Allogeneic hematopoietic cell transplantation is an effective therapy for ALL in adults, and it is highly recommended for high-risk patients such as those with older age, certain cytogenetic abnormalities and minimal residual disease (MRD).1, 2 Cord blood transplantations (CBT) are increasingly used as a stem cell source for allogeneic transplantation in ALL,3, 4, 5 and various conditioning regimens have been adopted in CBT, since its clinical introduction.6, 7, 8 Among them, high-dose cytarabine (HDCA) added to the conventional regimen of cyclophosphamide with TBI (CY/TBI) may be a promising strategy, because cytarabine has long been used as an effective agent during induction and consolidation chemotherapy for ALL.1 However, comparisons between HDCA/CY/TBI and CY/TBI are lacking, and the data on HDCA-related toxicity, as well as non-relapse mortality (NRM) and overall survival (OS) are not fully discussed. Therefore, we performed a cohort study by using the Japanese transplant registry database of ALL to compare the prognosis in patients, who underwent CBT after the HDCA/CY/TBI or CY/TBI regimen.
Data of adult patients (age⩾16 years) with ALL, who underwent a single-unit CBT as a first transplantation after CY/TBI (CY, total 120 mg/kg; TBI, 10–12 Gy) or CY/TBI plus HDCA (total dose, 6–12 g/m2) between 1 January 2000 and 31 December 2013 were obtained from the Transplant Registry Unified Management Program (TRUMP) in Japan. OS was calculated with the Kaplan–Meier method and compared by using log-rank tests. Factors with P<0.1 in the univariate analysis were subjected to a multivariate analysis by using the Cox proportional hazards model. Tumor-related mortality was defined as death without remission or after relapse,9, 10 and calculated by using Gray’s method considering NRM as a competing risk. Our protocol complied with the Declaration of Helsinki, and was approved by the Ethics Committee of Kyoto University, where the study was performed.
We extracted the data of 442 patients, 14 of whom were excluded because of missing essential data (HLA, GvHD prophylaxis or stage). Therefore, we evaluated 428 patients with ALL, aged 16–64 years (median age, 38 years), who underwent CBT after the conditioning regimen of CY/TBI (N=219) or HDCA/CY/TBI (N=209; Table 1). The median follow-up for survivors was 42.9 months (range, 1.2–149.1 months) after CBT.
The OS of the HDCA/CY/TBI group was superior to that of the CY/TBI group (Figure 1a; 69.1% vs 63.8% at 1 year; 60.1% vs 50.2% at 3 years after CBT). This difference was significant in the univariate analysis (Supplementary Table 1; hazard ratio (HR), 0.74; 95% confidence interval (CI) 0.56–0.98; P=0.03). Among other variables, older age (⩾40 years), advanced-risk disease (standard-risk was defined as ALL in the first hematological CR at the timing of CBT, whereas non-CR and second or later CR was considered advanced-risk disease), initial higher leukocyte count, GvHD prophylaxis with cyclosporine, and CBT during the earlier period (2000–2008) were associated with poorer survival (P<0.1). Nucleated cell counts in the graft had no significant difference in OS in the whole cohort or in each group of conditioning. In the multivariate analysis including these factors, the HDCA/CY/TBI group showed a significantly lower overall mortality than the CY/TBI group (Supplementary Table 1; HR, 0.75; 95% CI, 0.57–0.99; P=0.04). This superiority of OS in the HDCA/CY/TBI group was observed in each subgroup according to the patient characteristics, such as age, disease risk, phenotype, existence of abnormal chromosome, initial leukocyte counts and year of CBT. In addition, MRD (one of the most important prognostic factors1, 2) was determined by flow cytometric analyses in 80% of the cohort, and HDCA/CY/TBI showed the superiority in OS irrespective of the existence of MRD (data not shown). A difference in OS was detected even with the other common cutoff point for age (⩾35 years)5 (HR, 0.75; 95% CI, 0.57–1.00; P=0.05).
Relapse, tumor-related mortality and NRM were also calculated. Relapse in patients transplanted in CR was significantly reduced in the HDCA/CY/TBI group (Figure 1b). Tumor-related mortality including the entire cohort was also significantly lower in the HDCA/CY/TBI group (Figure 1c; Supplementary Table 2). Leukemia-free survival also showed superiority in the HDCA/CY/TBI regimen (HR, 0.77; 95% CI, 0.59–1.00; P=0.05). Post-CBT central nervous system (CNS) relapse was less often observed in HDCA/CY/TBI (0.9%) than in CY/TBI (2.7%; P=0.17) despite the higher incidence of CNS involvements before CBT in the HDCA/CY/TBI group (6.2% vs 3.6%). HDCA/CY/TBI was not found to induce any significant increase of NRM in the entire cohort (Figure 1d; Supplementary Table 2) or in any subgroup of patient age or disease risk (data not shown).
