A Phase 1 Trial of Targeted Immunotherapy with Daratumumab Following Myeloablative Total Body Irradiation (TBI)-Based Conditioning and Allogeneic Hematopoietic Cell Transplantation (HCT) in Children, Adolescents and Young Adults with High-Risk T-Cell Acute Lymphoblastic Leukemia and Lymphoma (T-ALL/T-LLy) (ALLO-T-DART): A Ptctc Facilitated Study

Document Type

Conference Proceeding

Publication Date

2-2025

Publication Title

Transplantation and Cellular Therapy

Abstract

Introduction: Allogeneic HCT (AlloHCT) offers curative treatment for high-risk and relapsed T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy), but post-HCT relapse remains a significant obstacle for long-term survival. CD38 is highly expressed in T-ALL/T-LLy and significant activity of the anti-CD38 antibody, daratumumab (DARA), was demonstrated in a recent clinical trial for relapsed/refractory disease (Bhatla et al., Blood 2024). We have developed a phase 1 trial (NCT04972942) to evaluate targeted immunotherapy with DARA after AlloHCT for relapsed T-ALL/T-LLy.

Objectives: The primary objective is to determine safety of targeted immunotherapy with DARA after total body irradiation (TBI)-based myeloablative conditioning and AlloHCT for children, adolescents, and young adults (CAYA) with high-risk T-ALL or T-LLy. Exploratory objectives will evaluate outcomes of receiving AlloHCT and post-HCT DARA on study and correlate those outcomes with novel biological and immunological studies, including measures of minimal residual or minimal detectable disease.

Methods: Patients ≤ 39-years, with relapsed T-ALL in second or subsequent remission or relapsed T-LLy with complete response after reinduction therapy are eligible. Participants will undergo myeloablative TBI-based conditioning and AlloHCT with best available donor. Safety of post-HCT DARA will be determined through a phase 1, time-to-event Bayesian optimal interval study design, evaluating 3 dose levels of DARA (IND 159396) in 15 subjects. If no excessive dose-limiting toxicity (DLT) is observed, an additional 15 subjects will be enrolled in a dose expansion cohort (DEC) for additional correlative studies and to guide future selection of a recommended phase 2 dose (RP2D) (Figure 1). All patients will have pre- and post-HCT correlative studies collected in blood, bone marrow, and cerebrospinal fluid, including NGS-based MRD.

Results: Three patients enrolled to date, each at dose level 1. Patient 1 completed protocol therapy and is alive in CR2 at 1 year post transplant. Patient 2 received 4 doses of DARA and was taken off protocol therapy due to diagnosis and treatment of moderate chronic GVHD. Of note, patient 2 had EBV reactivation and mixed chimerism prior to DARA prompting early taper of immune suppression that likely contributed to their chronic GVHD. Neither patient experienced an adverse reaction or definite DLT related to DARA. Patient 3 is too early to evaluate.

Conclusions: Novel strategies are needed to reduce relapse and improve survival after AlloHCT for relapsed T-ALL/T-LLy. ALLO-T-DART will (1) determine the safety and RP2D of post-HCT DARA and (2) collect data on novel biomarkers of response, MRD/MDD kinetics, and immune reconstitution after DARA treatment for relapsed T-ALL/T-LLy.

First Page

s433

Comments

Tandem Meetings of ASTCT and CIBMTR, Feb 12-15, 2025, Honolulu, HI

Helen DeVos Children's Hospital

Last Page

s434

DOI

10.1016/j.jtct.2025.01.666

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