Page 1299 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 70 Primary Myelofibrosis 1145

patients after splenectomy and can be controlled with ruxolitinib and MPD-RC. An EBMT trial included 103 MF patients trans-
therapy. planted from related (n = 33) or unrelated donors (n = 70), with 21%
of donors having at least one allele or antigen mismatch using a
fludarabine/busulfan/ATG regimen. Although all but two patients
Allogeneic Stem Cell Transplantation achieved initial engraftment, secondary graft failure or poor graft
function occurred in 11% of patients. The estimated 5-year event-free
aSCT is a potentially curative option in patients with PMF who have survival (EFS) and OS was 51% and 67%, respectively. One-year
an appropriate donor available. Successful transplantation is associ- nonrelapse mortality was 16%—similar among related and unrelated
ated with gradual resolution of BM fibrosis, reduction in spleno- donor transplants but significantly higher in mismatched transplants
megaly, and normalization of hematopoiesis (see box on Algorithm (38% vs. 12%). One third of patients developed grade II–IV acute
for Selection of Appropriate Patients for Stem Cell Transplantation GVHD (11% grade III–IV), with half of patients affected by chronic
Stratified According to Risk Status). GVHD (24% extensive). Relapse rate/treatment failure at 3 and 5
Most of our understanding of the role of aSCT in primary and years was 22% and 29%, respectively. As can be seen in Fig. 70.11,
post-PV/ET MF with conventional MA conditioning regimens comes age over 55 years, human leukocyte antigen (HLA) mismatching, and
from two retrospective series of transplants with more than 50 patients advanced disease are associated with decreased PFS and OS. However,
performed between 1979 and 2002. The median age of transplanted even in this high-risk group, the OS was approximately 40%.
patients was 42 and 43 years; treatment-related mortality (TRM) was Remarkably, patients younger than 55 years of age had a 5-year OS
27% and 33%, with 5-year survival of 47% and 58%, respectively. rate of 82%. Elimination of JAK2V617F after transplant was associ-
The 5-year probability of treatment failure caused by nonengraftment, ated with a reduced incidence of relapse.
relapse or persistent disease after transplantation was 36%, and the The prospective, multicenter phase II MPD-RC 101 trial included
failure of sustained engraftment was 10.7%, which occurred solely two parallel cohorts of patients: related donors (n = 32, 94% HLA
in patients receiving BM transplants from mismatched or unrelated matched) and unrelated donors (n = 34, 74% HLA matched).
donors. The probability of grade III–IV acute graft-versus-host disease Fludarabine/melphalan was used as a conditioning regimen with
(GVHD) was 33% and 21%, and extensive chronic GVHD was rabbit anti-thymocyte globulin (rATG) added in the unrelated donor
35% and 50%, respectively. Older age and factors associated with group. Patient characteristics were similar in the two groups, with 63
more advanced disease (Hg <10, increased number of RBC transfu- out of 66 patients having intermediate- to high-risk disease based on
sions, presence of osteomyelosclerosis, increased number of clonal Lille score. After a median of 25 months follow-up, OS was 75%
abnormalities) adversely affected the outcome. The Seattle group has (median not reached) in the related donor cohort and 32% (median:
updated their 15-year experience with 95 PMF and post-PV/ET MF 6 months) in the unrelated donor. Nonrelapse mortality at 59% was
patients who received MA busulfan and/or TBI-containing regimens. significantly higher in the unrelated group compared with 22% in
The 7-year actual survival rate was 61%, although 10% of patients the related group. Graft failure occurred in 36% (24% primary) of
died of recurrent or a persistent disease. Non-TBI–containing regimen unrelated transplants and 6% (3% primary) of related. The unrelated
of targeted busulfan/cytoxan resulted in an improved probability of cohort had double the rate of severe acute GVHD grade III–IV (21%
survival of 68%. These retrospective reports of MA allo-HSCT in PMF vs. 12%) but comparable rates of chronic GVHD (38% vs. 36%),
provided evidence that engraftment can be achieved and that a com- including extensive form (20% vs. 25%). Patients who were able to
plete and durable remission of the disease can occur in approximately achieve sustained stem cell engraftment experienced an overall
50% of patients. However, owing to the poor transplant outcomes response rate of 93% in the related group and 69% in the unrelated
in older patients, enrollment to this procedure represents a major group, with only four patients experiencing progression of disease.
