Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III
Hematology Disease Topics & Pathways:
Research, Translational Research
Methods: All adult pts receiving allo HCT with MRD, MUD or haplo donor were eligible. All recipients received NMA preparative regimen which included Cy 14.5 mg/kg on days -6 / -5 and PTCy (50 mg/kg) on days +3 / +4. Pts underwent standard clinical evaluations post-transplant for up to 2 yrs. This study was IRB approved and registered under NCI clinical trial (NCT03555851). Pharmacogenomics (PG): Recipient’s germline DNA was extracted from buccal swabs obtained prior to transplant. Candidate genes genotyped using next-generation sequencing included CYP2B6, CYP3A4/5, CYP2C8/9, CYP2C19, ALDH1A1/3A1, GSTP1, GSTM1, and GSTA1. Pharmacokinetics (PK): Blood samples were obtained on day –6 and day +3 within 15 minutes after the end of Cy infusion, and 2, 4, 8, 16, 20, and 24 hours (hrs) after infusion start. Concentrations of Cy and its metabolites hydroxycyclophosphamide (HCY) carboxyethylphosphoramide mustard (CEPM) and phosphoramide mustard (PM) were analyzed using a Waters Quattro Premier triple quadrupole mass spectrometer coupled to an Acquity UPLC system. Immune Profiling (IP): Mononuclear cells were isolated and cryopreserved from haplo donor apheresis products as well as from pts prior to transplant on day -6, day 0, and post-transplant days +3, +5, +14, +30, and 3, 6 and 12 months (mos) post-transplant. Immune effector and memory subsets surveyed by flow cytometry included: CD4, CD8 T cells and regulatory T cells (Treg). Descriptive analysis of recipient PG, cyclophosphamide (and related metabolites) PK, and T cell profiling was performed.
Results: Ten pts who underwent allo HCT were evaluated. This included 6 haplo, 2 MRD, and 2 MUD recipients. All pts received NMA conditioning with fludarabine, cyclophosphamide and irradiation. Four pts developed aGVHD, 1 pt grade I (MUD), 2 pts grade II (haplo), and 1 pt grade III (haplo). Two pts died on study from relapsed disease, 1 pt was taken off study after 6 mos with relapsed disease, 7 pts are alive, 5 of whom completed 2 years of follow up. Successful PG analysis was completed in 9 pts. PK assessments were completed in 10 pts with wide interpatient variability, Table 1 summarizes the median and Cmax range for each measured Cy metabolite. Pts with aGVHD had similar mean Cy metabolite Cmax compared to pts who did not develop aGVHD (Table 1). IP profiling in 10 pts showed relative T cell subset distribution (% PBMC) first peaked at day +5 (34.4±9.9%), with mainly T effector subsets and Treg detected, and nadired at 1 mo (10.8±7.5%) with an overrepresentation of central T memory cells followed by a rebound at 2 mo (34.6±16.7%) driven by CD8 effector & effector memory cells. The 4 pts with aGVHD trended towards higher TEff:Treg ratio at day +5 (2±0.6 vs 3.9±1.5); a trend also observed in the transplanted product (20.6±2.4vs 12±1.8).
Conclusion: Our results show the feasibility of assessing PK, PG, and IP in pts receiving PTCy. Early IP of both pts and transplanted product may pinpoint immune imbalance associated with aGHVD later masked during immune reconstitution. Study of a large number of additional pts may clarify the association between early IP and Cy metabolites concentrations with immune profile and with risk of aGVHD. Candidate single nucleotide polymorphisms will be used to evaluate the association of pharmacogenetics with Cy PK, IP, and clinical outcomes. We hope these data will help guide individualized dosing of PTCy to improve effectiveness and minimize toxicity.
Disclosures: Chojecki: Incyte: Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grunwald: Daiichi Sankyo, Gamida Cell, Gilead Sciences, Incyte Corporation, Invitae, Karius, Novartis, Ono Pharmaceutical, Pfizer, Pharmacosmos, Premier, Sierra Oncology, Stemline Therapeutics: Consultancy; Medtronic: Current equity holder in private company; Genetech/Roche, Incyte Corporation, Janssen: Research Funding; AbbVie, Agios/Servier, Amgen, Astellas Pharma, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, CTI BioPharma, Daiichi Sankyo, Gamida Cell, Gilead Sciences, Incyte Corporation, Invitae, Karius, Novartis, Ono Pharmaceuticals, Pfizer, ,: Consultancy. Ghosh: TH Therapeutics: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Beigene, Incyte, Karyopharm, Roche/Genentech, Novartis, Loxo Oncology, Genmab, Adaptive Biotech, ADC Therapeutics: Consultancy; Epizyme: Speakers Bureau; AbbVie: Research Funding; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria, Research Funding, Speakers Bureau; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie: Research Funding; Gilead, AstraZeneca, Bristol Myers Squibb, Phamacyclics, Janssen, Epizyme: Speakers Bureau; Janssen/Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte/Morphosys: Consultancy, Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Loxo/Lilly: Consultancy, Honoraria.
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