The role of autologous hematopoietic cell transplantation (AHCT) in the treatment of ALL remains unclear.1 Several phase III studies have failed to demonstrate the superiority of AHCT over conventional chemotherapy.2, 3, 4, 5 We hypothesized that an intensified approach might improve the outcomes of AHCT for adults with ALL. We used an intensive consolidation treatment with high-dose cytarabine and etoposide that has been used in AHCT for AML and has produced excellent hematopoietic cell mobilization.6 The aims of this consolidation therapy were to decrease leukemia cell burden in the patient, produce good progenitor cell mobilization and provide in vivo purging of the graft. We performed ex vivo purging of the graft with a combination of monoclonal antibodies and complement in order to further reduce leukemic contamination.7 We developed an intensified preparative regimen that would be unsuitable for allogeneic transplantation, but that we thought would be appropriate for autologous transplantation, based on the high-dose fractionated TBI (FTBI) plus etoposide program developed at the City of Hope National Medical Center,8 by adding CY 100 mg/kg. In order to ascertain the efficacy of the overall approach in a phase II study, we enrolled only high-risk patients who would be expected to have a very poor outcome if treated with chemotherapy alone and in whom no allogeneic hematopoietic cell donor was available or AHCT was not appropriate.
Each participant signed an institutional review board-approved, protocol-specific informed consent document in accordance with the federal and institutional guidelines. Patients between ages 16 and 60 were eligible for study entry in second remission, or in first remission of ALL if they were at high risk based on one or more of the following criteria: B-lineage disease with WBC count at diagnosis >30 000/mcl; high-risk cytogenetics, including t(9;22), t(4;11), other 11q23 abnormalities, or monosomy 7; or failure to achieve CR after a first course of induction chemotherapy.
We administered consolidation chemotherapy with cytarabine 2000 mg/m2 i.v. every 12 h for 8 doses on days 1–4 plus etoposide 40 mg/kg by continuous i.v. infusion on days 1–4. G-CSF 10 mcg/kg was given s.c. from day 14 through the completion of stem cell collection. PBPCs were collected when the WBC recovered to ⩾5000/mcl. A CD34+ enriched fraction was generated using Percoll gradient fractionation. For patients with B-lineage disease, monoclonal antibodies were used against CD 9, 10, 19 and 20, and for patients with T-cell disease, against CD 2, 3, 4, 5 and 8.7
FTBI was given in 11 fractions of 120 cGy each for a total dose of 1320 cGy from day −8 to −5. Fifty percent lung blocks were used throughout. A 300-cGy electron boost was given to the chest wall and ribs, and a single fraction of 400 cGy was given to the testes. Etoposide 60 mg/kg was given on day −4 and CY 100 mg/kg on day −2. The use of imatinib was allowed for patients with Ph+ ALL after its approval, and two patients received this agent.
Twenty-four patients with a median age of 39 years (20–56) and median WBC of 15 000/mcl (3–255) were enrolled. Eighteen patients were enrolled in first remission and six in second remission. Among the first remission patients, two were at high risk because of B-lineage disease with WBC >30 000/mcl (actual WBC 90 000 and 214 000, respectively); 4 patients had not achieved remission after their first course of chemotherapy; 12 patients had adverse cytogenetics, including 7 with t(9;22), 2 with t(4;11), 1 with another 11q23 abnormality and 2 with monosomy 7. The median time from achieving remission to study entry was 54 days (30–151).
During consolidation chemotherapy there was one case of TRM. Peripheral blood grafts were collected at a median of 1 day (1–4), and collection was started at a median of 22 days (18–27) from the initiation of chemotherapy. The median CD34+ total cell dose ( × 106/kg) collected was 37 (4.4–133). A median CD34+ dose of 14 (1.3–106) was saved as backup. The median CD34+ cell dose processed was 14.4 (2.3–44). The median CD34+ cell dose achieved after Percoll density fractionation was 10.8 (0.9–28) and that after antibody purging 6.7 (0.9–19.5).
There were four early relapses before transplant. Of 19 patients transplanted, there was one treatment-related death on day +55 caused by an air embolus when a patient disconnected himself from his i.v. line, and eight relapses. Ten patients remain in continuous remission with a median follow-up of 8.7 years (7.0–12.0). For all patients enrolled in the study, the 5-year EFS is 42% (95% confidence interval (CI) 22–61%) (Figure 1), TRM 9% (95% CI 0–21%), relapse rate 54% (95% CI 33–75%) and overall survival at 5 years 46% (95% CI 26–62%). For the patients who underwent transplant, 5-year EFS is 53% (95% CI 30–75%), TRM 5% (95% CI 0–15%) and relapse rate 44% (95% CI 21–67%).
If AHCT is to have a significant role in the management of ALL, the treatment program needs to be improved. In the setting of allogeneic transplantation, there is a clear trade-off between decreasing relapse and increasing TRM when the preparative regimen is intensified. However, it has been possible to show a benefit from intensified allogeneic preparative regimens in ALL, with higher doses of TBI reducing the relapse rate.9 In the autologous setting, it should be possible to use intensified preparative regimens without an increase in TRM. Our treatment program was well tolerated, with the major toxicity being mucositis. It is likely that the use of palifermin would decrease its severity.
We are encouraged both by the tolerability and by the efficacy of this treatment approach in this high-risk population. Further studies of improved and intensified approaches to AHCT for ALL appear warranted. CALGB is currently testing the efficacy of an AHCT approach to Ph+ ALL based on this experience.10
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The authors declare no conflict of interest.
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Linker, C., Damon, L., Martin, T. et al. Autologous hematopoietic cell transplantation for high-risk ALL. Bone Marrow Transplant 46, 460–461 (2011). https://doi.org/10.1038/bmt.2010.125
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