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Allogeneic SCT for myelofibrosis
Table 2. Summary of outcomes in the main studies on reduced intensity and myeloablative conditioning in myelofibrosis.
Conditioning intensity
RIC
RIC
MAC
Predominantly MAC
RIC
RIC
RIC
MAC RIC
N.
66
103
170 Sibling 117 MUD 33 Other
104
233
66
160
760 1423
Conditioning regimen
Flu Mel (sibling) Flu Mel + ATG (URD)
Flu Bu
Various
TBI based (n=15) Busulphan based (n=80); RIC (n=9)
Flu Bu (38%) Flu Mel (28%) Flu TBI. (22%)
Flu Bu FBM Flu Mel
Flu Bu (105) Flu Mel (55)
Common regimens BuCy or TBI based Flu Bu; Flu Mel
GvHD rates
Acute grade II-IV Sibling 38% URD 41%
Acute grade II-IV 26%
Chronic L:24%; E:24%
Overall survival
75% sibling 32% URD
67% at 5 years
39% at 5 years 31% at 5 years 31%at5years
61% at 7 years
56% for MSD, 37% URD, 34% MMUD
Similar OS, NRM and relapse rates
7-year OS was 52% for
the Flu Mel group and 59% for the Flu Bu group
Median OS= 6.6 years Median OS =5.3 years
Comments
Reference
Acute 43% 40%
24%
Chronic 40%
32% 26%
24% graft failure in the URD 49 group
Low rates of graft failure and 32
timely engraftment
Heterogeneous cohort; disease-
free survival long-term in 35
approximately 1/3
Improved survival with
targeted busulfan 46
dosing in BuCy
Donor type most important 77 determinant of outcome
100% donor chimerism was 78 seen more frequently at
day +30 and day +100 in
patients who received
FBM or Flu Mel than Flu Bu.
Flu Mel regimen appears 48 to induce more NRM than
the Flu Bu regimen; but with augmented disease control; similar outcomes.
Primary analyses; full analysis in preparation
No differences in NRM 34 between MAC/RIC
Worse outcome with MMUD and
poor Performance Status
Acute grade II-IV : 64% Chronic L+E: 84%
Acute grade II-IV : 37% Chronic at 1 year 42%
Acute grade II-IV 47%
68%
68 %
Acute 31% 53 %
Acute grade I-IV 29%
32%
Chronic 62% 49%
Chronic L/E 23/27% 20/32%
ATG: antithymocyte globulin; Bu: busulfan; Cy: cyclophosphamide; E: extensive; FBM: fludarabine, bis-chlorethyl-nitroso-urea/carmustine, melphalan; Flu: fludarabine; GvHD: graft-versus-host disease; L: limited; MAC: myeloablative conditioning; Mel: melphalan; MMUD: mismatched unrelated donor; MUD: matched unrelated donor; NRM: non-relapse mortality; OS: overall survival; RIC: reduced intensity conditioning; TBI: total body irradiation; URD: unrelated donor.
demonstrated that, in general, there were no serious adverse effects following the use of JAK inhibitors prior to allogeneic SCT with appropriate tapering.38-40 Of note the French phase II JAK ALLO trial, investigating the use of rux- olitinib before allogeneic SCT, was temporarily halted because of two cases of febrile cardiogenic shock and one of tumor lysis syndrome following ruxolitinib discontinua- tion.41 Subsequent experience has not demonstrated that either of these adverse events is common. Outcomes of 100 patients who had been exposed to JAK inhibitor therapy and underwent allogeneic SCT, between 2009-2014, were determined in a retrospective, multicenter study.42 The cohort was divided into five groups defined by clinical sta- tus/response to JAK inhibition: groups (i) clinical improve- ment (n=23), (ii) stable disease (n=31), (iii) new cytopenia/increasing blasts/JAK inhibitor intolerance (n=15), (iv) progressive disease: splenomegaly (n=18), and (v) leukemic transformation (n=13). The overall survival rate at 2 years after allogeneic SCT for the entire cohort was 61% (95% CI: 49-71%). The cumulative incidence of grade II-IV acute GvHD by day 100 was 37% (95% CI: 27-47%) and that of chronic GvHD by 2 years was 48%. Survival analyses performed based on response to JAK inhibition prior to allogeneic SCT revealed a 2-year overall survival
rate of 91% (95% CI: 69-97%) for patients with clinical improvement. However, it remains unclear whether the better post-transplant outcome in those achieving a clinical improvement was drug-related or simply reflected the pres- ence of an inherently more favorable disease phenotype. A multicenter, German study reported on 159 patients, 46 of whom had received pre-transplant ruxolitinib at any point with a median treatment duration of 4.9 months (range, 0.4-39.1 months).43 There was a trend towards a lower rate of relapse in the ruxolitinib group (9% versus 17%, P=0.2), with similar disease-free and overall survival rates. The hypothesis that pre-exposure to JAK inhibitors may modu- late the relapse risk requires further exploration. In a recent- ly published study of a small cohort of patients (n=12) undergoing allogeneic SCT for myelofibrosis, ruxolitinib (5 mg BID) was continued until stable engraftment.44 There was no graft failure and timely neutrophil engraftment, although the drug had to be discontinued in two patients, on days +17 and +18, because of post-engraftment cytope- nia. Of particular relevance, the rate of grade II-IV acute GvHD within the first 100 days was low at 8% although the cytomegalovirus reactivation rate was 41%. The use of peri-transplantation JAK inhibition to reduce the risk of GvHD remains an area of great interest. In conclusion, the
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