Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5–37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.
Allogeneic stem-cell transplantation (allo-SCT) represents a curative option for acute lymphoblastic leukemia (ALL). Myeloablative therapy with high-dose radiochemotherapy or chemotherapy alone followed by allo-SCT is the most powerful method for eradicating leukemic cells. Patients who experience relapse are candidates for allo-SCT, since few patients who have relapsed are cured using conventional chemotherapies.1 In adult patients with ALL in second complete remission (CR2), most studies have indicated a disease-free survival (DFS) rate of approximately 30%.2, 3 In contrast, allo-SCT for adult patients with ALL in first complete remission (CR1) is controversial, since allo-SCT is associated with significant transplant-related mortality (TRM). Whether allo-SCT is beneficial for ALL in CR1 remains unclear.4, 5 Some patients with certain high-risk factors, including specific cytogenetic abnormalities, should be offered allo-SCT in CR1.6
Elimination of leukemic cells following allo-SCT is attributable to two processes: the direct effect of chemoradiotherapy; and graft-versus-leukemia (GVL) effects. The role of GVL effects is less defined in ALL. Some case reports have demonstrated durable remission following donor lymphocyte infusion (DLI),7, 8 and several studies have shown that a GVL effect associated with graft-versus-host disease (GVHD) contributes to a reduction in ALL relapse after allo-SCT.9, 10, 11 However, these case reports and small studies might have suffered from patient selection bias. Two retrospective studies have suggested that GVL effects for ALL are weaker than those for myeloid malignancies.9, 12 In a study of 44 ALL patients treated using DLI, only three achieved remission ⩾1 year, and 3-year overall survival (OS) was 13%.13 DLI showed only limited benefit in the treatment of recurrent ALL after allogeneic CST.
A new strategy for transplantation using reduced-intensity conditioning for stem-cell transplantation (RIST) has been developed to reduce regimen-related toxicities while preserving antileukemic effects.14 This strategy decreases the risk of nonrelapse mortality and allows transplantation in elderly patients or those with organ dysfunction. Since RIST is based on a GVL effect, usefulness for ALL has not yet been clarified. Most prospective studies on RIST have included small numbers of patients with ALL, ranging from 1 to 9.14, 15, 16, 17, 18, 19 Five studies have reported using ⩾10 patients with ALL.20, 21, 22, 23, 24 Two retrospective multicenter studies focused on RIST for ALL.21, 22 Arnold et al21 reported that four of 22 patients were alive and disease-free at 5–30 months after RIST, and that seven died of TRM. In all four patients who survived following RIST, underlying diseases were in CR at the time of transplant. Martino et al22 summarized the features of patients from four prospective studies, including patients with advanced ALL. OS and TRM were 31 and 23%, respectively. Relapse rate was 33% in patients transplanted in CR, and 60% in those with overt disease.
The present study describes our experience of 31 patients with ALL who were treated using RIST.
Patients and methods
Diagnosis and classification of clinical subtypes of ALL
ALL was diagnosed on the basis of cytology, karyotype, and immunophenotyping of marrow cells. Patients had received induction/consolidation chemotherapy in accordance with local protocols.
A total of 33 patients with ALL underwent RIST at 18 transplant centers between October 2000 and November 2003. Patients who were not candidates for conventional myeloablative transplantation were considered for RIST. All patients satisfied one or more of the following inclusion criteria: age greater than 50 years, prior autologous transplantation with high-dose chemotherapy, and nonhematologic organ dysfunction. They all gave informed consent. Patient characteristics are shown in Table 1.
