We retrospectively assessed the outcome and pretransplantation predictors of the outcome in 118 patients aged ⩾50 years who received fludarabine-containing reduced-intensity allo-SCT (RIST) for B-cell ALL in the first or second CR. Eighty patients received transplants from unrelated donors. Seventy-eight patients were positive for the Ph chromosome. The median follow-up period was 18 months and the 2-year OS rate was 56%. The 2-year cumulative incidence of relapse and non-relapse mortality was 28% and 26%, respectively. The incidence of grades II–IV and III–IV acute GVHD was 46% and 24%, respectively. After 2 years, the incidence of chronic GVHD was 37%. Multivariate analysis of pretransplant factors showed that a higher white blood cell count (⩾30 × 109/L) at diagnosis (hazard ratio (HR)=2.19, P=0.007) and second CR (HR=2.02, P=0.036) were significantly associated with worse OS, whereas second CR (HR=3.83, P<0.001) and related donor (HR=2.34, P=0.039) were associated with a higher incidence of relapse. Fludarabine-containing RIST may be a promising strategy for older patients with B-cell ALL in their first remission.
The overall CR rate is very high (80–90%) for adult ALL due to the efficacy of induction therapy with relatively low toxicity, which allows many patients to receive postremission therapy. However, adult ALL has a poor long-term outcome, with the 5-year OS rate being only 39–50% despite aggressive chemotherapy1, 2 and declining to 15% for patients over 50 years old.3 At present, allogeneic hematopoietic SCT (allo-HSCT) is thought to be the most potent therapy for prevention of relapse in adult ALL patients. A recent large-scale prospective study showed that allo-HSCT from matched sibling donors achieved a better outcome compared with chemotherapy or autologous transplantation.4 However, Goldstone et al.4 reported that TRM is unacceptably high for high-risk older patients and this counteracts the reduced risk of relapse.4 Therefore, reduced-intensity conditioning allo-HSCT (RIST) is performed in older patients and those who are unsuitable for myeloablative conditioning with the aim of reducing TRM, although its antileukemic efficacy is uncertain.5, 6, 7 In general, the relationship between age and the prognosis of ALL patients aged between 20 and 65 years shows a continuum.3 Because most older patients are excluded from clinical studies, very few prospective trials have investigated the efficacy of chemotherapy and/or allo-HSCT tailored for older patients. Therefore, more clinical data are needed to establish the optimum transplant strategy for elderly patients with ALL. Accordingly, the objectives of this study were to analyze the outcome and identify pretransplant outcome predictors in older patients with B-cell ALL undergoing RIST.
Patients and methods
Patient selection and data sources
This study enrolled patients aged 50 years or older who received RIST for B-cell ALL in the first or second remission between 2000 and 2009 in Japan. Data were provided by the Japan Society of Hematopoietic Cell Transplantation (JSHCT), the Japan Marrow Donor Program (JMDP) and the Japan Cord Blood Bank Network (JCBBN). Information on transplantation was collected at 100 days after allo-HSCT, whereas the data concerning survival, disease status and long-term complications, including chronic GVHD and second malignancies, were renewed annually from follow-up forms. This study was approved by the data management committees of the JSHCT, JMDP and JCBBN. Informed consent was obtained from both recipients and donors in accordance with the Declaration of Helsinki Principles.
Peripheral blood stem cell (PBSC) donation from unrelated donor was not permitted until 2009 in Japan. If recipients have no suitable related donors, physicians choose alternative graft sources according to recipient’s condition and institutional strategy. HLA matching of related donor–recipient pairs was mainly performed using serologic typing methods. HLA matching of unrelated BM and umbilical cord blood (CB) was performed using low- or high-resolution molecular typing for HLA-A, -B and -C, and high-resolution molecular typing for HLA-DRB1.
