Only 30% of high-risk adult ALL patients in their first complete remission (CR1) are able to receive an HLA-matched sibling stem cell transplant. The role of haploidentical hematopoietic SCT (haplo-HSCT) in post-remission therapy is not well established. Recently, we developed a novel protocol for unmanipulated haploidentical transplantation. In this study, we compared haplo-HSCT with conventional consolidation and maintenance chemotherapy in adult high-risk ALL patients. Between January 2000 and December 2012, 104 patients received conventional chemotherapy and 79 patients received haplo-HSCT. Patients who underwent haplo-HSCT had significantly improved 3-year OS (72.5% vs 26.6%; P<0.001), 3-year disease-free survival (DFS) (63.9% vs 21.1%; P<0.001) and 3-year relapse (18.7% vs 60.5%; P<0.001) rates. The non-relapse mortality (NRM) rate was not different between patients treated with haplo-HSCT vs chemotherapy (19.2% vs 14.4%; P=0.80). In multivariate analysis, the only factor associated with improved OS, better DFS and low risk of relapse was haplo-HSCT. The only factor associated with high NRM was enrollment before 2006. In conclusion, haplo-HSCT may be an option for adults with high-risk ALL in CR1 who do not have an HLA-matched donor.
Unlike pediatric patients with ALL, adult ALL patients treated with chemotherapy have long-term survival outcomes that are far from satisfactory. Over the past 30 years, the OS rate has not surpassed 30–40%. Especiallypoor outcomes are seen in patients with high-risk characteristics,1,2 such as age>35 years, high WBC count at diagnosis and unfavorable chromosome rearrangements. More than 80% of the patients achieve a first CR (CR1);2 the major barrier to long-term survival is a high relapse rate following CR1. Post-remission therapy is necessary for all ALL patients, and it includes ongoing chemotherapy (conventional consolidation and maintenance chemotherapy) and allogeneic hematopoietic SCT (allo-HSCT).
HLA-matched hematopoietic SCT (HSCT) is an option for high-risk ALL patients. However, only 30% of the patients who need transplants have matched related donors available.3 In the past 2 decades, transplantation from alternative donors has improved significantly. For instance, haploidentical HSCT (haplo-HSCT) can provide all patients with a potential donor. In recent years, we developed a novel protocol for haplo-HSCT without in vitro T-cell depletion. This novel protocol includes a donor primed with G-CSF, a combination of PBSCs and BM stem cells, an intensive immunosuppressive regimen and antithymoglobulin in the conditioning regimen. Patients who receive unmanipulated haplo-HSCT can achieve results comparable to HLA-matched sibling transplantation and unrelated donor transplantation.4,5
However, the role of haplo-HSCT for post-remission therapy in adult high-risk ALL is not well established. In this study, we compared haplo-HSCT with conventional consolidation and maintenance chemotherapy in adults with high-risk ALL.
Materials and methods
This retrospective study examined consecutive patients at the Peking University Institute of Hematology between January 2000 and December 2012. Patients were selected for analysis if they fulfilled the following conditions: (1) adults (aged, 18–60 years); (2) newly diagnosed high-risk ALL (high-risk ALL was defined by the presence of any of the following factors: >35 years of age; high WBC count at presentation (⩾100 × 109/L for T lineage and ⩾30 × 109/L for B lineage); t(9;22) or BCR-ABL6); (3) received ongoing chemotherapy or haplo-HSCT in CR1.
The outcomes of patients who received haplo-HSCT or ongoing chemotherapy were compared.
The Ethics Committee of the Peking University People’s Hospital approved this study. All patients signed informed consent forms before treatment.
Induction chemotherapy/early intensification chemotherapy
The induction course included CY (750 mg/m2 on day 1), DNR (45 mg/m2 on days 1–3), VCR (4 mg weekly) and prednisone (1 mg/kg/day for 4 weeks). Early intensification therapy included MTX (1–1.5g/m2 on day 1) and L-asparaginase (10 000 IU on days 3–12). After 2006, imatinib (400 mg/day administered orally) was also used in Ph-positive ALL patients during or after the induction phase.
All patients who achieved CR1 continued to receive post-remission therapy. If a matched sibling donor or a suitable unrelated donor was available, patients received a transplant. For patients without HLA-identical related or unrelated donors, the decision to receive ongoing chemotherapy or haplo-HSCT was based on the desire of the patient.
