Post-Hematopoietic Cell Transplantation Relapsed Acute Lymphoblastic Leukemia: Current Challenges and Future Directions

Abstract

Allogeneic hematopoietic cell transplantation (allo-HCT) represents an important and potentially curative treatment option for adult patients with acute lymphoblastic leukemia. Relapse continues to remain the most important factor influencing overall survival post allo-HCT. We discuss early identification, clinical manifestations, and management of relapsed disease. Routine evaluation of measurable residual disease (MRD) and change in donor chimerism play a crucial role in early detection. Pivotal clinical trials have led to FDA approval of multiple novel agents like blinatumomab and inotuzumab. Combining targeted therapy with cellular immunotherapy serves as the backbone for prolonging overall survival in these patients. Donor lymphocyte infusions have traditionally been used in relapsed disease with suboptimal outcomes. This review provides insight into use of cellular therapy in MRD positivity and decreasing donor chimerism. It also discusses various modalities of combining cellular therapy with novel agents and discussing the impact of chimeric antigen receptor T-cell therapy in the setting of post allo–HCT relapse both as consolidative therapy and as a bridge to second transplant.

Keywords:

• acute lymphoblastic leukemia
• hematopoietic cell transplantation
• relapsed disease
• measurable residual disease
• MRD
• ALL
• CART
• DLI

Summary Points

1. Relapsed disease remains the most important cause for decreased OS and RFS for patient post allo-HCT for ALL.

2. Monitoring donor chimerism and MRD at regular interval enables early detection of relapse and early interventions.

3. The CNS is the most common site of extramedullary relapse post allo-HCT. Inability for donor T-cell to exert GVL in the CNS, due to the blood–brain barrier, has been postulated to make the CNS a sanctuary for relapse.

4. Relapsed disease is managed by combining chemo and targeted therapy with cellular therapeutic intervention.

5. Blinatumomab and inotuzumab are some of the agents that should be considered when aiming to achieve CR.

6. DLI is likely more efficacious in the setting of MRD-positive disease or prophylaxis rather than in situations of overt relapse.

7. CART therapy is a novel therapy that has shown very impressive responses. However, the remissions are short-lived, necessitating further consolidative HCT.

8. The risk-versus-benefit assessment of a consolidative HCT, or a second allo-HCT, must be analyzed sooner rather than later for every patient with relapsed disease. The choice of consolidative HCT would primarily depend on patient performance, donor availability, and availability of clinical trials.

9. Multiple novel anti-leukemic agents targeting menin inhibition, CD38, and Bcl-2 and McL-1 provide new avenues for improving outcomes.

10. There is a crucial need for designing clinical trials with novel agents to this specific population to improve outcomes. Utmost effort must be made to ensure that patients relapsing post HCT are enrolled in clinical trials and are referred to high-volume centers for further management.

Disclosure

The authors report no conflicts of interest in this work.