To the Editor:
Graft-vs.-host disease (GVHD) remains the most relevant complication following allogeneic hematopoietic stem cell transplantation (HSCT) . Unrelated donor (UD) transplant is associated with a higher incidence of GVHD, due to major and minor Human Leukocyte Antigen (HLA) disparities .
Antithymocyte globulin (ATG), plus a calcineurin inhibitor and methotrexate, has been the standard of care for GVHD prophylaxis in the setting of UD transplantation . Nevertheless, it can be associated with an increased risk in early opportunistic infections, in particular cytomegalovirus (CMV) reactivation  and considerable long-term relapse rate . Since the Baltimore experience, post-transplant cyclophosphamide (PTCy) was adopted as a GVHD prophylaxis platform worldwide for haploidentical transplant  and has been recently used in other donor settings .
We aim to compare PTCy and ATG as GVHD prophylaxis in UD HSCT. Primary end-points were non-relapse mortality (NRM), relapse, overall survival (OS) and graft-vs.-host disease/relapse-free survival (GRFS). Secondary end-points were GVHD, engraftment, early infections, and hospital stay.
A retrospective single-center cohort analysis was performed comparing PTCy (plus tacrolimus/mycophenolate, 08/2015–12/2019) vs. an historical cohort using ATG (plus tacrolimus/methotrexate, 01/2012–07/2015) in adult patients receiving a UD transplant for hematologic malignancies. PTCy dose was 50 mg/kg (days +3 and +4) and rabbit ATG formulation was used (doses varied between 7.5 and 15 mg/kg). Second transplants were excluded. Median follow-up time was 2.3 years. The study was done following the declaration of Helsinki. All patients signed informed written consent.
Neutrophil engraftment was defined as the first of two consecutive days above 500/mm3, platelets as the first day above 30.000/mm3 without transfusions support in the previous 3 days. Early infections, defined as within first 100 days, included bacteremia and CMV reactivation (positive viremia, measure with polymerase chain reaction technique, with or without end-organ disease) and CMV disease (including only end-organ disease). Severe hemorrhagic cystitis was defined as the need for cystoscopy due to bladder-urethral obstruction.
Statistical methods were calculated with easyR (version 1.3) and IBM SPSS Statistics (version 23). Engraftment, acute and chronic GVHD, NRM and relapse rate were analyzed with Grey’s Test, OS, and GRFS with Kaplan Meier. Bacteremia and CMV reactivation/disease were compared with Chi-Square, hospital stay with T-test. Multivariate analysis for acute GVHD GII–IV and NRM was performed with Fine-Grey test and for GRFS with Cox regression. Due to the sample population and number of events apart from the variable of interest, two other variables were included: for acute GVHD HLA-match (10/10 vs. ≤9/10 matched) and conditioning intensity (reduced intensity vs. myeloablative), and for NRM and GRFS HCT-CI/age (0–2 vs. ≥3) and DRI (low/intermediate risk vs. high/very high risk).
Fifty-six patients were included, 28 in the ATG and 28 in the PTCy group. Mean age was 36.9 years, 70% were fully HLA matched, 59% were male, 52% acute leukemia, 21% myelodisplastic syndrome, 38% HCT-CI intermediate/high risk, 23% DRI high/very high risk. Forty-five patients (80%) received a myeloablative conditioning and peripheral blood stem cell was the graft source in the vast majority (96%). Comparing the two subgroups according to these variables, apart from patient age (PTCy were older: 40.7 vs. 33.1 year, p = 0.01) there were no other significant differences.
Two patients in the ATG group developed primary graft failure, compared to no patient in the PTCy group (p = 0.49). PTCy patients had a nonsignificant later neutrophil engraftment (16.5 vs. 11.5 days, p = 0.26), with similar platelet engraftment (22 days vs. 19 days, p = 0.52). Forty-three percent of the patients in the PTCy group developed bacteremia vs. 36% in the ATG group (p = 0.78), 62% CMV reactivation vs. 82% (p = 0.13) and 25% CMV disease vs. 36% (p = 0.56). One patient in the PTCy group vs. none in the ATG group developed severe hemorrhagic cystitis. Similarly, the two groups had comparable hospital stay (28.9 days vs. 34.7 days, p = 0.11).