Study end points and definitions
The primary endpoints of the study were non-relapse mortality (NRM), relapse, leukemia-free survival (LFS) and OS. NRM was defined as death while in remission, and relapse was defined as hematological recurrence of leukemia. LFS was defined as survival without evidence of relapse or progression and OS was calculated from the date of allo-HSCT. Death from any cause was treated as an event and surviving patients were censored at the date of last contact. The day of engraftment was defined as the first of 3 consecutive days on which the ANC was ⩾0.5 × 109/L. Acute and chronic GVHD were diagnosed and graded according to established criteria.8, 9 We defined a reduced-intensity regimen as having the following dosage levels: BU <9 mg/kg, melphalan ⩽140 mg/m2 and TBI <500 cGy (single or fractionated) or <800 cGy (fractionated).10
The final date of analysis was 30 November 2010. We compared demographic factors and disease characteristics according to the donor source by using Fisher’s exact test for categorical data and the Mann–Whitney U-test for continuous variables. LFS and OS were estimated by the Kaplan–Meier method. The Cox proportional hazards model was used for univariate and multivariate analyses. Gray’s test was used to compare the cumulative incidence curves for relapse and NRM.11 Death without acute GVHD was defined as the competing event for acute GVHD, whereas death without neutrophil engraftment and second transplantation without engraftment were the competing events for neutrophil engraftment, NRM and second transplantation without relapse were the competing events for relapse, and relapse and second transplantation were the competing events for NRM. The proportional hazard regression model of Fine and Gray12 was used for univariate and multivariate analyses of these competing risks. All covariates with P<0.10 according to univariate analysis were entered into the multivariate model. All tests were two-sided and P<0.05 was considered to indicate significance. Statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R software (The R Foundation for Statistical Computing, version 2.13.0). More precisely, it is a modified version of R commander (version 1.6–3) that includes functions frequently used in biostatistics.13
Background of transplantation
The patient and graft characteristics are summarized in Table 1. A total of 187 patients aged ⩾50 years received RIST for ALL. Of these, 35 patients in non-remission, 32 patients with non-B cell (uncertain in 20, T cell in 10 and null cell in 2) and 2 patients aged ⩾70 years were excluded in this analysis. There were 118 patients in the study cohort and their median age was 59 years (range: 50–69 years). There were early pre-B-cell type in 6 patients, pre-B-cell type in 34 and common type in 78 according to immunophenotype classification. The median WBC count at diagnosis was 15.6 × 109/L (range: 0.8–1967 × 109/L). BM was the most common source of stem cells (55%), followed by cord blood (CB) (24%) and PB (21%). The median time from diagnosis to RIST was 200 days (range: 75–3372 days). TBI was used for 74 patients and its dosages were as follows: 200 cGy in 13 patients, 300 cGy in 9, 400 cGy in 52 and 600 cGy in 1.
Transplantation was carried out on HLA-matched related donors in 33 patients, HLA-mismatched related donors in 5, HLA-matched unrelated donors in 47 and HLA-mismatched unrelated donors in 33. RIST from unrelated donors was significantly more frequent in patients aged 60–69 years compared with those aged 50–59 years. T-cell depletion was performed in six patients (five patients with antithymocyte globulin and 1 with antilymphocyte globulin). The median time from diagnosis to RIST from related and unrelated donors were 154 days (range: 75–617 days) and 229 days (range: 79–3372 days), respectively (P=0.029). Furthermore, use of TBI and GVHD prophylaxis showed significant differences among patients with different donor sources (Table 1).
The median time until neutrophil engraftment after transplantation was 16 days (range: 9–39 days). Three patients died before day 35 without achieving neutrophil recovery. Sustained engraftment was achieved in 113 of the remaining 115 patients, whereas primary graft failure was confirmed in two patients who received CB transplantation. One patient died of primary graft failure on day 60, but the other was salvaged by repeat transplantation. The median time to platelet count recovery (⩾20 × 109/L) was 26 days (range: 0–154 days). Seven patients died within 60 days after transplantation and stable engraftment of platelets was seen in 102 of the 111 patients who survived beyond day 60.
Acute and chronic GVHD
The incidence of GVHD according to donor type is shown in Table 2. The cumulative incidence of grade II–IV and grade III–IV acute GVHD was 46% and 24%, respectively. Stem cell and donor sources were not associated with the incidence or grade of acute GVHD. The cumulative incidence of chronic GVHD after 2 years was 37%. Limited chronic GVHD was noted in 16 patients (16%), whereas 24 patients (24%) had extensive chronic GVHD. After RIST from related donors, there was a significantly higher incidence of chronic GVHD compared with after RIST from unrelated donors (P=0.012). Also, RIST with PB from related donors was associated with a significantly higher incidence of chronic GVHD than when BM or CB was the source (63% vs 36% and 37%, respectively; P=0.019).
