Allogeneic Hematopoietic Cell Transplantation in AML with Normal Karyotype and NPM1 Mutated FLT3-ITD Negative: A Retrospective Analysis from the Acute Leukemia Working Party of EBMT
Authors: Bazarbachi Ali , Labopin Myriam , Kharfan-Dabaja Mohamed A , Schwerdtfeger Rainer , Volin Liisa , Bourhis Jean-Henri , Socie Gerard , Deconinck Eric , Gedde-Dahl Tobias , Rambaldi Alessandro , Jindra Pavel , Schlimok Günter , Blaise Didier , Chevallier Patrice , Nagler Arnon , Schmid Christoph , Esteve Jordi , Mohty Mohamad 
Published: October 2019

Background: NPM1 mutation, in the absence of FLT3 internal tandem duplication (FLT3-ITD), confers a survival advantage and lower risk of disease relapse in AML with normal diploid karyotype. The prognostic significance of mutated NPM1 in the setting of allogeneic hematopoietic cell transplantation (HCT) for AML has not been described.

Patients and methods: we evaluated the post-transplant outcomes of 156 patients (females=83, 53.2%), median age of 54 (19.5-71) years, with normal diploid karyotype and NPM1 Mutated FLT3-ITD Negative, who underwent an allogeneic HCT between 2006 and 2012. Donor source was limited to matched-related (MRD) or matched-unrelated (MUD) donors, and cell source consisted of bone marrow (BM) or G–CSF mobilized peripheral blood stem cells (PBSC). Patient-, donor-, and disease-characteristics are summarized in Table 1.

Results: the median time from diagnosis to allogeneic HCT was 310 (89-3713) days and the median follow-up from time of allografting was 32 (2-86) months. Overall, the 2-year cumulative incidence of relapse (CIR)and non-relapse mortality (NRM) were 27% (20-35) and 13% (8-19) respectively, and the 2-year cumulative incidence of chronic GVHD was 37% (29-46). Finally, the 2-year leukemia-free survival (LFS) and the 2-year overall survival (OS) were 60% (51-68) and 70% (62-77), respectively. In univariate analysis, transplantation in CR1 was associated with lower2-year CIR [CR1=14% (7-23), CR2=37% (23-51), advanced/active=48%(26-67), p=0.0009], superior2-year LFS [CR1=75%(64-86), CR2=51% (36-65),advanced/active=30%(11-49), p<0.0001] and superior2-year OS [CR1=81%(72-91), CR2=67% (54-80), advanced/active=39% (19-59), p<0.0001]. Patients allografted from unrelated donors have higher 100-day cumulative incidence of > grade 2 acute GVHD [MUD=28% (19-39)vs. MRD=12%(5-22), p=0.02]. Patients older than 54.3 years had higher 2-year cumulative incidence of NRM [20% (11-31)vs. 7%[2-14], p=0.03] and inferior 2-year OS [61%(49-72) vs. 78% (68-88), p=0.02]. In multivariable analysis using a Cox proportional-hazard model, transplantation in CR1 resulted in lower2-year CIR and superior2-year LFS and OS.

Conclusions: AML disease status at allografting remains the most important predictor of post-allogeneic HCT outcomes despite expression of mutated NPM1. Survival outcomes are better when patients are transplanted in CR1>CR2>advanced/active. The impact of other molecular abnormalities in conjunction with NPM1 is yet to be established. Also, a future matched-controlled analysis comparing AML patients with mutated vs. wild-type NPM1 expression in the setting of allogeneic HCT is warranted.

Table 1 variables Results N, (%) Recipient gender F=83 (53%) M=73 (47%) Donor gender F=57 (37%) M=97 (63%) [missing=2] Female donor à male recipient Yes=21 (14%) No=133 (86%) [missing=2] Donor source MRD=66 (42%) MUD=90 (58%) Cell source BM=30 (19%) PBSC=125 (80%) BM+PBSC=1 (1%) Disease status at allogeneic HCT CR1=69 (44%) CR2=64 (41%) Advanced/active=23 (15%) Preparative regimen intensity RIC=85 (54%) MAC=71 (46%) ATG use Yes=84 (54%) No=72 (46%) GVHD prophylaxis CSA+MTX=77 (49%) CSA+MMF=41 (27%) CSA alone=28 (18%) Others=8 (5%) [missing=2] Recipient CMV serology Seropositive =101 (65%) Seronegative =54 (35%) [Unknown/missing=1] Donor CMV serology Seropositive =62 (40%) Seronegative =92 (60%) [Unknown/missing=2] Donor/recipient CMV serology D+/R+=48 (31%) D+/R-=14 (9%) D-/R+=52 (34%) D-/R-=39 (26%) [Unknown/missing=3]

Abbreviations : F: female, M: male, MRD: matched-related donor, MUD: matched-unrelated donor, RIC: reduced-intensity conditioning, MAC: myeloablative conditioning, CSA: cyclosporine A, MTX: methotrexate, MMF: mycophenolatemofetil, D: allograft donor, R: allograft recipient

Disclosures

No relevant conflicts of interest to declare.