Preparatory regimen and transfused stem cells
Transplantation procedures are shown in Table 1. Preparatory regimens comprised fludarabine(Flu)/busulfan with (n=3) or without rabbit anti-thymocyte globulin (ATG) (n=9), or with total body irradiation (TBI) at 4–8 Gy (n=2), or with both ATG and TBI (n=1),14, 17 Flu/melphalan (n=8),15 another fludarabine-based regimen (n=4),25 cladribine-based regimen (n=2), TBI at 2 Gy (n=2),16 and others (n=2). Either T-cell depletion or CD34-positive cell selection was performed in all patients. The median number of transfused cells was 3.9 × 106 CD34+ blood stem cells/kg (range, 0.98–7.5 × 106 cells/kg) or 3.2 × 108 marrow-nucleated cells/kg (range, 0.43–5.3 cells/kg).
The day of neutrophil engraftment was defined as the first of three consecutive days on which absolute neutrophil count was >500 cells/μl. The day of platelet engraftment was defined as the first of seven consecutive days on which the platelet count was >20 000/μl without platelet transfusion.
The diagnosis of GVHD was based on clinical evidence with histologic confirmation whenever possible. Acute GVHD within the first 100 days after transplantation was graded according to standard criteria.28, 29 Patients who survived at least 100 days were evaluated for chronic GVHD. Chronic GVHD was graded as limited (localized skin or single organ involvement) or clinically extensive.
TRM was defined as death without progression of underlying disease. OS was defined as duration of survival between transplant and either death or last follow-up. Progression-free survival (PFS) was defined as duration of survival after transplant without disease progression, relapse, or death. When ALL recurred before engraftment, the underlying disease was considered to have progressed on the day of transplant.
The major end point was 1-year PFS following RIST. Secondary end points included incidence of relapse, nonrelapse mortality, incidence and severity of GVHD, engraftment, complications, frequency of DLI, and OS. Patients were considered to have died of nonrelapse cause if no evidence of disease relapse or progression was apparent. Data were analyzed as of March 1, 2004.
Cumulative incidences of progression and progression-free mortality were evaluated using Gray's method, considering each other risk as a competing risk.30 OS and PFS were estimated using the Kaplan–Meier methods. Potential confounding factors considered in the analysis were age, sex, donor type (HLA-matched related donor vs alternative donor), stem cell source (bone marrow (BM) vs peripheral blood stem cells (PBSC)), HLA-mismatch, disease status, conditioning regimen, and development of grades II–IV acute GVHD. To evaluate the influence of these factors on PFS, proportional hazard modeling was used, treating the development of acute GVHD as a time-dependent covariate. Factors associated with at least borderline significance (P<0.10) on univariate analyses were subjected to multivariate analysis using backward stepwise proportional-hazard modeling. Values of P<0.05 were considered statistically significant.
Neutrophil counts did not decrease below 500/μl in one patient, while autologous blasts recovered in two patients. The remaining 30 patients achieved neutrophil engraftment within a median interval of 12.5 days (range, 8–26 days). Among 31 patients with neutrophil recovery, two patients never experienced thrombocytopenia and three patients died without platelet engraftment. The other 26 patients achieved platelet engraftment within a median of 13 days (range, 8–50 days).
GVHD and other complications
Two patients died within 100 days of transplant. Causes of death were diffuse alveolar damage and hemophagocytic syndrome.
A total of 15 patients (45%) developed grades II–IV acute GVHD. Maximal ratings were grade II (n=9), III (n=3), or IV (n=3). Acute GVHD was fatal in five patients. Of the 25 evaluable patients (64%) who survived longer than 100 days, 16 developed chronic GVHD.
Infections were documented in seven patients. Causative organisms included methicillin-resistant Staphylococcus aureus (n=3), Escherichia coli (n=1), Pseudomonas aeruginosa (n=1), Candida tropicalis (n=1), and Aspergillus species (n=1). Infections were fatal in four patients.
Noninfectious complications other than GVHD occurred in eight patients, and comprised: hepatic veno-occlusive disease (n=2); chronic subdural hematoma (n=1); hemophagocytic syndrome (n=1); interstitial pneumonitis (n=1); pleural effusion (n=1); idiopathic pulmonary syndrome (n=1); and engraftment syndrome (n=1).