The median follow-up period for the survivors was 18 months (range: 2–77 months). The 2-year LFS, OS, cumulative relapse rate and NRM were 66%, 56%, 28% and 26%, respectively (Figure 1). Detailed results, including the incidence of GVHD, are shown in Table 2, with stratification by donor source. Fifteen patients (14 with NRM and 1 with relapsed leukemia) died within 100 days after transplantation. They included 12 of the 57 patients receiving fludarabine+melphalan, but the conditioning regimen did not have a significant impact on 2-year OS (68% for fludarabine+i.v. BU, 64% for fludarabine+oral BU, 47% for fludarabine+melphalan and 63% for fludarabine+CY; P=0.472). When OS at 2 years was stratified according to stem cell source, it was 56%, 55%, 43% and 47% (P=0.301) for related BM, related PB, unrelated BM and unrelated CB, respectively. In addition, the 2-year OS of patients with (n=78) and without (n=40) the Ph chromosome was 58% and 52%, respectively (P=0.997). In this study, the information of pre- and post-transplant treatment with tyrosine kinase inhibitors was obtained in only 45 and 9 patients, respectively. Therefore, we could not do further analyses in the viewpoint of tyrosine kinase inhibitors treatment for Ph chromosome-positive ALL. The cumulative relapse rate in patients with unrelated donors was significantly low compared to those with related donors (22% vs 39% at 2 years, P=0.030). In subgroup analysis according to disease status at RIST, the difference of relapse rate at 2 years was significant in CR1 (13% vs 35%, P=0.019) but not in CR2 (54% vs 74%, P=0.140). In the patients transplanted from unrelated donors, there was no difference of relapse rate at 2 years between unrelated BM (n=52, 22%) and unrelated CB (n=28, 23%) (P=0.976). Patients who developed grade III and IV acute GVHD had significantly worse OS at 2 years than those with grade 0–II acute GVHD (20% vs 59%, P<0.001). Patients with severe acute GVHD also had a high NRM (grade 0–II: 22%; III–IV: 64%, P<0.001). In contrast, chronic GVHD did not influence the outcome.
The causes of death are shown in Table 3. Eighteen of the 38 patients with related donors died as did 34 of 80 with unrelated donors. Relapse and infection were the main causes of death. Infection was more common in patients with unrelated donors (35% vs 6%, P=0.021), whereas relapse was the most common cause of death in patients with related donors.
Using pretransplantation variables, the prognostic factors for OS, relapse and NRM were assessed by univariate analysis (Table 4). The WBC count at diagnosis (<30 × 109/L: 63%; ⩾30 × 109/L: 42%, P=0.012) and the disease status at transplantation (CR1: 60%; CR2: 36%, P=0.039) were associated with the 2-year OS (Figure 2). Disease risk at transplantation (CR1: 21%; CR2: 56%, P=0.016), type of donor (related: 39%; unrelated: 22%, P=0.030) and TBI (no: 39%; yes: 21%, P=0.031) had an influence on relapse, whereas the WBC count at diagnosis was a significant predictor of NRM (<30 × 109/L: 19%; ⩾30 × 109/L: 39%, P=0.017). According to multivariate analysis (Table 4), a high WBC count (HR=2.19; 95% confidence interval (CI): 1.24–3.89, P=0.007) and CR2 (HR=2.02; 95% CI: 1.05–3.89, P=0.036) were significant predictors of worse OS, while CR2 (HR=3.83; 95% CI: 1.73–8.48, P<0.001) and related donor (HR=2.34; 95% CI: 1.05–5.23, P=0.039) were significantly associated with a higher cumulative relapse rate. No risk factors for a higher cumulative NRM were identified. Other variables (including recipient age, sex, Ph chromosome, time from diagnosis to transplantation, conditioning regimen, donor source and TBI) were not identified as prognostic factors.
In the present study, we analyzed the outcome of elderly patients with B-cell ALL who underwent fludarabine-containing RIST and investigated potential prognostic factors. After transplantation in CR1 or CR2, 2-year OS was 56%, which was comparable to the results of previous large-scale retrospective studies of ALL patients in remission.14, 15 It was reported that the 3-year OS was 38% in patients receiving RIST in a study by the Center for International Blood and Marrow Transplant Research (CIBMTR), although the cohort included 93 Ph chromosome-negative ALL patients with a median age of 45 years (range: 17–66 years).14 According to a study by the European Group for Blood and Marrow Transplantation, the 2-year OS was 48% for 127 patients with a median age of 56 years (range: 45–73 years), including those with Ph chromosome-positive ALL.15 The 2-year cumulative incidence of relapse (28%) and NRM (26%) in the present study were also similar to the results of the above two studies. Those studies mainly involved comparison of RIST and myeloablative conditioning allo-HSCT, but we focused on the outcome stratified according to the donor source or conditioning regimen and pretransplant factors to identify predictors of survival in this study.
The optimum regimen of reduced-intensity conditioning for elderly ALL patients has not yet been defined. Cho et al.16 reported an excellent outcome for high-risk ALL patients in remission when they used conditioning with fludarabine and melphalan followed by transplantation from a matched sibling. We compared three fludarabine-containing regimens in this study. The 2-year OS achieved when BU, melphalan or CY was combined with fludarabine was 64%, 47% and 63%, respectively (P=0.287). In addition, 2-year OS showed no difference between i.v. BU (68%) and oral BU (64%). Unexpectedly, fludarabine plus BU achieved a better outcome than use of melphalan, although a significant difference was not confirmed. Owing to the small number of patients in each group and the short duration of follow-up, we could not find any differences of relapse and NRM among the regimens. To clarify the most suitable conditioning regimen for older patients with ALL, a prospective randomized study of fludarabine plus BU or melphalan seems to be warranted on the basis of our results.
