Allogeneic hematopoietic cell transplantation in patients with CALR-mutated myelofibrosis: a study of the Chronic Malignancies Working Party of EBMT

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR-and JAK2mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versushost disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALR mutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF.

CALR mutations possess unique prognostic relevance in myelofibrosis—before and after transplant

“…In the current edition of BMT, Hernandez-Boluda and colleagues report the European bone marrow transplant (EBMT) centers' experience on 346 relatively young (median age 57.4 years) CALRmutated patients with MF who received AHSCT at multiple European centers between 2010 and 2019 and followed for a median of 40 months [17]; 5-year survival was 63% (vs 50% in the JAK2-mutated comparative cohort) and even better at 71% in those receiving busulfan-containing conditioning regimens; comparison to a JAK2-mutated cohort revealed better outcome in terms of overall survival, non-relapse mortality (NRM), and relapse rate; in multivariate analysis, older age was the only variable associated with inferior survival, which is noteworthy considering the older age distribution of the comparator JAK2-mutated cohort. As an explanation for the post-transplant survival difference between JAK2 and CALR mutated cohorts, the authors entertained the possibility of higher frequency of HMR mutations in the former [18].…”

“…The study by Hernandez-Boluda et al [17]. is molecularly truncated by its lack of distinction between type 1/like (CALR-1) and type 2/like (CALR-2) CALR mutations and information on HMR mutations, including ASXL1, SRSF2, U2AF1-Q157 and others.…”

“…The presence of CALR-1 in MF portends a relatively less aggressive disease tempo, characterized by progressive splenomegaly and anemia, which appear to be sensitive to treatment with JAK2 inhibitors [28]; however, we are inclined to favor transplant in the presence of unfavorable karyotype or HMR mutations [29], as reflected in our current treatment algorithm for MF [2]. To that effect, we acknowledge the possibility of a more favorable post-transplant outcome in CALR vs JAK2 mutated patients with MF [16,17]. A particularly worrisome scenario involves the presence of multi-hit TP53, where AHSCT might not overcome its detrimental effect on survival; in a recent communication, 6-year post-transplant survival rates were 25% for multi-hit vs 56% singlehit vs 64% wild-type TP53 [30]; in the particular study, CALR muations were reported in 17% of 58 patients with multi-hit TP53 but information on further distinction between CALR-1 and CALR-2 was not availble.…”