Efficiency of high-dose cytarabine added to CY/TBI in cord blood transplantation for myeloid malignancy

Abstract

Cord blood transplantation (CBT) is an effective therapeutic option for adults with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after the conventional cyclophosphamide and total body irradiation (CY/TBI) regimen, but posttransplant relapse is still of high importance. High-dose cytarabine (HDCA) can be added to CY/TBI for an intensified regimen; however, its additional effects have not yet been completely elucidated. Therefore, we conducted a cohort study to compare the prognosis of HDCA/CY/TBI (n = 617) and CY/TBI (n = 312) in CBT for AML/MDS, using a Japanese transplant registry database. The median age was 40 years, and 86.2% of the patients had AML; high-risk disease was observed in 56.2% of the patients. The median follow-up period after CBT was approximately 3.5 years. Overall survival was significantly superior in the HDCA/CY/TBI group (adjusted hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.45-0.69; P < .01), and tumor-related mortality was lower (HR, 0.50; P < .01). The incidence of grade II to IV acute graft-vs-host disease (aGVHD) and chronic GVHD was significantly higher in the HDCA/CY/TBI group (HR, 1.33 and 2.30, respectively), but not grade III to IV aGVHD. Incidence of infectious episodes showed no significant difference. Nonrelapse mortality was not increased by the addition of HDCA. Higher-dose CA (12 rather than 8 g/m(2)) was more effective, particularly in patients at high-risk for disease. This study is the first to show the superiority of HDCA/CY/TBI to CY/TBI in CBT for AML/MDS. A large-scale prospective study is warranted to establish new conditioning regimens including HDCA administration.

Figure 1

Prognosis after CBT in each group of the conditioning regimen. (A) HDCA/CY/TBI showed significantly better OS than CY/TBI after being adjusted for confounding factors such as patient sex, age, PS, CMV serostatus, disease risk, pretransplant therapy period, HLA mismatch, and ABO mismatch (P < .01). (B) Tumor-related mortality, defined as death without remission or after relapse, was significantly higher in the CY/TBI group (P < .01 adjusted for the above-mentioned confounding factors). (C) NRM showed no significant differences between the 2 groups.

Figure 2

Subgroup analyses of OS in each group of the conditioning regimen. Superiority in OS of HDCA/CY/TBI (shown in Table 2) was analyzed in detail by each subgroup with respect to patient characteristics. Compared with the CY/TBI group, the unadjusted HRs of overall mortality in the HDCA/CY/TBI group were significantly lower than 1 (ie, HDCA/CY/TBI is prognostically advantageous) in almost all the subgroups. HRs are shown by black dots, and 95% CI ranges are indicated by black bars.

Figure 3

Clinical courses after CBT in each group of CY/TBI and HDCA/CY/TBI. The cumulative incidence of major events after CBT, such as engraftment, GVHD, and infection, are summarized. In each event, HRs in the HDCA/CY/TBI group were analyzed in comparison with the CY/TBI group after being adjusted for confounding factors. HRs are shown by black dots, and 95% CI ranges are indicated by black bars. Engraftment of neutrophils and platelets was in favor of HDCA/CY/TBI. The incidence of grade II to IV aGVHD and cGVHD was significantly higher in the HDCA/CY/TBI group, but not grade III to IV aGVHD. Addition of HDCA did not cause any increase in the incidence of infection episodes (including bacteria, fungi such as Candia spp. and Aspergillus spp., and viruses such as CMV and human herpes virus-6) compared with the conventional CY/TBI regimen.

Figure 4

OS with respect to the dose of CA in the HDCA/CY/TBI group. OS was calculated using the Kaplan-Meier method, and prognosis was compared between the 2 major dosages of HDCA (ie, 12 vs 8 g/m²). (A) OS was higher in the higher-dose HDCA group (12 g/m²) than in the lower-dose group (8 g/m²) (68.3% vs 61.6% at 1 year; 58.3% vs 50.5% at 3 years); this difference was significant (P = .04) after being adjusted for other confounding factors such as patient sex, age, PS, CMV serostatus, disease risk, pretransplant therapy period, HLA mismatch, and ABO mismatch. In the subgroup analyses according to disease risk, (B) higher-dose HDCA significantly showed the better OS in the high-risk group, but (C) not in the standard-risk group.