A total of 21 patients died, and disease progression was absent in nine of these cases. Causes of death included GVHD (n=6), idiopathic pulmonary syndrome (n=1), hemophagocytic syndrome (n=1), and sepsis (n=1). The remaining 12 patients died after leukemic progression, with eight deaths due to progressive disease, and other four attributable to complications associated with DLI (acute GVHD n=2) or second RIST (thrombotic microangiopathy, n=2; hepatic veno-occlusive disease, n=2).
Response to RIST
In all, 12 of 14 patients transplanted during relapse achieved durable remission (Table 2). In the other two patients, ALL recurred immediately after neutrophil engraftment. In seven patients with t(9:22)(q34;q11), minimal residual disease was monitored with reverse transcriptase-polymer chain reaction assay (RT-PCR) using bcr-abl-specific primers. Molecular remission was confirmed in four of the seven patients (Patients 4, 13, 26, and 27), with durations of 4.2, 4.6, 11.1, and 27.6 months, respectively.
OS and PFS
As of March 2004, 12 patients were alive in CR (n=9) and relapse (n=3) with a median follow-up of 11.6 months (range, 3.5–37.3 months). Probability of 2-year PFS and OS was 18.6% (95% confidence interval (CI), 2.4–34.9%) and 29.7% (95% CI, 11.7–47.7%), respectively (Figure 1). The median duration of overall survival was 177 days (range, 40–1119 days). Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively (Figure 2).
Actuarial 1-year PFS rates were 30.6% (95% CI, 7.7–53.5%) for the 19 patients transplanted in CR1/CR2 and 28.6% (95% CI, 4.9-52.2%) for the 14 patients transplanted in relapse or induction failure (P=0.26) (Figure 3).
Association between GVHD and OS
Among the 21 patients who survived without disease progression longer than 100 days, presence of grades II–IV acute GVHD tended to show better PFS compared with those without it; however, the difference was marginal (relative risk 0.45,. 95% CI 0.18–1.16, P=0.10) (Figure 4).
DLI was undertaken in six patients. Patient 4 received prophylactic DLI and achieved durable molecular remission until she died of bronchitis obliterans at 13.5 months after RIST. The remaining five patients underwent DLI following recurrence of ALL. Two patients (Patients 3 and 8) received DLI followed by second RIST. Patient 8 underwent second RIST 38 days after DLI, and died from progressive disease 29 days after second RIST. Patient 3 received DLI for central nervous system (CNS) relapse, and underwent second RIST. She relapsed again in the CNS and bone marrow, and died of disease progression 8.7 months after second RIST.
Response to DLI was evaluated in the remaining three patients (Patients 2, 17, and 23). One patient responded to DLI, and two died of acute GVHD. Patient 2 received DLI for emerging extramedullary disease. The lesion was controlled using local irradiation and DLI. However, ALL recurred in the BM and the patient experienced grade IV acute GVHD that eventually proved fatal. In Patient 17, peripheral blasts disappeared after DLI, but the patient died of gastrointestinal GVHD. Patient 23 died of disease progression without any response to DLI.
Prognostic factors for PFS
In univariate analyses, no variables were identified as significant prognostic factors for PFS (Table 3). Multivariate analysis was discontinued due to the lack of associated factors from univariate analyses.
GVL effects against ALL after allo-SCT have been discussed for almost 15 years.31, 32 A small but significant proportion of patients with advanced ALL achieve durable remission following RIST. Of the 14 patients transplanted in relapse, 12 achieved durable remission, and molecular remission was confirmed in four of the seven patients with t(9;22)(q34;q11) in this study. Considering that combination chemotherapy is usually ineffective at producing prolonged survival in patients with advanced ALL, the long-term PFS after allo-SCT suggests that durable allogeneic immune reactions continue to suppress leukemic progression.
