Outcome of allogeneic hematopoietic cell transplantation in patients with adult T‐cell leukemia

Abstract Adult T‐cell leukemia/lymphoma (ATL) is an aggressive peripheral T‐cell neoplasm, and the outcome of patients with ATL after chemotherapy is poor. Allogeneic hematopoietic stem‐cell transplantation (allo‐HSCT) is a curative treatment modality for ATL, and four factors, namely, age > 50 years, male recipient, lack of complete remission at transplantation, and transplantation of cord blood, were previously shown to be associated with poor survival. We retrospectively analyzed the outcome of 21 patients with ATL who had undergone allo‐HSCT at our hospital during a 3‐year period. Of 21 patients, all had at least one of the above risk factors, and 18 had two or more. With a median follow‐up of 19.7 months for living patients, the 1‐ and 2‐year overall survival (OS) rates after transplantation were 34% and 27%, respectively. All relapse/progression events occurred within 1 year after allo‐HSCT, and the cumulative incidence of relapse/progression at 1 year after allo‐HSCT was 46.9%. The 100‐day and 1‐year nonrelapse mortality (NRM) rates were 19% and 42%, respectively. No significant difference in OS was observed between myeloablative and reduced‐intensity conditioning regimens. The 3‐year OS (27%) of ATL patients who received allo‐HSCT and who had at least one adverse factor was somewhat poorer than the 3‐year OS of 33% identified in a nationwide study of allo‐HSCT in ATL patients in Japan. The high relapse/progression and NRM rates are major problems to be solved to achieve better outcome.

retrospective studies in Japan demonstrated that the 3-year OS rate was 33% in 386 ATL patients who underwent allo-HSCT. 8 Multivariate analysis revealed that four factors, specifically age > 50 years, male recipient, lack of complete remission (CR) at transplantation, and transplantation of cord blood, were associated with poor survival.
Allo-HSCT is an effective treatment option, but not all ATL patients are appropriate candidates for this therapy. In previous studies, the median ages of acute-and lymphoma-type ATL patients were 63 and 66 years, respectively, whereas the median age of patients who underwent allogeneic bone marrow transplantation (BMT) or peripheral blood stem-cell transplantation (PBSCT) was 53 years, and that in patients who received cord blood transplantation (CBT) was 55 years. 6,9,10 There has been no randomized comparison of chemotherapy alone vs allo-HSCT. Kawada et al 11 performed a retrospective analysis of treatment outcome in ATL patients and showed improved 3-year OS in allo-HSCT recipients over those receiving chemotherapy alone.
In a retrospective nationwide study, Fuji et al 12 also recently reported better OS in transplanted patients compared with nontransplanted patients. The objective of our study was to retrospectively analyze the outcome of ATL patients undergoing allo-HSCT at our institution.

| Definitions and clinical outcome variables
Overall survival was calculated from the day of HSCT or diagnosis until death or last observation, as indicated. Patients who remained alive at the time of the last follow-up were censored. The definition of a therapeutic response to chemotherapy was based on a previous report and its modification. 11,13 Response to treatment was divided into four categories: CR, partial remission (PR), stable disease (SD), and progressive disease (PD). Non-CR was defined as PR + SD + PD.
Myeloablative and reduced-intensity conditioning regimens were defined according to the Center for International Blood and Marrow Transplant Research criteria. 14 Nonrelapse mortality (NRM) was defined as death from any cause without disease relapse/progression.

| Statistical analysis
The Kaplan-Meier method was used to estimate OS, and the log-rank test was used to compare OS between two groups. All data were analyzed using SPSS version 20 software (SPSS, Chicago, Illinois).

| Outcomes
Primary

| DISCUSSION
In this study, the 2-year OS rate following allo-HSCT was 27%. Comparatively, the 3-year OS rate was 33% in a nationwide retrospective study of allo-HSCT in 386 ATL patients in Japan. 8 In that study, age > 50 years, male recipient, non-CR disease status, and cord blood as the graft source were adversely associated with OS by multivariate analysis. As for the effect of graft source on OS, two other nationwide retrospective studies in Japan also suggested inferior OS rates for CBT compared with allo-BMT or PBSCT; the 3-year OS rate was 36% in 586 ATL patients receiving allo-BMT or PBSCT, while the 2-year OS rate was 20.6% in 175 ATL patients receiving CBT. 9,10 Both age > 50 years and non-CR disease status at transplantation were independent risk factors in one of these reports, 9 whereas neither age nor disease status at allo-HSCT affected OS in the other report. 10 In this study, 19 patients (90.5%) were older than 50 years, 12 (57%) were male recipients, 20 (95%) had non-CR disease status at allo-HSCT, and 7 (33%) underwent CBT. Every patient in our study had at least one adverse factor, and 18 (85.7%) had two or more. This might have led to the relatively poorer outcome of allo-HSCT in ATL patients in this study compared with the nationwide study in Japan. showed that the development of grades 1 to 2 aGVHD was associated with improved OS compared with the absence of aGVHD. 10,17 In this study, 11 of 15 patients who survived for 100 days after allo-HSCT developed grades 1 to 2 aGVHD, and its presence had little effect on their OS (mean survival time, 11.8 months in patients with aGVHD vs 6.9 months in those without aGVHD, P = 0.88).
Inoue et al 15 reported that four factors, namely, disease status of SD/PD at allo-HSCT, lymphoma subtype, RIST, and time from diagnosis to allo-HSCT more than 7 months, were independently associated with risk of relapse/progression. These risk factors, however, failed to classify our ATL patients into different disease relapse/ ; c, conditioning regimen (myeloablative vs reduced-intensity); d, time from diagnosis to transplantation (7 months or less vs more than 7 months). CR, complete remission; PD, progressive disease; PR, partial remission; SD, stable disease progression risk categories after allo-HSCT. As for pretransplant disease status, our patients in CR or PR had higher relapse/progression rates after allo-HSCT compared with the report of Inoue et al, 15 although the relapse/progression rates after allo-HSCT were comparable in SD and PD patients. The smaller proportion of CR patients in this study (9% vs 67% in the report by Inoue et al) might be one reason why relapse/progression rates were higher in this study. The prognosis after relapse/progression in transplanted ATL was poor, and only one case (12.5%) obtained CR and was still alive at this writing.
Another reason for unfavorable OS after allo-HSCT was higher NRM in our study. Yoshimitsu et al 16

CONFLICT OF INTEREST
We have no financial relationships to disclose.