Treatment Outcomes of Adult Patients with B-Cell Acute Lymphoblastic Leukemia Relapsed after Allogeneic Stem Cell Transplant in the Era of Novel Immunochemotherapeutic Agents

Introduction: Prognosis of adult B-cell acute lymphoblastic leukemia (B-ALL) patients who relapsed after allogeneic stem cell transplant (SCT) was described to be extremely poor in the studies in the early 2010s. Although novel immunochemotherapeutic agents, inotuzumab ozogamicin (InO) and blinatumomab (Blina) improved treatment outcomes of relapse/refractory B-ALL patients, efficacy and safety of these agents in those with post-transplant relapse remain to befully elucidated.

Methods: This retrospective study included 150 adult B-ALL patients (Philadelphia chromosome [Ph]-negative; n=95, Ph-positive; n=55), who underwent the first SCT between 2010 and 2020 in the 20 KSGCT institutions and experienced a hematological relapse. The median age at relapse after the first SCT was 43 years (18–71 years). Patients were divided into 2 groups depending on whether their relapse occurred before or after InO and Blina were approved in Japan in 2018, the pre-InO/Blina group (n=95) or the post-InO/Blina group (n=55). Efficacy and survival analyses were performed on the patients with Ph-negative B-ALL only, and safety analyses were performed on allpatients. Overall survival (OS) was defined as the interval from the date of relapse after the first SCT to the date of death. Fisher’s exact test was used to compare binary variables. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. The Cox proportional hazard model was used for multivariate analysis (MVA) for OS. Values of p<0.05 were considered to indicate statistical significance.

Results: Of the 95 patients with Ph-negative B-ALL, 37 and 58 were in the post-InO/Blina group and the pre-InO/Blina group, respectively. Patient characteristics and transplant procedures were similar between the 2 groups, excluding larger proportions of patients treated with InO and/or Blina before the first SCT in the post-InO/Blina group in comparison with the pre-InO/Blina group (35% vs. 5%, respectively; p<0.01) and undergoing the first SCT in complete remission (CR) (84% vs. 57%, respectively; p=0.02). InO and Blina were used after relapse in the post-InO/Blina group in 17 (46%) and 20 (54%), respectively. The CR rate as the best response before a second SCT or the last observation and the OS rate in the post-InO/Blina group were significantly higher than the pre-InO/Blina group (CR: 77% vs. 36%, respectively; p<0.01, OS: 51% vs. 19% at 2 years after relapse, respectively; p<0.01). MVA for OS extracted relapse time as an independent risk factor (hazard ratio=0.51; p=0.02), besides disease status at the first SCT. Of the 34 patients in the post-InO/Blina group excluding 3 only with palliative care, chemotherapy, InO, and Blina were used as the first-line salvage therapy in 14, 13, and 7, respectively. There was a significant difference in the CR rates among the 3 groups (33% vs. 100% vs. 58%, respectively; p<0.01), but not in the OS (42% vs. 58% vs. 57% at 2 years after relapse, respectively; p=0.56). MVA for OS extracted PS at relapse as an independent risk factor, but neither InO nor Blina use as the first-line salvage therapy.

Of the 150 patients in the entire cohort, 32 and 30 received InO and Blina after relapse, respectively, and 69 underwent a second SCT. Of the 32 patients treated with InO, no patient developed veno-occlusive disease (VOD) during InO treatments; however, 5 (29%) of the 17 who underwent a second SCT after InO did. Shorter duration (<2.5 months) between InO administration and a second SCT was associated with a higher risk of VOD (56% vs. 0%; p=0.03), but either age or numbers of alkylating agents included in conditioning regimens of a second SCT were not. Of the 30 patients treated with Blina, 16 (53%) and 2 (7%) developed cytokine release syndrome (CRS) of any grade and grade 3 to 4, respectively, and 4 (13%) and 1 (3%) developed immune effector cell-associated neurotoxicity syndrome of any grade and grade 3, respectively. CR at Blina initiation was associated with a lower risk of CRS (31% vs. 79%; p=0.01).

Conclusions: The prognosis of adult Ph-negative B-ALL patients relapsed after the first SCT improved in the era of novel immunochemotherapeutic agents. Although safety profiles of InOand Blina treatments appeared acceptable, it is important to ensure an enough duration between InO administration and a second SCT to reduce VOD. Further investigations are warranted regarding the appropriate use of chemotherapy, InO, and Blina in these patients.