Optimal reduced-intensity regimens remain unclear for RIST for ALL. Even after achievement of CR following allo-SCT, patients with ALL display high levels of minimal residual disease associated with increased relapse rates.33 Most physicians believe that GVL effects are insufficient or may not have enough time to arrest advanced ALL, and that preparative regimens should be more intense in RIST for ALL compared with chronic-phase chronic myeloid leukemia or low-grade malignant lymphoma. Purine analog-based regimens were mostly used in this study, and chemotherapeutic agents such as melphalan, busulfan and 4–8 Gy TBI were added in 28 patients. These regimens might have been beneficial for establishing durable engraftment in RIST for advanced ALL, and might have contributed to temporary control of disease. The role of additional chemoradiotherapy needs to be further investigated in RIST for ALL.
Optimal timing of RIST for ALL remains unknown. Estimated 2-year PFS rates after RIST for high- and low-risk ALL were 8 and 42%, respectively. Outcomes for RIST are dismal unless therapy is given in CR1 (Figure 3). These findings are comparable to previous reports on conventional allo-SCT for ALL.34, 35 Disease status remains an important prognostic factor in RIST and decision-making as to when to proceed with allo-SCT in patients with ALL is difficult.
Response rates to DLI in ALL patients were low,12, 13 suggesting a limited GVL effect for ALL, especially after hematologic relapse. Only early intervention before clinical relapse can improve prognosis for these patients, by inducing GVL effects.13, 36 In our study, DLI induced remission in one of five patients who relapsed following RIST, accompanied by severe GVHD. Another two patients died of leukemic progression, and the other two patients died of GVHD following DLI. However, some patients dramatically benefit from DLI such as Patients 2 and 17 in our study, and the one reported by Slavin et al.7 Many publications suggest that the efficacy of DLI may be improved by activation of donor lymphocytes using in vitro or in vivo interleukin-2 with no prohibitive GVHD.37 Activation of donor lymphocytes is a possible future approach in an attempt to amplify the already well-documented GVL effect in ALL.
Two basic types of complications are associated with allo-SCT: regimen-related toxicity and GVHD. Nonrelapse mortality rate within 100 days of transplantation was 6.4% in this study. Reduced-intensity regimens cause less organ damage, contributing to lower rates of TRM. These findings are comparable to previous reports.14, 15, 38 GVHD represents another significant concern after RIST,39 which is frequently complicated by infections.40 Rates of acute and chronic GVHD were 45 and 64%, respectively. The balance between GVHD and GVL is delicate in allo-SCT. Augmentation of GVHD prophylaxis may hamper GVL effects, and leukemic cells cannot be eradicated by reduced-intensity conditioning alone. This study failed to show meaningful advantages of GVHD in preventing relapse of ALL following RIST, while GVHD remains the leading cause of TRM. At present, allo-SCT recipients receive uniform GVHD prophylaxis irrespective of the risk of underlying disease or patient condition. Intensification of GVHD prophylaxis is at least beneficial in RIST for low-risk ALL. Management of GVHD prophylaxis should be optimized considering risk of underlying disease and patient condition.
Our study indicates that RIST is worth considering for further intense evaluation. The technique may offer the best chance for hematologic remission and prolonged survival, given the poor prognosis after conventional chemoradiotherapy. However, this retrospective study was too small to provide definitive conclusions regarding RIST for ALL. Since our study included heterogeneous patient group, centers, and conditioning approaches, interpretation of the results requires caution. Further investigation and data are awaited to determine the indications and optimal transplantation procedures for ALL.
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We are grateful to Drs Takanori Teshima, Naoki Kobayashi, Takashi Ashida, Atsushi Woke, Issei Hatanaka and Shinji Nakao for their cooperation and detailed descriptions of their cases.
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Hamaki, T., Kami, M., Kanda, Y. et al. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients. Bone Marrow Transplant 35, 549–556 (2005) doi:10.1038/sj.bmt.1704776
- reduced-intensity hematopoietic stem cell transplantation
- acute lymphoblastic leukemia
- graft-versus-host disease
- regimen-related toxicity
- graft-versus-leukemia effect
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