Allogeneic SCT for Myelofibrosis – pro

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis. Several nonrandomized studies have indicated that allogeneic SCT for patients under the age of 55 is effective in prolonging survival in more than 50% of cases and in possibly curing the disease. A 1999 Consensus conference recommended that patients with the most severe prognosis are candidates.

Several studies suggest that unrelated allogeneic transplants with full conditioning are too toxic to be routinely advised. Allo-SCT is the only available therapy for patients with CIMF with potential to eliminate bone marrow fibrosis and possibly cure patients. Nonetheless, the use of fully myeloablative conditioning regimens has been associated with high morbidity and mortality. In particular, the age of patients undergoing allo-SCT proved to be a critical prognostic factor in one study, in which 14% of patients older than 45 years at the time of transplantation survived beyond 5 years of follow-up.

Recently, a retrospective analysis of the outcomes of 320 patients with CIMF receiving allo-SCT between 1989 and 2002 was published. Most patients received ablative conditioning with either total body irradiation (TBI) (n = 117) or busulphan (n = 150) and cyclophosphamide. Bone marrow was the graft source in 208 patients. HLA-identical sibling donors were used in 170 transplants, 117 were from a matched unrelated donor (MUD), and 33 were from an alternative related donor. The 100-day mortality rates were 22% after sibling transplants, 42% after MUD transplants, and 27% after alternative family donor transplants. Corresponding 5-year overall survival rates were 39%, 31%, and 31%, respectively. Multivariate analysis of 215 adult recipients of myeloablative transplants revealed that having an HLA-identical sibling donor, Karnofsky performance score =90%, younger age, more recent date of transplantation, and absence of blasts in peripheral blood prior to transplantation correlated with better survival. Eighteen patients with all of these factors had a 5-year probability of survival of 81%. Although the ideal conditioning regimen is yet to be defined, cyclophosphamide plus busulphan (with busulphan doses adjusted to achieve targeted plasma levels) resulted in better outcomes when compared with TBI-based regimens.

The introduction of reduced-intensity conditioning (RIC) nonmyeloablative regimens may be particularly applicable in CIMF. The main complication of allo-SCT in patients older than 45 years is transplant-related mortality rather than relapse. The patients in this age group represent the bulk of patients with CIMF, and employing low-intensity conditioning may improve their probability of survival. Sustained engraftment and durable responses have been reported in several case reports involving patients with advanced-stage CIMF who receive fluda-rabine-based RIC regimens. This appears to be a more promising option for these patients. However, there are no randomized controlled trials (RCTs) comparing allo-HSCT to any alternative/supportive therapy and no RCTs comparing myeloablative (MA) versus reduced intensity conditioning (RIC) allo-HSCT or form unrelated donors.

A Tefferi (2016) writes: Considering the lack of effective drug therapy in PMF, the risk of transplant‐related complications might be justified in those patients in whom median survival is expected to be <5 years and leukemic transformation risk >20%. These include DIPSS‐plus high or intermediate‐2 risk patients as well as those with high‐risk mutations. Non‐transplant candidates are best managed with experimental drug therapy. I have yet to be satisfied by the value of any currently available JAK inhibitor and strongly advise patients to continue participating in clinical trials.

A. Tefferi, Primary myelofibrosis: 2017 update on diagnosis, risk‐stratification, and management. Hematology Volume91, Issue12 December 2016,
Pages 1262-1271, 2012

Kröger NM e tal, Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.Leukemia. 2015 Aug 21. 

Scott BLGooley TASorror MLRezvani ARLinenberger MLGrim JSandmaier BMMyerson DChauncey TRStorb RBuxhofer-Ausch VRadich JP,Appelbaum FRDeeg HJ. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood. 2012 Mar 15;119(11):2657-64.

Animesh Pardanani,et al, Update On The Long-Term Efficacy and Safety Of Momelotinib, a JAK1 and JAK2 Inhibitor, For The Treatment Of Myelofibrosis. November 15, 2013; Blood: 122 (21)

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