Strategies to prevent relapse post HSCT / cellular therapy in B-ALL

During the ALL Hub Steering Committee meeting in November 2025, key opinion leaders met to discuss strategies to prevent relapse post hematopoietic stem cell transplantation (HSCT) or cellular therapy in B-cell acute lymphoblastic leukemia (B-ALL). The meeting opened with a presentation by Ibrahim Aldoss and featured a discussion including Charles Mullighan, José María Ribera, Sabina Chiaretti, André Baruchel, Wendy Stock, Daniel DeAngelo, and Anita Rijneveld.

During his presentation, Aldoss highlighted that despite advances in multi-agent chemotherapy and novel immunotherapies enabling an increased number of patients to undergo allogeneic (allo)-HSCT – a potentially curative approach in B-ALL – post-transplant relapse, as well as relapse following CAR T-cell therapy, remains a major cause of treatment failure.¹ He discussed several studies exploring relapse-preventive measures post‑transplantation (Figure 1), including established strategies such as tyrosine kinase (TKI) maintenance in patients with Philadelphia-chromosome positive (Ph+) ALL. He shared clinical study data for newer strategies, such as the use of blinatumomab, inotuzumab ozogamicin, or prophylactic donor-derived CAR T-cell therapy, which have shown promising initial activity in patients with B-ALL.¹ Aldoss also outlined the major considerations that influence the decision to initiate maintenance therapy after allo-HSCT or salvage therapy post-CAR T-cell therapy (Figure 2).²

Key points

• Despite advances in novel strategies for the treatment of B-ALL, post-transplant relapse remains a major cause of treatment failure.³
• Multiple factors influence relapse risk and can be used to guide maintenance therapy decisions.¹ These include underlying disease characteristics (e.g. high-risk), measurable residual disease (MRD) status at transplant, intensity of the conditioning regimen, post-HSCT complications and the characteristics of the therapeutic agent to address the underlying disease biology.^1,2
  • A study evaluating the prognostic value of next-generation sequencing-based MRD in 158 adult patients with B-ALL/T-cell ALL undergoing HSCT found that the detection of pre-transplant MRD and post-transplant MRD was associated with an increased risk of relapse.⁴
  • For patients undergoing allo-HSCT or CAR T-cell therapy, MRD assessment should be performed before allo-HSCT or CAR T-cell therapy (for patients in hematologic remission) and approximately every 2–3 months for at least the first year after allo-HSCT or CAR T-cell therapy.⁵
• There are several established and innovative strategies being explored as preventive measures post‑transplantation.¹
• Established therapies, such as TKI maintenance in patients with Philadelphia-chromosome positive (Ph+) ALL, have been shown to reduce the risk of relapse.^1,6-9
  • In a retrospective study of 473 patients with de novo Ph+ ALL who underwent allo-HSCT, 157 patients received TKI after allo-HSCT.⁶ In the post-transplant period, prophylactic TKI was a significant factor for improved leukemia-free survival (hazard ratio [HR], 0.44; p = 0.002) and overall survival (HR, 0.42; p = 0.004), and a lower relapse incidence (HR, 0.40; p = 0.01).⁶
• Several studies have shown that preemptive or prophylactic donor lymphocyte infusion (DLI) post-transplantation, guided by MRD status or loss of chimerism, may prevent overt relapse in patients with B-ALL.^1,10-13
  • To address the risk of graft-versus-host disease (GvHD) post DLI, a pilot study showed that a repetitive schedule of low-dose DLIs every 2 months for at least 36 months reduced both relapse and GvHD rates in patients with high-risk ALL (n = 11) post allo-HSCT.¹³
• Newer strategies, including the use of blinatumomab, inotuzumab ozogamicin, or prophylactic donor-derived CAR T-cell therapy, in patients with B-ALL have shown promising initial activity.^1,14-16
  • Blinatumomab: A phase II trial (NCT02807883) showed that blinatumomab maintenance therapy after allo-HSCT was feasible, with a manageable safety profile, in 21 patients with high-risk B-ALL.¹⁴
  • Inotuzumab ozogamicin: A phase I trial (NCT03104491) assessed the safety and efficacy of low-dose inotuzumab ozogamicin maintenance therapy after allo-HSCT in 18 patients with high-risk ALL.¹⁵ Low-dose inotuzumab ozogamicin maintenance therapy after allo-HSCT had a favorable safety profile, with no incidence of sinusoidal obstruction syndrome.¹⁵
  • Prophylactic donor-derived CAR T-cell therapy: A study investigated the use of prophylactic donor-derived CAR T-cell infusion after allo-HSCT in 23 patients with high-risk B-ALL.¹⁶ When compared with a contemporary cohort of 44 patients with high-risk B-ALL who did not receive post-transplant maintenance therapy, patients who received prophylactic donor-derived CAR T-cell infusion had reduced relapse rates.¹⁶
• To prevent relapse following CD19 CAR T-cell therapy in patients with B-ALL, current strategies focus on modifying pre-infusion risk factors, enhancing CAR T-cell persistence, and optimizing consolidation strategies to extend durable remissions.³
  • Intervention strategies include preemptive consolidative HSCT, re-infusion with CAR T-cells, administering T-cell antigen-presenting cells following CAR T-cell therapy, treatment with full human or humanized CAR T-cells and the development of next-generation CAR T cells to target more than one antigen.³
• In patients who relapse post CAR T-cell therapy, the relapse phenotype can inform salvage strategies.³ For example, treatment options for patients with a relapse phenotype of CD19 negative ALL include chemotherapy, CD22-targeted therapies (inotuzumab ozogamicin) or experimental therapies such as B-cell activating factor-receptor (BAFF-R) CAR.³
• Further studies are needed to determine the optimal strategies to prevent relapse post allo-HSCT and for salvage therapy following CAR T-cell therapy.¹