To address the clinical courses that led to the differences in survival and relapse, we focused on the engraftment, GvHD and several common complications after CBT in each group (Supplementary Table 3). The HDCA/CY/TBI group showed a higher proportion of neutrophil engraftment after CBT (Supplementary Table 3; Supplementary Figure 1A). The median periods to reach neutrophil engraftment were not significantly different between the groups (23 days in HDCA/CY/TBI vs 22 days in CY/TBI; P=0.11). Platelet recovery was observed in a significantly larger proportion of patients (Supplementary Table 3; Supplementary Figure 1B) and in earlier days after CBT in the HDCA/CY/TBI group (45 vs 52 days; P<0.01). The incidence of acute GvHD showed an increase in HDCA/CY/TBI; however, there was no significant difference incidence between the groups (Supplementary Table 3; Supplementary Figure 1C), whereas the incidence of chronic GvHD (cGvHD) was significantly higher in the HDCA/CY/TBI group (HR, 1.86; P<0.01; Supplementary Table 3; Supplementary Figure 1D). Concerning other post-CBT complications, the addition of HDCA did not increase any types of infectious episodes (Supplementary Table 3), whereas CNS toxicity and thrombotic microangiopathy (TMA) were documented more frequently in HDCA/CY/TBI (Supplementary Table 3).
We compared the causes of NRM between CY/TBI and HDCA/CY/TBI to investigate the consequences of these differences on the clinical courses (Supplementary Table 4). The major causes of NRM were infection and organ failure in both groups, and there were no significant differences in the incidence of death causes between the two regimens, including TMA and GvHD. No cases of fatal CNS toxicity were documented in our cohort. These indicate that cGvHD and other HDCA-related complications could be controlled, and that they did not induce additional fatal complications in the HDCA/CY/TBI group.
The present cohort study on the HDCA/CY/TBI regimen in CBT for ALL revealed two major findings: (1) the HDCA/CY/TBI regimen improved OS through reduction in relapse and tumor-related mortality; and (2) addition of HDCA increased the incidence of cGvHD, CNS toxicity and TMA after CBT, but was not related to a higher NRM.
First, we clearly showed the superiority of HDCA/CY/TBI over CY/TBI concerning OS. This result may be due, in part, to the strong anti-leukemia effects of HDCA. Compared with normal dose of cytarabine, HDCA can exert stronger effects because of its longer time in contact with leukemia cells11 and its broader distribution in the whole body, including the cerebrospinal fluid;12 these pharmacokinetic and pharmacodynamic features of HDCA can support our findings of reduced relapse and improved prognosis.
Furthermore, a stronger GvL effect in the HDCA/CY/TBI regimen, indicated by the higher incidence of cGvHD in this group, may also be involved in reducing the incidence of relapse; the occurrence of cGvHD is known to be closely correlated with the existence of strong GvL effects.13 The intensity of conditioning regimens is reportedly related to GvHD incidence,14 and a higher incidence of GvHD in HDCA/CY/TBI was indeed observed in a previous study of AML.10 These dual effects of HDCA, that is, anti-leukemia effect and enhanced stronger GvL effect, may work synergistically to reduce tumor-related mortality and account for the superiority of HDCA/CY/TBI after CBT.
Second, we showed that HDCA/CY/TBI is related to a higher incidence of CNS toxicity and TMA among various common post-transplant complications, in addition to cGvHD. The prognosis is seldom severe after a CNS complication; however, sufficient attention should be paid as a common adverse event after the HDCA/CY/TBI regimen. On the other hand, TMA, which is caused by vascular endothelial cell injury, is not specific to HDCA, but related to a higher intensity of conditioning regimens and to post-transplant GvHD in general.9, 15 TMA can sometimes be a fatal complication, and prophylaxis for TMA such as recombinant thrombomodulin15 may be considered in HDCA/CY/TBI. Despite the higher incidence of these complications, the total NRM and its causes showed no differences between HDCA/CY/TBI and CY/TBI, which supports the feasibility of this HDCA/CY/TBI regimen in myeloablative CBT for ALL.
This study has some limitations due to its retrospective cohort nature, such as selection bias in the choice of conditioning regimens, although the patient characteristics in Table 1 showed no significant differences between the two groups. Information on the CBT centers where each patient received transplantation was not available from this database. To overcome these limitations, randomized controlled studies comparing HDCA/CY/TBI and CY/TBI should be planned. These studies will be helpful in establishing new myeloablative conditioning regimens, including HDCA administration, and in improving the total prognosis of ALL.
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We thank all the physicians and data managers at the centers who contributed valuable data on transplantation to the Japan Society for Hematopoietic Cell Transplantation, all the cord blood banks in Japan and TRUMP. This study was supported by research funding from the Ministry of Education, Science, Sports, and Culture in Japan to T Kon.
Y Ar designed the study, reviewed and analyzed data, and wrote the paper; T Kon, AS, JT and SM interpreted the data and revised the manuscript; ST, T Kob, NU, YO, JI, HK, MS, AY, YK, MT, TI and Y At contributed to the data collection and provided critique for the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on Bone Marrow Transplantation website
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Arai, Y., Kondo, T., Shigematsu, A. et al. High-dose cytarabine added to CY/TBI improves the prognosis of cord blood transplantation for acute lymphoblastic leukemia in adults: a retrospective cohort study. Bone Marrow Transplant 51, 1636–1639 (2016). https://doi.org/10.1038/bmt.2016.242
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