Busulfan- or Thiotepa-Based Conditioning in Myelofibrosis: A Phase II Multicenter Randomized Study from the GITMO Group

Abstract

We report a randomized study comparing fludarabine in combination with busulfan (FB) or thiotepa (FT), as conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with myelofibrosis. The primary study endpoint was progression-free survival (PFS). Sixty patients were enrolled with a median age of 56 years and an intermediate-2 or high-risk score in 65%, according to the Dynamic International Prognostic Staging System (DIPSS). Donors were HLA-identical sibling (n = 25), matched unrelated (n = 25) or single allele mismatched unrelated (n = 10). With a median follow-up of 22 months (range, 1 to 68 months), outcomes at 2 years after HSCT in the FB arm versus the FT arm were as follows: PFS, 43% versus 55% (P = .28); overall survival (OS), 54% versus 70% (P = .17); relapse/progression, 36% versus 24% (P = .24); nonrelapse mortality (NRM), 21% in both arms (P = .99); and graft failure, 14% versus 10% (P = .96). A better PFS was observed in patients with intermediate-1 DIPSS score (P = .03). Both neutrophil engraftment and platelet engraftment were significantly influenced by previous splenectomy (hazard ratio [HR], 2.28; 95% confidence interval [CI], 1.16 to 4.51; P = .02) and splenomegaly at transplantation (HR, 0.51; 95% CI, 0.27 to 0.94; P = .03). In conclusion, the clinical outcome after HSCT was comparable when using either a busulfan or thiotepa based conditioning regimen.

Impact of spleen size and splenectomy on outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis: A retrospective analysis by the chronic malignancies working party on behalf of European society for blood and marrow transplantation (EBMT)

“…This topic has been under frequent debate. A previous French experience showed a modest favorable effect of splenectomy on relapse risk; 7 conversely, in a prospective phase‐II EBMT trial investigating FluBu+ATG RIC platform, splenectomy was associated with a >3‐fold increase in relapse incidence, 9 whereas other research groups have demonstrated no effect on relapse risk 6,8,10 . Certain biological and clinical evidence can sustain the hypothesis that splenectomy per se can affect disease recurrence and progression after transplant.…”

“…Previous work has suggested that “huge” splenomegaly may be associated with a higher risk of graft failure, a significant delay in hematopoietic recovery and an increased occurrence of poor graft function 5,6 . However, conflicting results have been reported in terms of both overall survival (OS) and relapse rates 7‐10 . By way of example, Bacigalupo et al documented a lower non‐relapse mortality (NRM) and improved survival in patients undergoing allo‐HCT with spleen diameters <22 cm 8 .…”

The role of allogeneic stem-cell transplant in myelofibrosis in the era of JAK inhibitors: a case-based review

“…Despite these observations, it remains uncertain if splenectomy prior to transplantation is associated with improved outcomes. At present, there is some evidence to support pretransplant splenectomy [49][50][51], but postoperative complications, present in around one-half of all patients [52], could lead to delays in HSCT. Therefore, it is accepted that clinical decisions on surgical reduction of spleen size should be made on an individualized basis [19].…”

“…Accordingly, RIC with fludarabine + thiotepa was adopted in the present case. A recent prospective randomized study compared fludarabine in combination with busulfan or thiotepa as conditioning regimen in 60 patients undergoing HSCT for MF, showing comparable clinical outcome in the two arms [51]. However, other available data are somewhat discrepant on the outcomes of patients undergoing fludarabine-melphalan based RIC regimens [54,61].…”

Splenectomy before allogeneic hematopoietic cell transplantation for myelofibrosis: A French nationwide study

“…Indeed, there are several reports of faster platelet and/or neutrophil count recovery in splenectomized patients. [3][4][5][6][7][8][9][10][11][12][13] The results regarding other post-transplant outcomes are inconsistent; some studies have found longer overall survival after pretransplant splenectomy, 8,13,14 whereas others observed a higher risk of relapse. 15 In the current issue of the American Journal of Hematology, Polverelli et al showed that splenectomy was associated with a lower rate of non-relapse mortality but a higher relapse rate in MF patients, and with a better overall survival in those with a massive splenomegaly.…”