Introduction The therapeutic utility of a second allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains uncertain in patients with relapsed hematological malignancies following initial allo-HSCT. Given the lack of randomized studies and conflicting reported outcomes, this retrospective evaluates the efficacy, safety, and risk factors influencing outcomes of second transplantation, predominantly haploidentical transplantation.

Methods This study retrospectively analyzed 58 patients with hematologic malignancies who underwent second allo-HSCT at Peking University Institute of Hematology between January 2018 and December 2023. Survival distributions were estimated using Kaplan-Meier analysis, with between-group comparisons by log-rank test. Cox proportional hazards models evaluated associations between survival outcomes and covariates; variables with P <0.2 in univariate analysis were included in multivariate models. Treatment-related mortality (TRM) was assessed using competing risk analysis. Statistical significance was defined as P <0.05 (two-tailed).

Results This study enrolled 58 patients who underwent second allo-HSCT, including 34 males (58.6%) and 24 females (41.4%), with a median age of 33 years (11-59 years). The median follow-up time was 19.5 months (1.3-62 months). Among the survivors, the follow-up duration was 27.2 months (19.1-62 months). The patients undergoing secondary transplantation are mainly acute myeloid leukemia (AML), and also include acute lymphoblastic leukemia (ALL), myelodysplastic syndrome (MDS) and others. Eleven patients (19.0%) had a hematopoietic cell transplantation comorbidity index (HCT-CI) ≥3. Thirty-nine cases (67.2%) accepted TBI-based regimens for the second allo-HSCT, and 19 cases (32.8%) accepted Bu-based regimens. Prior to second transplantation, 41 patients (70.7%) were in complete remission (CR)/CR with hematologic recovery(CRh)/CR with incomplete count recovery (CRi), while 17 patients (29.3%) had non-remission (NR) disease. Modified donor lymphocyte infusion (DLI) had been administered to 15.5% of patients before the second transplantation. Regarding donor selection, 93.1% of patients received grafts from alternative donors for the second transplantation, including 22 (22/54, 40.7%) with confirmed HLA loss. 20.4% (11/54) patients underwent donor switch from matched sibling donor (MDS) to haploidentical donor (HID) for their second transplantation.

Among the 58 patients undergoing second transplantation, 25 cases (43.1%) developed aGVHD, including 19 cases (19/25, 76.0%) with grade II-IV aGVHD. cGVHD was observed in 32 (55.2%) patients (moderate-severe, 18/32, 56.3%). Cytomegalovirus (CMV) activation occurred in 29 patients (50.0%). Epstein-Barr virus (EBV) activation occurred in 6 patients (10.3%).

All evaluable patients achieved successful and sustained hematopoietic reconstitution, with confirmed complete donor chimerism. One-year and 2-year overall survival (OS) rates after the second transplant were 52.1% and 49.9%, respectively. As of the data cutoff, two patients died at 1.3 and 2 months post second transplantation with persistent non-response (NR). Twelve of the remain 56 patients relapsed after the second transplantation, with a median relapse time of 5.5 (3.0-13.5) months. One-year and 2-year disease-free survival (DFS) was 46.5% and 41.7%. Both 1-year and 2-year cumulative incidence of relapse (CIR) was 21.8%. TRM following the second transplant was 5.3%, 31.9% and 36.8% at 3 months, 1 year and 2 year, respectively. In total, 28 patients have died. The causes of death are persistent NR (2/28, 7.1%), relapse (5/28, 17.9%), graft versus host disease (7/28, 25.0%), infection (11/28, 39.3%) or other (3/28, 10.7%). Age >55 and/or hematopoietic cell transplantation comorbidity index (HCT-CI≥3) and short initial remission duration (≤8 months) contributed to significantly inferior OS and higher TRM.

Conclusions Our center implemented a strategy combining donor switching and post-transplant maintenance therapy for second transplantation in hematological malignancy patients with post-transplant relapse. The approach demonstrated significant reduction in relapse risk after second transplantation while maintaining comparable OS and TRM. However, the limited sample size and inherent selection biases of retrospective study exist. Prospective studies are warranted to validate prognostic factors affecting outcomes after second transplantation.

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2025
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