Characteristics of the validation cohort

The validation cohort comprised 4060 adult patients with AML who were transplanted in first complete remission in the most recent period (median year 2019, range 20182021). In contrast to the discovery cohort which included patients between 45 and 65 years of age (median 55.6 years), patients in this validation dataset were one decade older (median 63.4 years, range 5575). In total, 48 different conditioning regimens were used (Supplementary Table2). Baseline characteristics are shown by TCI group in Table1. In this validation cohort, 1934 (48%) and 1948 (48%) patients were assigned to the low, and intermediate TCI group, respectively, while a high TCI was less prevalent (n=178, 4% of patients). As expected, there was an inverse relationship between age and TCI, with a median age of 65 years (interquartile range [IQR], 61.368.4), 62 years (IQR, 58.865.9) and 59 years (IQR, 56.863.3) for the low, intermediate, and high TCI groups, respectively (p<0.0001). About 1833% of patients among TCI groups had a low (80%) Karnofsky Performance Score (KPS) and/or high (3) HCT-CI, with patients in the low TCI category more likely to have a lower KPS80% and a higher HCT-CI3 (p<0.0001). Except for the more frequent use of matched sibling donors in the high TCI cohort (p<0.0001), other characteristics were distributed equally between the 3 TCI groups. The most often used immunosuppressive drug combination for graft versus host disease (GvHD) prophylaxis was cyclosporine/mycophenolate mofetil (34.8%, 31.3% and 31.6%) or cyclosporine/methotrexate (34.9%, 32.5% and 39%), whereas post-transplant cyclophosphamide (PTCY) was used in 8.8%, 11.3% and 13.9% of TCI low, intermediate, and high groups, respectively (Table1). The median follow-up of survivors was 22.3 months (IQR, 20.823.2). The outcomes for the entire population were as follows: cumulative incidence of d100 NRM was 6.2% (95% CI 5.57), of d180 NRM was 10.2% (95% CI 9.311.2), of 2-year NRM was 19.2% (95% CI 17.820.5), of REL was 25.7% (95% CI 24.227.3), of acute graft-versus-host disease (GVHD) grades II-IV was 22.1% (95% CI 20.823.4), of acute GVHD grades was III-IV 7.6% (95% CI 6.88.5), of chronic GVHD was 31.7% (95% CI 30.133.4) and of extensive chronic GVHD was 14.2% (95% CI 1315.5). The estimate of LFS and OS at 2 years was 55.1% (95% CI 53.356.9) and 62.2% (95% CI 60.463.9), respectively. Graft failure was low and did not differ between TCI groups (p=0.34), results not shown. Causes of death are given in Supplementary Table3 with original disease the main cause in each TCI category.

The risk of NRM in the validation group followed the same pattern as in the discovery cohort, with a monotonic increase in NRM rate from lower to higher TCI (Fig.1). In the unadjusted comparison, the TCI provided a highly significant risk stratification for d100, d180 and 2-year NRM, with the cumulative incidences being 4.5% (95% CI, 3.75.5), 8.2% (95% CI, 79.6) and 16.5% (95% CI, 14.718.5) in the low TCI group, rising to 7.3% (95% CI, 6.28.5), 11.6% (95% CI, 10.113.1) and 21.4% (95% CI, 19.423.5) in the intermediate TCI group, and further increasing to 12.4% (95% CI, 8.117.8), 17% (95% CI, 11.823.1) and 23.5% (95% CI, 17.230.5) in the high TCI group, respectively (p<0.0001 for all comparisons) (Table2). In a multivariable model including baseline characteristics known to impact NRM such as age, KPS, and HCT-CI score (complete case analysis n=3791), TCI group assignment was found to be strongly and independently associated with NRM (Table3). Relative to the low TCI group, the HRs for d100, d180 and 2-year NRM in the intermediate TCI group were 1.95 (95% CI 1.422.69, p<0.0001), 1.62 (95% CI 1.262.08, p<0.0001) and 1.44 (95% CI 1.201.74, p<0.0001), and in the high TCI group were 4.00 (95% CI 2.27.28, p<0.0001), 2.86 (95% CI 1.764.64, p<0.0001) and 1.87 (95% CI 1.252.80, p=0.003), respectively. In a pairwise comparison between high and intermediate TCI groups, high TCI was associated with an increased risk for early NRM (d100 NRM: HR 2.05; 95% CI 1.173.57, p=0.012; 180 NRM: HR 1.76; 95% CI 1.122.78, p=0.015) but not for 2-year NRM (p=0.19). Besides TCI category, other independent prognostic factors for NRM were incremental age, HCT-CI score 3, KPS score 80%, unrelated donor (early NRM) and a female to male transplantation (2-year NRM) (Table3).

Non-relapse mortality (NRM) for entire validation cohort stratified by Transplant Conditioning Intensity (TCI) category (low, intermediate, high).

In univariate analysis, the REL rate was significantly higher in the low TCI group (29.7%, 95% CI 27.432.1) when compared to the intermediate (21.9%, 95% CI 19.824.0) and the high (25%, 95% CI 17.932.6) TCI group (p<0.0001) (Fig.2). By using the multivariable complete case analysis previously mentioned, TCI group was found to be an independent predictor for REL (Table3). When compared with the low TCI group, the REL risk was significantly decreased in the intermediate TCI group (HR 0.66; 95% CI 0.570.78, p<0.0001), however, we observed only a non-significant reduced REL risk trend in the recipients receiving high TCI regimens (HR 0.79; 95% CI 0.551.13, p=0.20). REL was significantly influenced by adverse cytogenetics and the use of a bone marrow graft (Table3). There were no significant associations between TCI group and LFS or OS (data not shown), except a borderline better OS for high versus low TCI (HR 1.35; 95% CI 1.011.81, p=0.043).

Relapse (REL) for entire validation cohort stratified by Transplant Conditioning Intensity (TCI) category (low, intermediate, high).

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