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Allogeneic SCT for myelofibrosis
survival of 75% versus 20%) and there was a lower inci- dence of acute GvHD with RIC regimens than with MAC. Almost 10 years ago, Patriarca et al. reported on the 20-year experience of the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO) in which 48 patients underwent MAC and 52 were given RIC regimens.50 Intensity of the conditioning regimen did not significantly influence either overall sur- vival or relapse incidence. More recently, a preliminary analysis from the CMWP of the EBMT by McLornan et al. reported on a total of 2,183 patients who underwent allo- geneic SCT for myelofibrosis; regimen intensity was assessed by standard EBMT criteria.34 Conventional MAC regimens were utilized in 760 patients while 1,423 received RIC regimens. Donor sources were similar: MAC cohort, 309 (41%) matched sibling donors and 451 (59%) unrelated donors; RIC cohort, 543 (38%) matched sibling donors and 880 (62%) unrelated donors. In the preliminary analyses, no statistically significant differences in engraftment, GvHD, NRM, progression-free survival and overall survival rates were found between these two large RIC and MAC cohorts; the final multivariate analysis is awaited. Lastly, the exact role of T-cell depletion strategies in allogeneic SCT for myelofibrosis requires clarification. In addition to the above discussions, retrospective analyses by Robin et al., on behalf of EBMT, have demonstrated that in the matched sibling donor setting, use of antithymocyte globu- lin decreased acute GvHD rates without increasing the relapse risk.51
Alternative donors
Mismatched related donor transplantation in myelofibrosis
Until recently, overall experience remained restricted because of historical fears of graft rejection and GvHD and exclusion from clinical trials. The EBMT group recently described a retrospective study of 56 myelofibrosis patients (median age, 57 years; range, 38-72 years) who underwent mismatched related donor transplantation.52 In this cohort, 70% received MAC and 30% received RIC; the source of hematopoietic stem cells was bone marrow in 66% of cases and peripheral blood in 34%. Conditioning approaches var- ied, reflecting the heterogeneous nature of this cohort, but the most commonly used was thiotepa, busulfan and flu- darabine (TBF) and post-transplant cyclophosphamide. Encouragingly, neutrophil engraftment by day 28 was achieved by 82% of the cohort, at a median time of 21 (range, 19-23) days. Primary graft failure occurred in five patients and secondary graft failure in seven, with two patients dying before engraftment. The cumulative inci- dence of acute GvHD at day +100 was 28% for grade II-IV and 9% for grade III-IV disease. The cumulative incidence of chronic GvHD at 1 year was 45%. The 1- and 2-year overall survival rates were 61% (range, 48-74%) and 56% (range, 41-70%), respectively. The cumulative incidence of relapse was 19% (range, 7-31%) and the NRM was 38% (range, 24-51%) at 2 years. The exact role of transplantation from mismatched related donors in myelofibrosis does, therefore, require further clarification but this study demonstrates that engraftment is feasible with acceptable rates of GvHD and overall survival, although cumulative NRM rates remain somewhat high.
Umbilical cord blood stem cell transplantation
In the setting of myelofibrosis, Takagi et al. initially reported on 14 patients who had undergone RIC umbilical
cord blood transplantation, predominantly high-risk can- didates with secondary acute myeloid leukemia.53 Neutrophil engraftment was achieved in the vast majority (92%) at a median of 23 days and full donor chimerism, where evaluable, was rapidly achieved. Survival was poor with a 4-year overall survival rate of only 28%, perhaps not surprisingly given the high-risk population. More recently, a series of 35 umbilical cord blood transplant recipients (median age, 54 years), registered under EURO- CORD, was reported: seven had developed blast phase myelofibrosis and almost half underwent splenectomy.54 The most common conditioning regimen was total body irradiation, cyclophosphamide and fludarabine (TCF). Cord blood units were 5/6 (23%) and 4/6 (77%) HLA- matched. Neutrophil engraftment was achieved in 28/35 patients at a median time of 30 days and a total of 14 patients displayed graft failure (4 underwent a second transplant procedure). The 2-year overall and event-free survival rates were 44% and 30% respectively. In the RIC setting, all recipients undergoing TCF conditioning achieved both neutrophil and platelet engraftment and there was an association between utilization of this regi- men and improved event-free survival.
Blast phase myelofibrosis and allogeneic stem cell transplantation
Historically, the outcome of patients with blast phase myeloproliferative neoplasms has been extremely poor. A recent retrospective analysis of 410 patients with blast phase myeloproliferative neoplasms, not focusing on allo- geneic SCT, revealed a sobering median survival of 3.5 months.55 Intensive chemotherapy resulted in complete remission or complete remission with incomplete count recovery rates of 35% and 24%, respectively, and even following allogeneic SCT the 3-year survival rate was 32%. This retrospective work suggested that allogeneic SCT has a role in improving short-term survival but dura- bility of response remains under question although the authors did acknowledge that the overall cohort of patients who underwent allogeneic SCT was small. The EBMT group published data on 46 patients who under- went allogeneic SCT for blast phase myelofibrosis and confirmed the importance of achieving complete remis- sion prior to transplantation, which was also demonstrat- ed in a retrospective collaborative French study.56,57 The transplant-related mortality rate at 1 year was acceptable at 28% and the 3-year progression-free and overall sur- vival rates were 26% and 33%, respectively. The impact of both karyotype and mutational landscape on determin- ing outcomes following transplantation for blast phase myelofibrosis is an area of active research and considera- tion should be given to post-transplant maintenance strategies.
Post-transplant outcomes and complications
Impact of mutations on transplant outcome
Early studies investigating the impact of the mutational landscape on the outcomes of allogeneic SCT yielded con- flicting results.32,58 Retrospective studies revealed a signifi- cant adverse impact of lack of the JAK2V617F mutation on overall survival after allogeneic SCT for myelofibrosis whereas a CALR mutation was associated with improved overall survival and less NRM.59,60 The impact of more extensive mutational profiling was recently investigated in
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