Consolidation/maintenance chemotherapy. Consolidation therapy included eight cycles of CY (750 mg/m2 on day 1), DNR (45 mg/m2 on days 1–3), VCR (4 mg on day 1) and prednisone (1 mg/kg/day on days 1–7), alternating with MTX (1 g/m2). Maintenance therapy included oral mercaptopurine (60 mg/m2/day on days 1–28), MTX (20 mg/m2 weekly), VCR (4 mg on day 1) and prednisone (1 mg/kg/day on days 1–7). Central nervous system prophylaxis was administered 16 times via intrathecal injection with 50 mg arabinoside and/or 10 mg MTX and 5 mg dexamethasone when CR was achieved. The total duration of the treatment was 24 months after CR.
Haploidentical transplantation. Donor selection, HLA typing and stem cell harvesting have been described previously.4,5 In brief, the conditioning therapy consisted of cytarabine (4 g/m2/day on days −10 to −9), BU (before January 2008, 4 mg/kg/day orally on days −8 to −6; after January 2008, 3.2 mg/kg/day intravenously on days −8 to −6), CY (1.8 g/m2/ day on days −5 to −4), semustine (250 mg/m2 orally on day −3) and antithymocyte globulin (from 2003 to 2004; 20 mg/kg/day, porcine (Bioproduct, Wuhan, China) on days −5 to −2; for all other cases, 2.5 mg/kg/day, rabbit (Sang Stat, Lyon, France) on days −5 to −2). Transplant recipients received CsA, mycophenolate mofetil and short-term MTX for prevention of GVHD.
Imatinib (400 mg/day) was initiated in the first 90 days after allo-HSCT for Ph-positive ALL patients. Imatinib treatment was scheduled for 3 to 12 months after HSCT, until BCR-ABL transcript levels were negative for at least three consecutive tests or until molecular remission was sustained for at least 3 months, as described in our previous report.7 Twelve patients received alternating low-dose IL-2, as previously described.8 For Ph-negative ALL, detection of minimal residual disease (MRD) was based on the results of flow cytometry and the presence of Wilms’ tumor gene-1 after transplantation.9 Two patients received modified DLI after MRD was detected10 post-HSCT.
Definitions, follow-up and statistics
CR was defined as: (1) no circulating blasts or extramedullary disease; (2) trilineage hematopoiesis and <5% blasts in the BM; (3) ANC >1.0 × 109/L and plt count >100 × 109/L; (4) no recurrence for 4 weeks. Relapse was defined as the reappearance of blasts in the blood or BM (>5%), or at any extramedullary site, after CR. Non-relapse mortality (NRM) was defined as death from any cause other than relapse. The last follow-up for all surviving patients was 1 November 2013.
The primary endpoint was OS, and the secondary endpoints were disease-free survival (DFS), relapse and NRM. OS was calculated as the date of CR to the date of last follow-up or death. DFS was calculated as the date of CR until the date of first relapse, death from any cause or the last follow-up for patients alive in CR1. Cumulative incidence of relapse (CIR) and NRM were calculated as the date of CR to the time of recurrence or the time of death while in CR, respectively.
Patients in the chemotherapy group may relapse very early, and the bias introduced by including such patients should be avoided. Therefore, landmark analysis was used when comparing the outcomes of patients receiving haplo-HSCT to those receiving chemotherapy. The landmark day was set as the median time from CR1 to haplo-HSCT.
As the median time from CR1 to haplo-HSCT was 4 months (range, 3–5 months), MRD was evaluated before assignment during the fourth month for the chemotherapy group or before HSCT. These data were available for patients enrolled in 2006 or later.
OS and DFS curves were plotted by using the Kaplan-Meier method, and they were compared using two-tailed log-rank tests. NRM and CIR were calculated by using R statistical software, version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria). The analysis for potential prognostic factors included age (⩽35 years vs >35 years), sex (male vs female), Ph-status (positive vs negative), MRD before assignment (positive vs negative), treatment choice (chemotherapy vs haplo-HSCT) and year enrolled (before 2006 vs 2006 onward). For univariate analysis, comparisons were made by using chi-squared tests for categorical variables and Mann-Whitney tests for continuous variables. Factors with P⩽0.20 in the univariate analysis were included in a Cox proportional hazards model for multivariate analysis by using SPSS software 13.0 (IBM Corporation, Armonk, NY, USA). In addition, high WBC count, treatment choice, Ph status, age and MRD before assignment were always included in the multivariate analysis. The significance level was fixed at P=0.05, and all P-values were two-sided, unless otherwise stated. We also calculated 95% confidence intervals (CI).