The other main aim of this study was to identify factors associated with the outcome of fludarabine-containing RIST for elderly B-cell ALL. According to previous studies, factors such as age, immunophenotype, WBC and cytogenetic abnormalities are associated with the outcome of chemotherapy and/or transplantation for ALL.17 The Ph chromosome is the most frequent and clinically significant abnormality in adult ALL, with an incidence ranging from 15 to 50% among older patients with B-cell ALL.18 Use of tyrosine kinase inhibitors combined with chemotherapy has altered the prognosis of these patients.19 We could not obtain detailed information about tyrosine kinase inhibitor treatment before or after transplantation and minimal residual disease from the registry data, but the Ph chromosome was not a risk factor in the present retrospective study. Taken together with previous reports,7, 20 RIST for Ph chromosome-positive ALL in CR1 is thought to be a hopeful strategy from the viewpoint of curability.
The better outcome of patients who underwent RIST in CR1 compared with CR2 was confirmed in this study, as demonstrated in previous reports.7, 14, 15, 16, 20 The European Group for Blood and Marrow Transplantation reported that patients in CR1 had a lower NRM (18% vs 44%, P=0.01) and higher OS (52% vs 20%, P=0.003) at 2 years after transplantation than patients beyond CR1, which strongly supports the importance of RIST for patients with a favorable disease status.7 Cho et al.16 also reported that RIST achieved a better outcome in CR1 patients than in CR2 patients with respect to relapse (14.8% vs 55.6%, P=0.07) and OS (74.7% vs 21.7%, P=0.01).16 They identified a GVL effect of chronic GVHD, because chronic GVHD was associated with a significantly lower incidence of relapse (4.8% vs 45.5%, P=0.02). In our study, patients with unrelated donors had a lower relapse rate than those with related donors, but chronic GVHD was conversely seen in the patients with related donors. These results may have been influenced by the unique situation in Japan that PB as a stem cell source is only available from related donors. As one of the possible explanations, the longer time from diagnosis to RIST in patients from unrelated donors might influence on patient’s selection with favorable prognosis.
The WBC count at diagnosis and the disease status were two important prognostic factors in this analysis. A cutoff value of 30 × 109/L has often been used in clinical studies of B-cell ALL and its significance has been shown in previous reports.3, 17 Marks reported that a WBC >25 × 109/L at diagnosis predicted a worse outcome for adult patients with ALL in CR1/2 who received transplantation after either full conditioning (n=1421) or reduced-intensity conditioning (n=92).14 However, there has been no report about the clinical impact of WBC at diagnosis on survival among patients receiving RIST alone. Therefore, our results support the WBC count at diagnosis as one of the useful parameters for stratifying patients in studies of RIST.
Although there are limitations because this was a retrospective study based on registry data from multiple centers, our cohort consisted of a relatively large number of B-cell ALL patients aged 50 years or older and this study had the unique characteristic of investigating elderly B-cell ALL patients with 66% being Ph chromosome-positive. In contrast with the stem cell sources available in Western countries, only BM or CB was transplanted from unrelated donors in this study because transplantation with unrelated PB was not approved in Japan until 2009.
In conclusion, the results of this study support further investigation of fludarabine-containing RIST for ALL in the elderly, especially for patients in CR1, although longer follow-up is needed to confirm the durability of remission and the quality of life.
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We thank all of the staff from the participating institutions of the Japan Society for Hematopoietic Cell Transplantation for their assistance and cooperation.
The authors declare no conflict of interest.
HK (Kanamori) designed the study, analyzed the data and wrote the draft version of this manuscript. HN, MT, KI, TY, TF, KM and TE submitted and cleaned the data; T-NI, YM, RS and HS collected and reviewed the data; And SM, SK, HK (Kato), SN, KI, AS and JT interpreted the results and critically revised the manuscript.
An erratum to this article is available online at https://doi.org/10.1038/bmt.2013.179.
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Kanamori, H., Mizuta, S., Kako, S. et al. Reduced-intensity allogeneic stem cell transplantation for patients aged 50 years or older with B-cell ALL in remission: a retrospective study by the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation. Bone Marrow Transplant 48, 1513–1518 (2013) doi:10.1038/bmt.2013.140
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