Page 178 - 2020_02-Haematologica-web

M.-A. Perales et al.
Discussion
Acute myeloid leukemia remains one of the main indi- cations for allogeneic stem cell transplantation, and with an aging population, it is expected that both the incidence of AML and the number of transplants in older patients with AML will increase.18 Furthermore, recent trends also show an increase in haploidentical transplants with use of post-transplant cyclophosphamide for GvHD prophylaxis. Although an earlier CIBMTR report showed no difference in survival after haplo-identical and MUD transplantation, transplant outcomes in patients older than 50 years were not analyzed as a separate cohort.6 In the setting of HLA- matched sibling donor transplantation for patients older than 50 years with hematologic malignancy, survival was higher compared to MUD transplants with donors aged <50 years in patients with performance scores of 90 or 100.10 In those with performance scores 80 or lower, there were no significant differences in survival by donor type.10 With the increasing use of haplo-identical donors for AML, the current analysis sought to study whether sur- vival after haploidentical donor transplantation would be better compared to transplantation of grafts from a young MUD (donor age 18-40 years). The results showed a sur- vival advantage after MUD transplantation that can be attributed to lower relapse risks. Our findings lend sup- port to our hypothesis that a young MUD should be the donor of choice when available. Furthermore, the data presented here suggest comparable times to transplanta- tion in both treatment groups, confirming timely access to unrelated donors is no longer a barrier.
The prognostic significance of donor age and donor- recipient HLA match in the setting of unrelated donor transplantation has been confirmed in several reports, including a recent report that concluded there was a 5.5% increase in the hazard ratio for overall mortality for every 10-year increment in the age of the donor.11,19 The observed excess mortality with increasing donor age was attributed to higher non-relapse mortality and not leukemia recurrence.11 In contrast, the effect of donor age for haplo-identical transplants is mixed. In a relatively young population with hematologic malignancy that pre- dominantly used parental donors, a male donor under 30 years of age was associated with best survival.20 On the other hand, for adults with hematologic malignancy, nei- ther donor-recipient relationship or donor age was associ- ated with transplant outcomes. In the current analysis, the better HLA-matching between the recipient and the unrelated donor may have also improved survival after MUD transplantation. Higher survival was recorded after HLA-matched sibling compared to haploidentical trans- plant for patients with acute leukemia who were older than 55 years confirming the importance of HLA match- ing for allogeneic transplantation.9
Unlike other reports that compared haploidentical to MUD or HLA-matched sibling transplants, relapse risks after MUD transplants were lower in the current analysis after adjusting for cytogenetic risk, transplant condition- ing intensity and graft type.6-9 Predictably, relapse was higher in patients with poor risk cytogenetics, in recipi- ents of reduced intensity conditioning regimens, and after transplantation of bone marrow.21 The recent Blood and Marrow Transplant Clinical Trials Network trial, BMT CTN 0901, showed higher relapse in patients with AML conditioned with reduced intensity regimens and was
consistent with other reports demonstrating the benefit of myeloablative regimens for AML.22 Furthermore, a recent CIBMTR report on graft type and haploidentical transplants demonstrated lower relapse risks with periph- eral blood compared to bone marrow, but without a sur- vival advantage.5 Consistent with clinical practice, recipi- ents of haploidentical transplants were more likely to receive bone marrow and reduced intensity conditioning regimen. Therefore, we carefully addressed the effect of conditioning regimen intensity (P=0.2) and graft type (P=0.6) in the model for survival and found none. Nevertheless, it is plausible that the observed higher relapse risk associated with haploidentical transplanta- tion may, in part, be attributed to the low-dose TBI, cyclophosphamide and fludarabine regimen, the predom- inant regimen for haploidentical transplants in the current analysis. As shown by others, we found that both acute and chronic GvHD were lower in recipients of haploiden- tical transplantation.5 The decreased risk of chronic GvHD, however, was restricted to the recipients of bone marrow graft. As the use of peripheral blood increases in haploidentical transplants, we will likely observe increased rates of chronic GvHD.5 This remains a signifi- cant consideration, particularly in the older patient where the morbidity and impact on quality of life associated with chronic GvHD can be significant.23-25
The current analysis has several limitations related to the use of data reported to an observation registry. First, we are unable to study donor choices and it is possible that some transplant centers prioritize the selection of a haploidentical donor. Second, we are unable to properly separate the effect of conditioning regimen and graft type, as these factors are confounded with donor type. Third, while every attempt was made to adjust for the observed difference in survival, there may be several unknown or unmeasured factors we could not consider. Finally, it should be noted that we did not observe a cen- ter effect, although fewer centers performed haploidenti- caltransplants.
While the use of haploidentical transplantation with post-transplant cyclophosphamide is increasing rapidly, and several early studies suggest similar outcomes to patients transplanted with matched related or unrelated donors, it remains important to analyze outcomes in spe- cific patient populations and diseases. In the current analysis, with its focus on patients aged 50 years or older with AML in first or second remission, we observed high- er mortality after haploidentical compared to MUD trans- plantation with donors younger than 40 years. We acknowledge donor selection is ideally studied in the set- ting of a controlled clinical trial. However, the disparate availability of MUD and related haploidentical donors remains a challenge, and attempts to study outcomes of donor choice both retrospectively and prospectively may be necessary.
Funding
The CIBMTR is funded by Public Health Service Grant U24-CA076518 from the National Cancer Institute, the National Heart, Lung and Blood Institute and the National Institute of Allergy and Infectious Diseases; Grant U10HL069294 from National Cancer Institute, the National Heart, Lung and Blood Institute; contract HHSH250201200016C with Health Resources and Services Administration; Grants N00014-15-1-0848 and N00014-16-
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haematologica | 2020; 105(2)