Comparison of Stem Cell Transplantation with Reduced Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for Children with Acute Lymphoblastic Leukemia

Background: Allogeneic stem cell transplantation (SCT) is the most intensive therapeutic modality for children with acute lymphoblastic leukemia (ALL) who are resistant to the conventional chemotherapy. The preparative regimen given to those patients is mostly myeloablative conditioning (MAC) and it is the major cause of short or long term post-transplant complications in spite of the potent anti-leukemic effect. Reduced intensity conditioning (RIC) regimen is commonly applied to elderly patients who are ineligible to MAC regimen but only a small number of children received RIC regimen to date and the precise transplant outcome of SCT with RIC regimen for children with ALL is not well understood. To interpret the clinical implication of RIC regimens in children, we have conducted nationwide retrospective analysis by comparing the transplant outcomes with RIC and MAC regimens in children with ALL.

Patients and Methods: From 2000 to 2010, 1334 children with ALL undergone their first allogeneic SCT either by RIC (n=133) or MAC (n=1201) regimen in Japan. Clinical outcomes of SCT was accumulated in the database of The Japan Society for Hematopoietic Cell Transplantation (JSHCT) and the definition of RIC or MAC was based on the internationally recognized criteria in which MAC was defined as > 8Gy of fractionated TBI, >5Gy of single TBI, >8mg/kg or >280mg/m² of busulfan, otherwise categorized as RIC. Disease status at transplant for RIC/MAC was first complete remission (CR, 60/508), 2nd CR (27/347), and more advanced stages (42/329), respectively, (P=0.125). Stem cell source for RIC/MAC was related bone marrow (BM, 33/380), unrelated BM (36/410), related peripheral blood (11/78), and unrelated cord blood (53/333), respectively, (P=0.017). Serological HLA compatibility of RIC/MAC was matched (66/750), or mismatched (62/426), respectively, (P=0.007)

Results: In univariate analysis, five year overall survival (OS) of RIC and MAC in each disease status were not significant different, i.e. 75.2% and 73.4% at first CR (P=0.991), 50.5% and 56.7% at 2nd CR (P=0.748), and 26.7% and 30.3% at more advanced stages (P=0.683), respectively. Five year relapse free survival (RFS) of RIC and MAC in each disease status were also not different, i.e. 62.3% and 68.2% at first CR (P=0.249), 46.6% and 54.0% at 2nd CR (P=0.519), and 14.9% and 27.0% at more advanced stages (P=0.295), respectively. Neutrophil engraftment was obtained 91.7% in RIC and 96.2% in MAC by day 100 (P=0.491). Five year relapse rate was significantly higher in RIC than MAC, i.e. 43.1% vs 33.6%, P=0.020, but five year treatment related mortality (TRM) of RIC and MAC was not significantly different, i.e. 15.7% vs 15.3%, respectively (P=0.952). In multivariate analysis adjusted by other covariates, conditioning regimen of RIC compared to MAC did not significantly affect OS (HR=1.10, P=0.488), RFS (HR=1.25, P=0.093), relapse (HR=1.11, P=0.530), TRM (HR=0.89, P=0.621) or engraftment (HR=0.99, P=0.983). In 133 RIC patients, poor prognostic factors of OS identified in multivariate analysis were advanced stages at SCT (HR=3.91, P<0.001), other than unrelated BMT (HR=0.457, P=0.040), and that of RFS was age of younger than 1 year old (HR=2.28, P=0.006), advanced stages at SCT (HR=5.49, P<0.001) and conditioning regimen without TBI (HR=0.484, P=0.012).

Conclusion: Our data showed that SCT with RIC for children with ALL showed similar transplant outcome compared to those who received MAC. These data suggest that RIC regimen could be considered as one of the therapeutic modality of SCT for children with ALL who needs allogeneic SCT. RIC may have a role also for children, since it may reduce late effects of MAC regimen or high-dose TBI for long-term survivors. To confirm these results, prospective randomized study with multi-institutional basis is mandatory.