Presentations - Macon & Joan Brock Virginia Health Sciences at Old Dominion University

Impact of Pre-Conditioning Clofarabine on Engraftment and Cell Recovery in Allogeneic Transplantation Using Post-Transplant Cyclophosphamide

Poster #: 40
Session/Time: A
Author: Remy Lloyd
Mentor: Kentaro Minagawa, MD, Ph.D.
Co-Investigator(s): 1. Yoshitaka Inoue, MD, Ph.D., Penn State Cancer Institute, Milton S. Hershey Medical Center 2. Priya Ramach&rula, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 3. Curtis McInnis, DO, Penn State Cancer Institute, Milton S. Hershey Medical Center 4. Samatha Ankireddy, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 5. JosephCioccio, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 6. Kevin Rakszawski, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 7. Myles Nickolich, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 8. Natthapol Songdej, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 9. William Christopher Ehmann, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 10. Joseph Mierski, MS, Penn State Cancer Institute, Milton S. Hershey Medical Center 11. Brooke Silar, Penn State Cancer Institute, Milton S. Hershey Medical Center 12. Caitlin Vajdic, Penn State Cancer Institute, Milton S. Hershey Medical Center 13. Hiroko Shike, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 14. Kentaro Minagawa, MD, Ph.D., Penn State Cancer Institute, Milton S. Hershey Medical Center 15. Shin Mineishi, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center 16. Hong Zheng, MD, Ph.D., Penn State Cancer Institute, Milton S. Hershey Medical Center 17. Seema Naik, MD, Penn State Cancer Institute, Milton S. Hershey Medical Center
Research Type: Clinical Research

Abstract

Introduction: For relapsed or refractory AML (r/r AML), an allogeneic hematopoietic stem cell transplant (allo-HCT) is a potentially curative treatment. Yet, relapse rates are high, and non-relapse mortality is concerning due to the incidence of infectious complications and graft-versus-host-disease (GVHD). Clofarabine, a purine nucleoside antimetabolite, is a safe and effective conditioning agent that can be used for high-risk leukemia. We demonstrated Clofarabine/busulfan conditioning is an effective regimen for r/r AML. More recently, we reported its efficacy using Clofarabine as a pre-conditioning (pre-Clo) before allo-HCT for non-remission hematological malignancies, which suggests this strategy can be expanded for the application to high-risk AML such as TP53 biallelic mutated MDS/AML. Despite the intensity of this regimen, the engraftment of patients with pre-Clo was comparable to others, including lymphocyte recovery. We hypothesized that pre-Clo may give additional immunosuppression, which may benefit high-risk hematological malignancies by facilitating donor T-cell chimerism.

Methods: In this retrospective study at our institution, we included 175 peripheral blood allo-HCT patients who received PTCy as GVHD prophylaxis from April 2017 to March 2024. Using the propensity-score matching, we analyzed the effect of pre-Clo (N=19) on neutrophil/platelet/lymphocyte engraftment and donor cell chimerism achievement compared to a cohort without pre-Clo (control; N=19). Propensity matching factors included age, patient sex, disease (AML, ALL, CML/MDS), HCT Comorbidity Index, Karnofsky Performance Status, number of prior HCT, donor type, and conditioning intensity. Because pre-conditioning is intentionally reserved for those with active disease, disease status, and bone marrow blast percentage before transplant were not matched. Engraftment was defined as the first day achieving >20,000/µL platelets, >200/µL lymphocyte counts, and the first of three consecutive days achieving >500/µL neutrophils, respectively.

Results: Median age was 49 and 57 for pre-Clo and the control cohort, respectively, and AML patients comprised 63.2% of each group (pre-Clo: 15.8% ALL, 21.1% CML/MDS; control: 21.1% ALL, 15.8% CML/MDS). Overall survival at 1-year post-transplant was encouraging at 42% for pre-Clo (58% for the control cohort). Of note, these two groups vary regarding disease activity, given that most pre-Clo cases were non-CR (89.5% in pre-Clo, compared to 10.5% in the control group). As expected, there was no difference between both groups found in neutrophil (p=0.785) or lymphocyte (p=0.299) engraftment. Pre-Clo may be associated with delayed platelet engraftment (p=0.141). There were no differences in donor total or T-cell chimerism at 30, 60, or 90 days after allo-HCT. Still, when stratified with those who received HLA-matched donors (47.4% of each cohort), the pre-Clo group showed increased donor total and T-cell chimerism at day 60 after allo-HCT (total cell p=0.026; T-cell p=0.029). This effect continued to day 90 only for T-cell chimerism (total cell p=0.768; T-cell p=0.029), and may suggest enhanced immunosuppressive activity of pre-Clo, and anticipated enhanced graft-versus-leukemia effect, specifically in the context of an HLA-matched donor. These trends were not observed in patients receiving HLA-mismatched transplants because HLA-mismatched, including haploidentical donors, facilitate full donor T-cell chimerism by themselves, masking any influence pre-Clo might have. Further, post-transplant CD4+ counts appeared to trend lower in the pre-Clo group, continuing to around 6 months (limited patient data available; pre-Clo N=6 and control N=7, p=0.073), which could be concerning for a higher incidence of infectious complications in the pre-Clo group.

Conclusion: Considering these trends and the similar lymphocyte recovery in both groups, more precise analysis of lymphocyte fractions after pre-Clo should be undertaken. Additional investigation is warranted to validate the efficacy of pre-Clo followed by allo-HCT for r/r AML and other hematological malignancies by understanding how this may affect GVHD and graft-versus-leukemia on top of the anti-tumor effect of Clofarabine by itself.