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ATG vs. PTCy in haploidentical transplantation in ALL
non-relapse mortality. Although most patients received albative doses of TBI, a lower non-relapse mortality was associated with TBI-based condtioning compared to chemotherapy alone (HR=0.59; P=0.02). An explanation for this intriguing observation is unknown, but it is possi- ble that younger patients with better performance scores and co-morbidity indices were more likely to receive ablative TBI. It should be noted that previous EBMT reports have indeed suggested better leukemia-free sur- vival related to TBI use in ALL patients, but this was due to a lower relapse incidence and not to a decrease in non- relapse mortality.28-30
With respect to post-transplant relapse, a statistically significant, 10% absolute improvement was noted in favor of PTCy compared to the ATG group. It is likely that the higher risk of relapse in the ATG group was driv- en by the higher proportion of patients with advanced ALL (30%). Indeed, advanced disease status was a strong independent predictor of ALL relapse. Given the unique biology of ALL it is also possible that, as fewer patients given ATG received TBI as part of their conditioning, this may have increased the relapse incidence in this group, although not to a statistically significant extent.28,29,31 Disease relapse was the most common cause of death in both groups, highlighting the need for further studies on mitigating post-transplant ALL relapse.
In univariate analysis, improved leukemia-free survival, overall survival and GRFS rates were noted in the PTCy group compared to ATG group (P<0.05), however, in multivariate analysis, only leukemia-free survival and overall survival remained significantly improved. This could perhaps be due to a higher proportion of patients with advanced disease together with the higher relapse incidence in the ATG group. Indeed, the leukemia-free survival in the ATG group in this study was inferior to that in the prospective study by Wang et al., possibly due to the greater proportion of patients in this study with advanced age and disease status.27 Nevertheless, 15% and 20% improvements in leukemia-free survival and overall survival, respectively, were noted in the PTCy group. For both these outcome measures, disease status at the time of haploidentical HCT and Karnofsky Performance Score were strong independent predictors of survival. Albeit limited by the small sample size, a subset analysis evalu- ating outcomes stratified by graft source (peripheral blood vs. bone marrow) showed interesting results (Online Supplementary Table S2). In peripheral blood hap- loidentical HCT recipients, the 2-year leukemia-free sur- vival, overall survival and GRFS rates were significantly better in the PTCy group, in which there was also a trend toward lower non-relapse mortality. It is worth noting that the relapse risk was similar in the ATG and PTCy groups in peripheral blood haploidentical graft recipients. In contrast, for bone marrow haploidentical HCT, no dif- ferences were noted in leukemia-free survival, overall sur- vival, GRFS or non-relapse mortality between the ATG and PTCy groups. However, the 2-year relapse incidence among bone marrow graft recipients receiving ATG pro- phylaxis was 55% compared to 33.7% with PTCy pro- phylaxis (P=0.06). Although not statistically significant, it
is plausible that the inferior relapse and survival out- comes in the ATG group are at least partly due to the high relapse risk in the bone marrow graft recipients.32
The inherent limitations of this study are reflected by the nature of the data captured by a registry. Detailed information regarding remission status, such as minimal residual disease, and conditioning regimen, including TBI dose and the timing and dose of PTCy and ATG adminis- tration, were not uniformly available. For instance, details pertaining to the type of ATG product (thymoglobulin vs. ATG-Fresenius) were unavailable in the registry. The dose of ATG was documented for only 81 subjects, with the median dose being 20 mg/kg. By univariate analysis, the only impact of ATG dose (< or ≥20 g/kg) on transplant outcomes, was a lower incidence of grade II-IV acute GvHD associated with a higher ATG dose (23% vs. 53%; P=0.007) (Online Supplementary Table S3). The registry data precluded evaluation of the reason for choosing a specific graft source, GvHD prophylaxis platform or conditioning regimen for an individual patient. Haploidentical HCT with ATG was more likely during an earlier time period compared to PTCy (median, 2011 vs. 2015). It is, there- fore, possible that improvements in transplant technology and supportive care may have had an impact on these out- comes. To address this potential bias, we performed a uni- variate analysis restricted to the years 2007-2014, and found that the use of PTCy as GvHD prophylaxis was still associated with improved leukemia-free and overall sur- vival (data not shown), congruent with results for the entire study duration. As expected, institutional practices and preferences may skew the data. However, no “center effect” was noted except for chronic GvHD by regression analysis. The sample size limited the power to detect small differences and interactions between variables and transplant outcomes in our population. With a median fol- low-up of approximately 2 years, it is not known whether these results will remain unchanged with longer-term fol- low-up. Notwithstanding these limitations, this analysis is the largest and only comparative study evaluating out- comes of haploidentical allogeneic HCT in adult ALL patients given PTCy or ATG as the backbone of their GvHD prophylaxis. It is noteworthy that, compared to ATG, PTCy as GvHD prophylaxis was associated with improved leukemia-free survival and overall survival and lower relapse risk.
In conclusion, in the absence of prospective, random- ized data, our results suggest that PTCy as GvHD pro- phylaxis may be considered over ATG in patients with ALL undergoing haploidentical HCT. Our data warrant confirmation in prospective randomized studies.
Disclosures
No conflicts of interest to disclose.
Contributions
AN and MM conceived and designed the study; ML collected, assembled and analyzed data; ASK, AN and ML prepared the first draft of the manuscript; and all authors contributed to data interpretation, helped revise the manuscript, and gave final approval of the manuscript.
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