Splenectomy before allogeneic hematopoietic stem‐cell transplantation for myelofibrosis: Tumor burden matters!
Authors: Vincent T. Ho, Alessandro Rambaldi
Journal: American Journal of Hematology (2020)

Although allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for patients with myelofibrosis (MF),1 it has traditionally been hampered by poor engraftment and increased transplant related complications. Massive splenomegaly associated with advanced disease burden often leads to poor performance status and cachexia, rendering these patients more prone to the rigors of transplantation.2 Furthermore, sequestration of donor hematopoietic cells in very large spleens can negatively affect engraftment, leading to persistent cytopenias and prolonged transfusion requirements after HCT.3 Several retrospective studies indicate that splenectomized patients have faster post-transplantation granulocyte and platelet recovery than those not splenectomized.4-6 However, splenectomy can be associated with significant morbidity and mortality due to bleeding, thrombosis, infectious complications and also an increased risk of post-transplant lymphoproliferative diseases7 and graft vs host disease.8 Overall, the available retrospective studies provide no clear evidence for either a significant advantage or disadvantage of splenectomy on post-transplantation outcome. Most of these studies are restricted to splenectomized patients who underwent HCT and are limited by selection bias, not considering patients whose transplants were abandoned due to the complications of splenectomy. The question of whether MF patients with sizeable spleens should undergo pre-transplant splenectomy or, alternatively, splenic radiation, and how these interventions affect engraftment, relapse and survival after HCT remains largely unknown. In this issue of the American Journal of Hematology, two important studies from the European Bone Marrow Transplant (EBMT) registry and the French-language Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC) lend new important insight into the role of pre-transplant splenectomy. In the EBMT study, Polerelli et al. reported the outcome of a large European series of transplants recorded in the EBMT registry.9 They identified a cohort of 1195 MF patients transplanted between 2000 and 2017, after either fludarabine-busulfan or fludarabine-melphalan regimens. This EBMT registry paper highlights some remarkable findings. First, non-relapse mortality (NRM) was reduced by splenectomy as well as by T cell depletion, younger patient age, and when a matched related donor (MRD) was used compared to a matched unrelated (MUD) and mismatched unrelated (MMUD). However, splenectomy, Tcell depletion, older age and earlier transplant year were associated with a higher risk for disease relapse. Not surprisingly, and in line with several previously published studies, the overall survival (OS) was not significantly improved. However, the spleen size before transplant matters, and increasing spleen size at the time of transplant was significantly associated with worse overall survival. In addition, compared to non-splenectomized patients with spleen >15 cm, NRM and OS were significantly improved in splenectomized patients. Interestingly, the effect of spleen size (>15 cm compared to <5 cm) was no longer significant on OS in subset analysis of patients undergoing myeloablative conditioning. Second, splenectomy was performed in 16% of patients, but its frequency decreased over the time-period analyzed (from 28% in 2000-2009 vs 14% in 2010-2017). Most likely, the introduction of ruxolitinib or other experimental JAK1/2 inhibitors as a bridge to transplant treatment for splenomegaly might explain this trend. Also, patients could have been referred to transplant more timely according to international recommendations.10 To complement the results of the EBMT study, Bossard et al. from the SFGM-TC reported their multi-center retrospective analysis of 530 MF patients who were registered between 2008 to 2017 with the French bone marrow transplant registry for unrelated donor search with intent for allo-HCT.11 This cohort of patients was followed out for subsequent outcomes used a multistate model with four states (“RFGM registration”; “splenectomy”; “death before allo-HCT”, and “allo-HCT”) to evaluate the association between splenectomy and the incidence of allo-HCT. With a median follow-up time of 6 years, they reported 81 splenectomies, of whom 65 then underwent allo-HCT, nine died after splenectomy (without allo-HCT), and seven were alive but had not undergone allo-HCT. Among the 16 splenectomized patients who did not subsequently receive allo-HCT, there were only two cases in which splenectomy were determined to have prevented transplantation: one from a post-operative pancreatic fistula, and another due to post-operative infection. In bi-variable and multivariate analyses, there were no significant differences in the rate of death between splenectomized and non-splenectomized patients. These results (only two of 81 splenectomies had surgical complications that prevented transplantation) suggest that splenectomy before HSCT in MF patients is safe and associated with a low likelihood of derailing allo-HCT plans. In patients with MF undergoing HCT, the tumor burden is usually massive when the conditioning regimen starts since in most cases no effective cytoreductive treatment is given before transplant. The presence of an otherwise unmanageable huge spleen is often the reason why a general hematologist eventually refers the patient to transplant but this may represent an important reason for transplant failure. The EBMT study, similarly to other studies, suggests that the intensity of the conditioning regimen is important in patients with massive splenomegaly.12 However, the intensity of the conditioning regimens adopted in MF has to be reduced in many cases due to the advanced age, and the many concomitant diseases preventing the use of full myeloablative approach.13 Undoubtedly, splenectomy before transplant allows the immediate removal of several logs (ie, kilograms!) of tumor burden. Despite the huge number of transplants analyzed, the typical biases of a retrospective study remain as significant possible confounders. However, taken together, these two studies, for the first time, convincingly show that pre-transplant splenectomy in patients with MF, especially those with higher risk disease, are associated with improved overall survival after HCT, and that pre-transplant splenectomy can be safely performed in most cases, with low likelihood of complications that would preclude subsequent transplantation. Since randomized studies to address this question of splenectomy are unlikely to be done, these two studies represent significant contributions to the field and should have potential practice-changing ramifications. The authors declare no conflict of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study