Risk Factors for Overall Survival in Children with High Risk Acute Myeloid Leukemia (HR AML) after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) with Different Intensity of Conditioning Regimens

Background: Traditionally, children with AML undergo аllo-HSCT with myeloablative conditioning (MAC). It is known that MAC is associated with significant transplant-related morbidity and mortality. Reduced-intensity conditioning (RIC) is used in patients not eligible for conventional conditioning therapy due to poor performance status and severe toxic complications after previous chemotherapy. RIC is a well-established treatment strategy in adult patients with comorbidities. But there is no conclusive evidence to support efficacy of RIC allo-HSCT in children suffering from different malignant diseases including AML.

The aim: To compare efficacy of different intensity conditioning regimens in children with high risk (HR) AML (according to AML-BFM protocols 1998 and 2004) and to identify factors which have a prognostic significance for overall survival (OS).

Patients and methods: Retrospective analysis was performed in 192 patients (pts) with AML (median age of 10 years (0.5-18 y.o.), who received allo-HSCT at R.M. Gorbacheva Research Institute between 08/2000 and 09/2019. MAC (busulfan- or treosulfan-based) were used in 109 pts: 1^st CR – 46 pts (MRD+ n=11), 2^nd CR – 18 pts, 3^rd CR - 1 pt, relapse - 44 pts. Allo-HSCT with RIC were performed in 83 pts: 1^st CR – 32 pts (MRD+ n=13), 2^nd CR -19 pts, 3^rd CR - 4 pts, relapse -28 pts (p=0,674). RIC consisted of fludarabine (30 mg/m²/d x 5 days) + melphalan (70 mg/m²/d x 2 days) or fludarabine (30 mg/m²/d x 5 days) + busulfan (4 mg/kg/d x 2 days). Indication for RIC allo-HSCT was poor performance status (Lansky/Karnofsky score≤70%), or organ dysfunction due to previous therapy, or infectious complications at the moment of allo-HSCT. Allo-HSCT from matched related donor was performed in 30 pts (16%), from matched unrelated donor – in 98 pts (51%), haploidentical – in 64 pts (33%) and the donor distribution was not different between groups (p=0,878). Post-transplant Cy was included in GVHD prophylaxis regimens in 102 pts (53%). OS were estimated using Kaplan-Meier curves. Univariate analyses were performed using the log rank test for OS, Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model.

Results: Median follow-up was 5 years for МАС, 4.5 years for RIC. In both groups the median time to neutrophil engraftment >=0,5x10⁹/l was D+16 (range D+8-52). Engraftment was observed in 67 pts (81%) after RIC and 94 pts (86%) after MAC (p=0,231). OS after RIC allo-HSCT in the 1^st CR was 76% and after MAC – 68% (p=0,014), in 2^nd CR 50% after RIC and 54% after MAC (p=0,058), in advanced disease 14% after RIC and 16% after MAC (p=0,394). The transplant-related mortality rate was 19% after RIC and 22% after MAC (p=0,546). Risk of relapse was 28% after RIC and 26% after MAC (p=0,456). Factors influencing OS after MAC were: 1) Remission status at the moment of allo-HSCT (р=0.001); 2) Presence of aGVHD grade I-II (р=0,005); 3) Relapse or MRD+ status after allo-HSCT (р=0.012); 4) Lansky score >70% (р=0,024). Factors influencing OS after RIC were: 1) Remission status at the moment of allo-HSCT (1^st remission) (p=0,001); 2) Lansky score >70% (р=0,004).

Conclusion: The effectiveness of RIC and MAC is comparable in children with HR AML, but RIC demonstrated better results in 1^st CR. The presence of I-II grade aGVHD had positive effect in MAC. Factors influencing OS in both groups were disease status at the moment of allo-HSCT and performance status before allo-HSCT

The use of RIC can be effective in patients, especially those who have undergone allo-HSCT in the 1^st remission, while minimizing regimen-related toxicity in children who have undergone previous intensive treatment. Multicenter studies are warranted, especially for patients in the first CR, where long-term complications are of most importance.