Acute GVHD grades II–IV incidence was significantly lower in PTCy patients compared to ATG (100-day and 1 year 25% and 29% vs. 50% and 57%, p = 0.03) (Fig. 1a) with similar grades III–IV (100-day and 1 year 3.6% and 3.6% vs. 10.7% and 14.3%, p = 0.16). We analyzed the possible association between CMV reactivation and aGVHD incidence and no correlation was found. Moderate-severe chronic GVHD incidence was comparable between the two groups (2 years 4% vs. 11%, p = 0.46).
NRM was significantly lower with PTCy than with ATG (100-day and 2 years, 10.7% and 19% vs. 25% and 46%, p = 0.04) (Fig. 1b). Infections-related NRM, although inferior in the PTCy group was not statistically significant (2 years 15 vs. 21%, p = 0.26). With similar relapse rate (2 years 25 vs. 25%, p = 0.93), PTCy patients showed a significantly higher OS (1 and 2 years 61% and 61% vs. 39% and 30%, p = 0.04) (Fig. 1c) and GRFS (1 and 2 years 54% and 54% vs. 29% and 20%, p = 0.02) (Fig. 1d).
We performed multivariate analysis for acute GVHD GII–IV, OS and GRFS. PTCy showed an independent significantly better outcome in the risk of acute GVHD GII–IV (HR 0.37, 95% CI 0.16–0.87), OS (HR 0.40, 95% CI 0.18–0.90) and GRFS (HR 0.38, 95% CI 0.18–0.82).
In the coming years, PTCy may become the standard of care for GVHD prophylaxis in many donor settings . The present study, with the limitations of a single-center retrospective analysis, contributes to this tendency by describing a low NRM (below 20% at 2 years) and high GRFS (above 50% at 2 years) after UD transplant.
Our results are consistent with previous publications of PTCy in UD. Kanakry et al., in a prospective single arm trial of busulfan-fludarabine conditioning with PTCy as the only GVHD prophylaxis for bone marrow HLA-matched donor transplant (sibling and UD), described around 50% 100-day acute GVHD GII–IV, 16% 1 year NRM and 65% 2 years OS . Similarly, an EBMT study of HLA-matched (sibling and UD) reported better outcomes with PTCy plus other two immunosuppressive drugs than PTCy alone or combined with 1 drug . They reported less than 30% 100-day acute GVHD GII–IV, 14% NRM and 60% 2 years OS.
Few comparisons between PTCy and ATG in UD have been published [10,11,12]. EBMT reported the experience with both prophylaxis platforms in HLA-mismatched UD . There was an advantage in severe acute GVHD incidence and GRFS for PTCy, and a trend to a better outcome in NRM and OS. A similar comparison was recently published by a multicenter group from France and Italy . Again, PTCy outcomes were better than ATG in a retrospective analysis, with a significant reduction in acute GVHD GII–IV and higher GRFS and OS. A group from Russia reported a better outcome with PTCy compared to an historical cohort with ATG in matched and mismatched UD transplants . Acute GVHD GII–IV incidence was reduced at least a 50%, chronic GVHD from 65 to 16%, 2 years NRM occurred in less than half of the cases than in ATG group and OS and GRFS increased around 30% and 40% respectively.
Similarly, in our comparison, PTCy patients showed better outcomes than the ATG group, with a GVHD GII–IV incidence reduction of around 50%, as was the NRM benefit, and a twofold improvement in GRFS and OS. In accordance with the above mentioned comparisons, there was no difference in relapse rate between the prophylaxis strategies.
To conclude, PTCy seems to be a better GVHD prophylaxis due to a lower GVHD incidence, better NRM and higher GRFS. Prospective comparisons are needed in order to have stronger conclusions.
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Berro, M., Rivas, M., Trucco, J. et al. Post-transplant cyclophosphamide demonstrates lower non-relapse mortality and better graft-versus-host disease/relapse-free survival compared with antithymocyte globulin in unrelated donor hematopoietic stem cell transplantation. A single-center experience. Bone Marrow Transplant (2020). https://doi.org/10.1038/s41409-020-01146-0