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Haploidentical versus unrelated donor HSCT for active AML
(per 10 years) and cytomegalovirus positivity were associ- ated with higher NRM (HR=1.18, 95% CI: 1.08-1.28, P<10-3; and HR=1.37, 95% CI: 1.07-1.77, P=0.01, respec- tively), while RIC compared to MAC and KPS ≥90 were associated with lower NRM (HR=0.64, 95% CI: 0.49-0.84, P=0.001; and HR=0.52, 95% CI: 0.41-0.64, P<10-3; respec- tively) (Table 4). Notably, no effect was observed for the type of donor.
In addition, no significant differences were found in GRFS according to donor type in the multivariate analysis. Three factors were associated with a better GRFS: longer time from diagnosis to transplantation, RIC versus MAC, and a KPS ≥90. Patients with poor cytogenetics had a lower GRFS (Table 4).
As shown in Online Supplementary Table S2, most events happened within the first year after HSCT.
Finally, in order to reduce the effects of confounding fac- tors, we performed a weighted analysis on propensity scores (weighted average treatment). The results of the weighted Kaplan-Meier and Cox analyses confirmed the study results as described in Table 5. In the weighted analysis on propensity scores, the Haplo PTCy group had a significantly lower incidence of grade III-IV acute GvHD compared to that of patients in the UD 10/10 group (8.9% versus 14.5%, respectively, P=0.04), as confirmed by Cox analysis (P=0.049).
Causes of death
Leukemia was the most common cause of death (accounting for 50% of the deaths in the Haplo PTCy group, 54% in the UD 10/10 group, and 54.5% in the UD 9/10 group). GvHD was the second most common, being the cause of death in 11.5% of the patients in the Haplo PTCy group, 12.1% in the UD 10/10 group, and 15.2% in the UD 9/10 group. Infection was the cause of death in 27%, 20.8%, and 20.6% of the patients in the Haplo PTCy, UD10/10 and UD 9/10 groups, respectively.
Discussion
In the present study, we compared the transplantation outcomes after Haplo HSCT with PTCy versus transplan- tation from matched (10/10) or mismatched (9/10) UD in AML patients with active disease. The LFS rate was about 25% and the OS rate about 30% after HSCT for this high- risk population with advanced disease with no difference between Haplo PTCy and UD 10/10 or 9/10. Rates of acute GvHD grades II-IV and of chronic GVHD were sim- ilar between Haplo PTCy and UD 10/10, and the same
held true for the 2-year NRM. It is important to note that higher rates of grades II-IV acute GvHD and chronic GvHD were observed in the UD 9/10 group without there being an impact on RI. Although we could hypothesize a stronger graft-versus-leukemia effect after Haplo PTCy than after UD HSCT, we did not observe differences in terms of RI or LFS. This finding is in accordance with those of our previous study, in which we compared relapse rates between patients with primary refractory AML undergoing allogeneic transplantation from unrelat- ed versus sibling donors and found no difference.13 One hypothesis is that, besides the very strong tolerance induc- tion mediated by the PTCy in the Haplo setting in the case of active leukemia, the very aggressive biology of the dis- ease and its refractoriness to several lines of chemothera- py lead to fast disease progression and relapse early after transplantaion. Thus, the graft-versus-leukemia effect, even across broad HLA disparities, is too weak or too slow to control the leukemia.
Of note, about 37% of patients received a RIC regimen in our study. As expected, the NRM rate was significantly lower in the RIC group than in the MAC group, with no difference in RI between the two groups. In all, LFS, OS, and GRFS were significantly better after RIC than after MAC. We could hypothesize that this is because even a high intensity conditioning regimen does not have a strong impact on this chemo-refractory leukemia. In our current study, 384 of the patients received a sequential approach with aplasia-inducing chemotherapy followed by the conditioning regimen. However, the question of which treatment should be used in a given patient cannot yet be answered. In a recent meta-analysis of leukemic patients with induction failure, Wattad et al. concluded that HSCT without prior salvage chemotherapy and HSCT in CR after salvage therapy resulted in comparable survival outcomes, and both strategies were significantly superior to HSCT performed after failure of salvage thera- py.33 In the present study, no differences in outcome were found between patients who received MAC or sequential regimens. One hypothesis to explain this is that the refrac- toriness of the malignant leukemic clone to chemotherapy makes the conditioning regimen unable to induce remis- sion, or even a transient response allowing sufficient time for the alloreactive cells to mediate the graft-versus- leukemia effect.34
Importantly, an interval from diagnosis to transplant longer than the median was a negative prognostic factor for LFS, OS, RI and GRFS in multivariate analysis. These data, which are consistent with those of a study by Craddock et al.14 and our previous results,13 highlight the
Table 3. Univariate analysis for acute graft-versus-host disease and chronic graft-versus-host disease.
Acute GvHD II-IV
Acute GvHD III-IV Chronic GvHD Extensive chronic GvHD PMN day 30
Haplo PTCy
28.2% (21.8-34.9)
8.9% (5.3-13.7) 19.3% (13.6-25.7) 11% (6.7-16.4) 85.5% (79-90.2)
UD 10/10
30.6% (27.8-33.4)
14% (11.9-16.2) 25.6% (22.7-28.6) 11.6% (9.6-13.9) 92.3% (90.5-93.7)
UD 9/10
36.3% (31.3-41.2)
16.1% (12.5-20.1) 27.4% (22.6-32.4) 11.6% (8.3-15.4) 92.2% (88.9-94.6)
P value
0.04
NS
NS
NS
<10-3
P value Haplo PTCy versus UD 10/10
NS
NS
NS
NS
<10-3
P value Haplo PTCy versus UD 9/10
0.03
0.02
0.04
NS
<10-3
Data are presented as percentages with 95% confidence intervals in brackets. ext: extensive; GvHD: graft-versus-host disease; haplo: haploidentical; PTCy: post-transplant; PMN: polymorphonuclear neutrophil; PTCy: post-transplant cyclophosphamide; UD: unrelated donors.
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