therapeutic dilemma in PMF patients who are primarily diagnosed at Neither disease diagnosis (primary or secondary MF), HLA mis-
ages in excess of 60 years. match, presence of JAK2V617F mutation, nor age >57 years showed
The advent of non-MA, reduced-intensity conditioning (RIC) a statistically significant effect on survival. The only factor that cor-
regimens for aSCT has resulted in decreased TRM and has expanded related with improved survival was related donor type, as seen in Fig.
the use of this treatment modality to older patients. Rondelli and 70.12. The low/intermediate-1–risk patients in the unrelated group
coworkers provided one of the initial retrospective reports on the had better survival than the intermediate-2/high-risk patients,
outcome of 21 intermediate- to high-risk PMF patients (without whereas there was no difference in survival between these two DIPSS
leukemic transformation) with a median age of 54 years (range: groups in the related group.
27–68 years) who underwent RIC preparation and utilized a periph- The German group has analyzed the effect of multiple risk factors
eral blood stem cell (PBSC) source in 18 cases and related donors in related to patient, disease, and transplant characteristics on survival
18 cases. This trial was conducted at multiple institutions belonging after RIC SCT and developed a predictive model based on three risk
to the MPD-Research Consortium (MPD-RC). Predominantly factors: age ≥57, JAK2 WT status, and presence of constitutional
fludarabine-based RIC regimens allowed engraftment in all but one symptoms. Five-year OS in the absence of any risk factors was 90%.
patient with TRM of 10% and 2-year OS rates of 87%. Durable The presence of one or two risk factors reduced 5-year OS to 74%
remission was achieved in 17 out of 18 patients alive 12–122 months and 51%, respectively. Patients who had all three risk factors did
(median: 31 months) after transplant. Three patients relapsed, with extremely poorly after RIC SCT, with a 1-year OS of 25%. Despite
two of them able to achieve remission following second transplanta- inferior outcomes in older patients, SCT is feasible, as demonstrated
tion and donor lymphocyte infusion. Thirty three percent of patients by a retrospective study of aSCT of 30 PMF patients between the
developed acute GVHD grades II–IV (9% grade III–IV), and 72% ages of 60 and 78 (median: 65) years transplanted at four major
developed chronic GVHD, with 44% being extensive. United States academic centers with 3-year OS and PFS rates of 45%
Recent CIBMTR retrospective data derived from an analysis of and 40%, respectively.
223 patients who underwent RIC fludarabine-based allogeneic One of the limitations of widely applying aSCT to more patients
transplantation between 1997 and 2010 showed the probability of with PMF is the lack of access to appropriate donors. Takagi and
5-year survival to be 47%. Donor type was the only significant factor coworkers from Japan reported surprisingly positive results with
to impact survival, with 5-year OS in the related donor arm of 56% umbilical cord blood (UCB) grafts for RIC allogeneic transplantation
versus matched unrelated donor of 48% and mismatched unrelated in adults (median age: 57.5 years) with various hematologic disorders
donor of 34%. A trend toward decreased mortality was observed in associated with extensive BM fibrosis (PMF, post-MPN AML, and
patients with low/intermediate-1 DIPSS score versus intermediate-2/ MDS-related AML). The estimated probability of survival at 4 years
high-risk DIPSS. for this group was 28.6%, which is modest but considerably superior
The use of RIC PBSC transplantation in patients with advanced to that which would be anticipated with presently available chemo-
MF has been evaluated prospectively in two phase II trials by the therapy regimens for such high-risk disease. Retrospective analysis of
European Group for Blood and Marrow Transplantation (EBMT) 35 high-risk MF patients (20% blast-phase myelofibrosis, median