Factors Affecting Post-Transplant Relapse of Acute Lymphoblastic Leukemia (ALL) in Children According on the Intensity of Conditioning

Background:

Relapse of ALL remains the major cause of transplant failure. Relapse incidence after allo-HSCT is described in 30-40% of patients. Patients with ALL receive allo-HSCT with MAC more often because after RIC more relapses are expected.

The aim: To compare the frequency of relapse after allo-HSCT with RIC vs with MAC and to analyze the factors influencing the risk of relapse depending on the intensity of conditioning regimens.

Patients and methods:

Between 12/2000 and 09/2019 at RM Gorbacheva Research Institute a total of 235 children with ALL (median age of 10 years (0,5-18), underwent allo-HSCT. MAC (busulfan- or treosulfan-based) were used in 163 pts: 1st CR - 30 pts (MRD+ n=13), 2nd CR - 58 pts, 3^rd or 4 CR - 27 pts, relapse - 48 pts. Allo-HSCT with RIC were performed in 72 pts: 1st CR - 12 pts (MRD+ n=9), 2nd CR - 29 pts, 3^rd or 4 CR - 14 pts, relapse -17 pts. 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). Matched related allo-HSCT was performed in 37 pts (16%), matched unrelated - in 128 pts (54%), haploidentical-in 70 pts (30%).

Cumulative incidence functions were used to estimate relapse incidence and NRM in a competing risk setting. Univariate analyses were performed using Grey test for cumulative incidences. Multivariate analyses were performed using the Cox proportional-hazard model.

Results:

Median follow-up was 5,4 and 4,5 years for МАС and RIC, respectively. Relapses were diagnosed in 105 pts (44%) during 1-39 months after allo-HSCT (median 7.5 months) (90% relapses were during first 18 mo), 74 pts after MAC; 31 pts after RIC (p=0,549). Relapses occurred significantly less frequent (p=0,007) in patients who had CR at the moment of allo-HSCT - 61 pts (35%) (RIC -32%; MAC -37%) compared patients who had a relapse or primary resistance 44 pts (68%) (RIC-74%; MAC - 65%). The risk of relapse after MAC is influenced by the presence of acute GVHD (p=0,007), the source of HSCs (PBSC vs BM, p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001). The risk of relapse after RIC is influenced by the presence of acute GVHD (p=0,042), age at the moment of allo-HSCT 1-10 years (p=0,032), and the status of the disease (CR vs relapse) at the moment of allo-HSCT (p=0,001).

Multivariable analysis confirmed a significant impact of disease status at the moment of allo-HSCT whit MAC (p=0,001) and with RIC (p=0,002).

Presence of aGVHD was additional factor associated with lower relapse risk in multivariate analysis in pts after MAC (p=0,005).

Patients with active disease at the moment of HSCT had higher relapse-free survival after RIC (RIC-23% vs MAC- 12%, p=0,012). Salvage patients in whom the relapse was documented after HSCT had 28% and 38% probability of long-term OS after RIC and MAC, respectively (p=0,572).

Conclusion:

Relapse incidence after allo-HSCT with MAC and with RIC is comparable. The most significant factor affecting the risk of relapse is the status of the disease at the moment of allo-HSCT.