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4242 A Phase 1 Study of CD38-Bispecific Antibody (XmAb18968) for Patients with Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
clinical trials, Research, Biological therapies, Bispecific Antibody Therapy, Clinical Research, Therapies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Guru Subramanian Guru Murthy, MBBS1, Bijal D. Shah, MD2, Adam S Duvall, MD3, Jessica T. Leonard, MD4, Talha Badar, MD5, Cecilia Y. Arana Yi, MD6, Tyce Kearl, MD7*, Arielle Baim8*, Alexandra M. Harrington, MD, MT(ASCP)8, Aniko Szabo, PhD8* and Ehab L. Atallah, MD9

1Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI
2Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
3Department of Medicine, University of Chicago, Chicago, IL
4Department of Hematology & Medical Oncology, Oregon Health and Science University, Portland, OR
5Mayo Clinic, Jacksonville, FL
6Hematology/Oncology, Mayo Clinic, Scottsdale, AZ
7Division of Hematology/Oncology, Medical College of Wisconsin, MIlwaukee, WI
8Medical College of Wisconsin, Milwaukee, WI
9Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI


Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) has remained poor. CD38 is a transmembrane glycoprotein that is highly expressed in T-ALL and is potentially targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We designed a phase I clinical trial to assess the safety and tolerability of XmAb18968 in patients with T-ALL.


We conducted a multicenter, open label, phase I dose escalation study of XmAb18968 (NCT05038644). Patients aged ≥18 years with relapsed/refractory T-ALL or T-lymphoblastic lymphoma (T-LBL), ECOG PS 0-2 and adequate organ function were eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, prior therapy with daratumumab in the last 6 months and active acute graft-versus-host disease. Dose escalation was conducted using 3+3 design, and 4 separate dose levels were studied [0.8mg, 1mg, 1.3mg, 1.5mg]. XmAb18968 was administered intravenously on days 1, 8, 15, 22 on a 28-day cycle. During cycle 1 alone, day 1 dose was fractionated and administered over 2 days to minimize the risk of significant cytokine release syndrome (CRS). Treatment was continued until progression or unacceptable toxicity. The primary objective was to determine the safety and dose limiting toxicity (DLT) and secondary objective was to determine the preliminary efficacy. Correlative studies included pharmacokinetics, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy, and direct glycopeptide analysis.


Four patients with relapsed/refractory T-ALL have been enrolled so far at dose level 1 (0.8mg) with 3 of them being evaluable for response (one patient came off study before DLT period). Median age was 62 years (34-74), all response evaluable patients had early T-precursor ALL (ETP-ALL), and one patient (25%) was previously treated with allogeneic HCT, CD7 CAR-T therapy and daratumumab. Grade 3 or higher adverse events are summarized in Table 1. CRS grades 1 was noted in 25% of patients, no grade ≥3 CRS or neurotoxicity (any grade) was seen. Of the 3 evaluable total patients, 2 patients had achieved complete response (CR) after 1 cycle of therapy (one patient had prior allogeneic HCT, CD7 CAR-T therapy and daratumumab) (Table 2). The two responders remain on treatment.


XmAb18968, a novel CD-38 bispecific antibody appears safe and is showing response at the starting dose level in T-ALL. The study is currently enrolling additional patients with T-ALL. Updated analysis with additional patients and details on correlative studies examining mechanisms of therapeutic efficacy will be reported at the main meeting.

Disclosures: Guru Murthy: Cardinal Health: Honoraria, Other: Advisory panel; Rigel: Speakers Bureau; Amgen: Consultancy; Kite: Honoraria, Other: Advisory panel; Pfizer: Honoraria, Other: Advisory Panel; BeiGene: Honoraria, Other: Advisory panel. Shah: Moffitt Cancer Center: Current Employment; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Leonard: Takeda: Consultancy; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Kite/Gilead: Consultancy; Pfizer: Consultancy. Baim: Takeda: Research Funding; Novartis: Research Funding. Atallah: Takeda: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; Abbvie: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding.

*signifies non-member of ASH