Between January 2000 and December 2012, there were 480 newly diagnosed adult ALL patients in our center; 275 of these patients were high-risk patients. After 1–2 cycles of chemotherapy, 249 (90.5%) patients achieved CR1. Next, 50 patients received HLA-matched sibling transplants (n=44) or unrelated donor transplants (n=6). As the median time from CR to haplo-HSCT was 4 months (range, 3–5 months), the landmark was 4 months. Sixteen patients relapsed before the landmark and they were excluded from the analysis. The final analysis included 183 patients in CR1, which included 104 patients who received ongoing chemotherapy and 79 patients who received haplo-HSCT. These 183 patients were the subjects of our study (Figure 1).
The characteristics of the 183 patients are summarized in Table 1. The median age was 40 years (range, 18–60 years) and 113 patients (61.7%) were aged >35 years. There were 92 (50.3%) male and 91 (49.7%) female patients. Ph-positive ALL was identified in 62 patients (33.9%). High WBC counts were observed in 76 patients (36.1%) at initial diagnosis. The median follow-up for all patients was 23 months (range, 6–129 months), whereas the median follow-up for the 87 survivors was 37 months (range, 11–129 months).
Most characteristics were comparable between the haplo-HSCT and conventional consolidation and maintenance chemotherapy groups (Table 1), except for age and the time of enrollment. More patients received transplants after 2006 (74/79 vs 63/104; P<0.001), and chemotherapy group patients were older than transplantation group patients (44 vs 33 years; P<0.001).
Haplo-HSCT was performed for 79 patients after a median time of 4 months (range, 3–5 months) from CR1. At 100 days after transplantation, the cumulative incidences of grade 2–4 acute GVHD and grade 3 or 4 acute GVHD were 48.8% (95% CI=45.8–51.8%) and 8.8% (95% CI=5.8–11.8%), respectively. At 2 years after transplantation, the cumulative incidences of chronic GVHD and extensive chronic GVHD were 58.6% (95% CI=56.6–60.6%) and 24.7% (95% CI=22.2–27.2%), respectively.
Comparison between haploidentical transplantation and chemotherapy
At the time of the last follow-up, 87 patients were alive. Of the 96 deaths, 69 were attributed to relapse and 27 were from causes other than relapse (Table 2). The most frequent cause of TRM was infection.
The 3-year OS, DFS, CIR and NRM were 46.0%, 40.0%, 48.8% and 15.6%, respectively. Patients who underwent haplo-HSCT had significantly improved 3-year OS (72.5% vs 26.6%; P<0.001), 3-year DFS (63.9% vs 21.1%; P<0.001) and 3-year CIR (18.7% vs 60.5%; P<0.001) rates (Figure 2). Analysis of patients in subgroups based on age (>35 vs ⩽35 years), Ph status (positive vs negative) or high WBC count at diagnosis (yes vs no) showed that the transplantation group was still superior to the conventional chemotherapy group (Table 3). However, the groups were not different before 2006; the haplo-HSCT group was only significantly superior to the chemotherapy group in the 2006 and later subgroup. There was no difference in NRM between the haplo-HSCT and chemotherapy patients in the whole cohort (19.2% vs 14.4%; P=0.80) or in subgroups (Table 3).
Prognostic factors for outcomes
Our multivariate analysis for the whole cohort included treatment choice (haplo-HSCT vs chemotherapy), age (⩽35 vs >35 years), Ph status (positive vs negative), time of enrollment (before 2006 vs 2006 and later) and high WBC count (yes vs no). In the whole cohort, haplo-HSCT was the only factor associated with improved OS, better DFS and decreased relapse rate. The only factor associated with high NRM was enrollment before 2006 (Table 4).
In the haplo-HSCT group, age (⩽35 vs >35 years), Ph status (positive vs negative), time of enrollment (before 2006 vs 2006 and later) and high WBC count (yes vs no) were analyzed for their impact on OS, DFS, CIR and NRM. The only prognostic factor for poor OS, poor DFS and high relapse rate was enrollment before 2006. None of the factors were prognostic for NRM (Table 5). In the chemotherapy group, patients aged ⩽35 years had better OS, and enrollment before 2006 predicted NRM. None of the factors were prognostic for DFS and relapse (Table 6).
To exclude the impact of the year of enrollment, we analyzed the subgroup of patients enrolled in 2006 or later. Data about MRD before assignment were also available for analysis. We found that haplo-HSCT and negativity for MRD were associated with improved OS, better DFS and decreased relapse rate. No prognostic factors were identified for prediction of NRM. Haplo-HSCT was significantly superior to chemotherapy. In addition, there was no difference in NRM between the haplo-HSCT and chemotherapy groups.
