Page 120 - 2019_03-Haematologica-web

E. Brissot et al.
Statistical analysis
Patient-, disease-, and transplant-related variables were com- pared between the three groups (Haplo PTCy, UD 10/10, UD 9/10) using the chi-square test for categorical variables and the Mann-Whitney test for continuous variables. The median follow- up was estimated using the reverse Kaplan-Meier method. Variables considered were patient’s age at transplantation, donor/recipient gender, interval from diagnosis to transplantation, cytogenetic group, type of conditioning (RIC/MAC/FLAMSA), source of stem cells (peripheral blood stem cells versus bone mar- row), patient/donor cytomegalovirus serology, Karnofsky Performance Status (KPS) at the time of transplantation, in vivo T- cell depletion, and year of transplantation. Factors that significant- ly differed between the three groups with P-values of <0.05, and all known as potential prognostic factors were included in the final models. Cumulative incidence functions were used to estimate relapse incidence (RI) and NRM in a competing risk setting, because death and relapse compete with each other. To study chronic GvHD, we considered relapse and death to be competing events. Probabilities of LFS and OS were calculated using Kaplan- Meier estimates. Univariate analyses were performed using the Gray test for cumulative incidence functions and the log-rank test for LFS and OS. Associations of patient and graft characteristics with outcomes were evaluated in multivariate analysis, using a Cox proportional hazards model. All tests were two-sided.
We used propensity score weighing to control for pre-treatment imbalances in observed variables. The following factors were included in the propensity score model: patient’s age, time from diagnosis to transplantation, year of transplant, status at trans- plant, cytogenetic group, donor/patient cytomegalovirus serology, conditioning (RIC versus MAC), and gender matching (female donor to male recipient versus other). Propensity scores were esti- mated using generalized boosted models.
As the study question was whether Haplo PTCy could replace UD 10/10 or UD 9/10, we weighted the groups receiving either UD 10/10 or UD 9/10 HSCT to match the characteristics of patients receiving Haplo HSCT, by estimating the average treat- ment effect among the treated group (Haplo HSCT being the treated group). We then used pairwise average treatments to fit the weighted Kaplan-Meier and Cox models separately for Haplo PTCy versus UD 10/10 HSCT and Haplo PTCy versus UD 9/10 HSCT.
The type I error rate was fixed at 0.05 for determination of fac- tors associated with time to events. Analyses were performed using the R statistical software version 3.2.3 (R Development Core Team, Vienna, Austria). Propensity score analysis was performed using the mnps function of the Twang package and weighted analyses using the survey package.
Results
Patients, disease and transplant characteristics
Data were obtained from 218 reporting centers (Online Supplementary Data). The patients’ and disease characteris- tics are summarized in Table 1. Of the total 1693 HSCT, 1111 were UD 10/10, 383 were UD 9/10 and 199 were Haplo PTCy. The three cohorts of patients differed for several variables (Table 1). The median follow-up was longer for the UD 10/10 and the UD 9/10 groups than for the Haplo-PTCy group. The follow-up completeness index at 2 years, which is the ratio of total observed per- son-time and the potential person-time of follow-up at 2 years32 was 73% for Haplo PTCy, 76% for UD 10/10 and 80% for UD 9/10. Significantly more patients received
MAC regimens in the Haplo PTCy group in comparison to both the UD 10/10 and the UD 9/10 groups. There were more cytomegalovirus-positive recipient-donor pairs in the Haplo-PTCy group. Peripheral blood stem cells were, as expected, the main source of stem cells in the UD 10/10 and UD 9/10 groups, while peripheral blood stem cells represented 52.8% of the stem cell source in the Haplo- PTCy group.
Engraftment and graft-versus-host disease
The cumulative incidence of engraftment at day 30 was 85.5% [95% confidence interval (95% CI): 79-90.2], 92.3% (95% CI: 90.5-93.7) and 92.2% (95% CI: 88.9-94.6) in the Haplo PTCy, UD 10/10 and 9/10 groups, respective-
ly (P<10-3 for both comparisons).
Lower incidences of all acute GvHD grades were
observed after Haplo PTCy than after UD 9/10. The cumulative incidences of grade II–IV acute GvHD were 28.2% and 36.3%, respectively (P=0.03) and those of severe grade III–IV acute GvHD were 8.9% and 16.1%, respectively (P=0.02) (Table 3). No difference was observed in the incidence of grade II-IV acute GvHD between the Haplo PTCy and UD 10/10 groups (P=NS).
At 2 years, the cumulative incidence of chronic GvHD was lower in the Haplo PTCy group than in the UD 9/10 group (19.3% and 27.4%, respectively, P=0.04), while no difference was found in the incidence of chronic GvHD between the Haplo PTCy and UD 10/10 groups (P=NS) (Table 3). The cumulative incidence of extensive chronic GvHD was similar in the three groups of patients (Haplo PTCy - 11%, UD 10/10 -11.6% and UD 9/10 -11.6%).
The percentages of patients who achieved CR within 100 days were 79.7%, 77% and 78.3% in the Haplo PTCy, UD 10/10 and UD 9/10 groups, respectively (P=NS). Performing a landmark analysis at day 100 for comparing outcomes between patients who achieved CR before day 100 to those who did not indicated that CR seems to be a surrogate marker for subsequent outcome. The probability of being alive and free of disease 1 year after HSCT was only 13.7% for patients who did not achieve CR before day 100 (data not shown).
We also analyzed chronic GvHD as a time-dependent variable demonstrating that the association of chronic GvHD with a lower RI [hazard ratio (HR)=0.77, 95% CI: 0.60-0.99, P=0.04) was counterbalanced by a higher NRM (HR=1.98, 95% CI: 1.38-2.84, P<10-3), and thus did not translate into better LFS (P=NS).
Leukemia-free survival, overall survival, relapse incidence and non-relapse mortality
In univariate analysis, the LFS rate at 2 years was 22.8% in the Haplo PTCy group versus 28% in the UD 10/10 group and 22.2% in the UD 9/10 group (P=NS) (Figure 1A, Online Supplementary Table S1). Multivariate analysis showed lower LFS rates in patients with poor cytogenetics (HR=1.35, 95% CI: 1.11-1.62, P=0.002), those transplant- ed in second relapse in comparison to those transplanted in primary refractory AML (HR=1.31, 95% CI, 1.03-1.65, P=0.03), and in patients transplanted from cytomegalovirus seropositive donors (HR=1.22, 95% CI: 1.05-1.41, P=0.01). In contrast, better LFS was associated with KPS ≥90 at transplantation (HR=0.66, 95% CI: 0.58- 0.76, P<10-3), with a shorter time from diagnosis to trans- plantation (HR=0.99, 95% CI: 0.98-0.99, P=0.02), and with RIC in comparison to MAC (HR=0.84, 95% CI: 0.71-
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haematologica | 2019; 104(3)