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D.P. McLornan et al.
majority of patients in 2018 who proceeded to allogeneic SCT had been exposed to JAK inhibitor therapy. The JAK inhibitor should be tapered down over a 10- to 14-day peri- od so that JAK inhibition therapy is ceased just before the commencement of conditioning or prior to stem cell return. Whether the best strategy for patients receiving JAK inhibitor therapy with a view to allogeneic SCT is to under- go the transplant at the time of best response or whether the procedure should be delayed until a further trigger occurs remains difficult to determine and hence patient- stratified approaches are required. Of note, JAK inhibitors are additionally becoming established in the treatment of steroid refractory GvHD, although this is outside the pur- pose of this review.45
Conditioning intensity and regimen?
Myeloablative conditioning for allogeneic stem cell transplantation in patients with myelofibrosis
Historically, the majority of MAC platforms consisted of total body irradiation with or without high-dose cyclophosphamide and early toxicity, NRM and GvHD rates were high, especially for older individuals.25,35 (Table 2). The large CIBMTR study reported on 289 patients who underwent allogeneic SCT between 1989 and 2002, 79% of whom received MAC – predominantly busulfan + cyclophosphamide and total body irradiation with or with- out cyclophosphamide.25 The day +100 transplant-related mortality rate was 18% for those undergoing allogeneic SCT from an HLA-matched sibling and 35% for those receiving a graft from an unrelated donor. Approximately one-third of the patients achieved long-term (5 years) relapse-free survival. Kerbauy et al. reported on 104 patients, with a median age of 45 years (range, 18-70 years), 95 of whom received MAC. The NRM rate at 5 years was 34% and there were significant rates of acute grade II-IV GvHD (64%) and chronic GvHD (84%).46 The estimated 5- year survival rate was 61% (95% CI: 43-65%) for the entire cohort. Those undergoing MAC with targeted levels of busulfan in combination with cyclophosphamide (120 mg/kg) had a significantly higher probability of overall sur- vival (68%). For younger recipients planned for MAC allo- geneic SCT, our preference is towards busulfan + cyclophosphamide in an attempt to reduce therapy-related morbidity.
Reduced intensity conditioning for myelofibrosis allogeneic stem cell transplantation – what evidence exists to guide the choice of regimen?
Due to age distribution, the vast majority of patients undergoing transplantation will receive RIC. However, the term RIC covers a highly heterogeneous group of treat- ments as regards both immunosuppressive and moderate myeloablative properties. According to the EBMT consen- sus, RIC regimens are strictly defined as those which do not fit the definition for MAC or non-myeloablative regimens.47 Historically, published RIC platforms were admixed and reflected local practice (Table 2). The first prospective, EBMT multicenter phase II trial of RIC allogeneic SCT in myelofibrosis enrolled 103 patients between 2002-2007.32 Conditioning was uniform and consisted of busulfan (10 mg/kg) orally (or equivalent IV dose)/fludarabine (180 mg/m2) and T-cell depletion achieved with antithymocyte globulin (Fresenius, Graefeling, Germany) at a dose of 3 x 10 mg/kg (for related transplantation) or 3 x 20 mg/kg (for
unrelated donor transplantation). Primary graft failure rates were low (~2%) and timely engraftment of both neu- trophils (median, 18 days; range, 10-84 days) and platelets >20 x 109/L occurred (median, 22 days; range, 8 -145 days). Rates of acute GvHD were acceptable at 27% for grade II- IV and 11% for grade III-IV. The cumulative incidence of NRM at 1 year was 16% (95% CI: 9-23%) and was signif- icantly higher in the mismatched donor setting than in the fully matched donor setting (38% versus 12%; P=0.003). The cumulative incidences of relapse at 3 and 5 years were acceptable at 22% and 29%, respectively. Multivariate analysis suggested a higher 3-year relapse incidence with splenectomy (HR: 3.6) and Lille HR score (HR: 5.23). HLA- mismatched transplantation was a risk factor for both ther- apy-related mortality and adverse overall survival. Updated survival analyses revealed estimated 5- and 8-year overall survival rates of 68% and 65%, respectively. More recently, the two most frequently used RIC regimens for myelofibro- sis - fludarabine-busulfan (FB) and fludarabine-melphalan (FM) were compared in a retrospective study of 160 patients (FB: n=105, FM: n=55) with a median follow up >5 years.48 Conditioning protocols were uniform, the FM regi- men consisted of fludarabine 90 mg/m2 and melphalan 140 mg/m2 and the FB regimen consisted of intravenous busul- fan (or oral equivalent) 8 mg/kg, fludarabine 180 mg/m2 and antithymocyte globulin-Fresenius®. After statistical weight- ing, the incidence of acute GvHD was 62% for the FM group and 31% for the FB group while chronic GvHD rates were 49% and 53%, respectively. Although the FM regi- men had more pronounced early toxicity, the long-term outcome of patients treated with the two regimens was similar. Multivariate analysis failed to demonstrate signifi- cant differences regarding overall survival or disease-free survival although individuals undergoing FM conditioning had relapse rates of <5%. In both groups, the use of a HLA- mismatched unrelated donor was associated with worse outcomes as regards NRM, overall survival and progres- sion-free survival. A prospective, multicenter, phase II MPD-RC study investigated the use of FM conditioning in 66 patients recruited between 2007-2011.49 Those with sib- ling donors (n=32) received FM whereas those with unrelat- ed donors (n=34) received FM + antithymocyte globulin. Significantly inferior results were seen with unrelated donors than with sibling donors: with a median follow up of 25 months, the overall survival rate was 75% in the sib- ling group compared to only 32% in the unrelated donor group (HR: 3.9; 95% CI: 1.8-8.9; P<0.001). Moreover, con- siderable NRM rates were observed in the unrelated donor setting. Of note, this small study did not determine out- come differences between matched or mismatched unrelat- ed donors, in contrast to other studies.32,34
Can we realistically compare myeloablative versus reduced intensi- ty condition in allogeneic transplantation for myelofibrosis?
There are no current, prospective trials comparing RIC with MAC for myelofibrosis and conclusions from retro- spective studies are not always straight forward. In a well- described cohort of 92 patients undergoing allogeneic SCT between 1982-2009, 40 patients received MAC and 52 RIC regimens.27 No differences existed with regards to day +100 transplant-related mortality. The probability of survival at 5 years was 49% for patients given MAC and 59% for those given RIC (P=0.125). However, RIC platforms were associ- ated with markedly improved outcome for those <60 years old compared to those who were older (estimated 5-year
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haematologica | 2019; 104(4)