The majority of hematologists prefer HSCT for high-risk adult ALL patients;11 however, the role of allo-HSCT is still controversial.6 Comparison of allo-HSCT with maintenance and consolidation chemotherapy has only been performed with matched sibling donors. The role of transplantation from alternative donors for high-risk adult ALL has not been well established. In this retrospective cohort study, we found that haplo-HSCT was superior to conventional chemotherapy for adult high-risk ALL. The risk of relapse was much lower in the transplantation group, which translated to improved OS.
Several other centers have reported outcomes of haplo-HSCT for adult ALL. Aversa et al.12 reported T-cell-depleted transplantation in 65 adult ALL patients (19 in CR1, 23 in CR2 and 23 in relapse). The cumulative 2-year incidence of relapse for the 42 patients transplanted in remission was 24%. For the 19 high-risk ALL patients in CR1, the EFS was 28%. The cumulative incidence of NRM was 45%, most of which was due to infection. In another European study13 of 24 high-risk adult ALL patients in CR1 who received haplo-HSCT, the NRM was 61%, the relapse rate was 26% and the leukemia-free survival was 13%. However, these reports do not directly compare conventional chemotherapy with haplo-HSCT.
The relapse rate of the transplantation group in the current study was 19.2%, which is consistent with our previous reports (18.8–24.3%)14, 15, 16 and similar to other reports.12,13,17 The low relapse rate after HSCT may be attributable to several factors. First, allo-HSCT appears to be the most effective antileukemia treatment, presumably owing to a GVL effect that has been illustrated in several studies.6,18,19 Furthermore, our previous study demonstrated that haplo-HSCT might be associated with a superior GVL effect than HLA-identical sibling donor grafts in high-risk acute leukemia.20 In addition, the decreased relapse rate may be owing to some preemptive strategies for preventing relapse, such as risk-stratified DLI10 or low-dose IL-2,8 which is administered at our center, and early prophylactic imatinib for Ph-positive ALL patients after transplantation.7,21
The toxicity of transplantation in previous studies may explain why a reduced relapse rate did not translate to improved survival. In the Medical Research Council and Eastern Cooperative Oncology Group study, the 5-year relapse rate was significantly lower in high-risk patients who received transplantations (donor vs no donor, 37% vs 63%, P<0.001). However, the 5-year OS of high-risk adult ALL patients with donors vs those without donors was 41% vs 35% (P=0.2) owing to a high rate of NRM in the transplantation group (36% vs 4%). In early studies, haplo-HSCT was hampered by a high mortality rate from GVHD and infection. The NRM in some reports12,13,17 remains high (45–61%). Over the last decade, haplo-HSCT has developed, and TRM has been dramatically reduced. Our previous reports have demonstrated that patients who receive unmanipulated haplo-HSCT can achieve outcomes comparable to HLA-matched sibling transplantation or unrelated donor transplantation.4,5 Reduced TRM in the present study may help advance multiple fields: improved prevention and management of GVHD,22 new anti-infection drugs23 and other advances.
Some may argue that the overall NRM in the chemotherapy group was high. Therefore, the superiority of haplo-HSCT may be due to low OS in the chemotherapy group rather than an advantage of treatment choice. We acknowledge that the patients treated before 2006 have a very high NRM rate. However, we performed subgroup analysis and found that patients treated after 2006 had an NRM rate of ~10%, which is acceptable according to the literature.24 Importantly, haplo-HSCT was still superior to chemotherapy after 2006. Of course, future prospective studies are needed to confirm the benefits of haplo-HSCT.
Several limitations of our study are discussed below. First, it is important to note that this was a retrospective, nonrandomized study. Owing to the ethical dilemma of randomizing patients regardless of donor availability, most studies of allo-HSCT for high-risk adult ALL patients in CR1 are performed by using donor vs no donor assignments. Until recently, there were no real randomized studies. As the role of haplo-HSCT has not been well established, and there were no randomized data available on this issue, our paper presents a direct comparison. We believe this study provides useful information. On the basis of the encouraging results of this retrospective study, we are now preparing to initiate a related prospective study. In addition, although the patient characteristics were comparable between the two groups, the fact that patients were grouped on the basis of the desires of the patients may have introduced great bias. For example, patients in the transplantation group were younger, and more of them received treatment in recent years. Although we reanalyzed the data in subgroups and multivariate analysis, our findings should still be confirmed in prospective studies. Finally, cytogenetics were not evaluable in ~10% of patients in both groups. Although the proportion of Ph positivity was similar in the two groups, we acknowledge that this is a limitation of this study.
In summary, this study suggests that haplo-HSCT is an option for adults with high-risk ALL in CR1 who do not have an HLA-matched donor. Future prospective studies are needed to confirm our results.
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We thank Editage (www.editage.cn) for their assistance in editing this manuscript.
The authors declare no conflict of interest.
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