of the authors that pre-transplant splenectomy cannot be routinely recommended although it is clear that individual patient-stratified assessment should occur. Low- dose splenic irradiation prior to transplantation has been explored in small cohorts of patients, but overall there is insufficient evidence on this strategy.36,37
What is the role of JAK inhibitors before transplantation for myelofibrosis?
Many questions arise from the use of JAK inhibitors in the myelofibrosis transplant algorithm. Following the phase III trials, COMFORT-I and –II, confirming the efficacy of the JAK1/JAK2 inhibitor ruxolitinib (Novartis, Switzerland) in myelofibrosis, many potential allogeneic SCT recipients have been treated with this agent.5,6 JAK inhibitors collec- tively are attractive agents given that they may improve Performance Status, reduce splenomegaly and potentially shorten time to engraftment and may dampen an inherent- ly pro-inflammatory milieu. Earlier and more recent studies
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haematologica | 2019; 104(4)