Correlation between Pre-Apheresis Biomarkers and Development of Severe Cytopenias and Therapy-Related Myeloid Neoplasms in Non-Hodgkin Lymphoma Patients Undergoing Chimeric Antigen Receptor T-Cell Therapy

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has shown substantial promise in treatment of hematological malignancies, including non-Hodgkin Lymphoma (NHL). A subset of patients develop prolonged cytopenia, comprising quality of life, increasing healthcare utilization, and imparting considerable morbidity and mortality. Therapy-related myeloid neoplasms (t-MN), typically seen in patients who receive DNA-damaging agents such as radiotherapy and alkylators, have also been observed in CAR-T recipients.

CAR-Hematotox score predicts the development of hematotoxicity in CAR-T recipients using laboratory parameters obtained at lymphodepleting (LD) chemotherapy, a timepoint when the patient has already gone through leukapheresis thus committed to the CAR-T process. Therefore, it is critical to identify patients at the highest risk of prolonged cytopenia and/or t-MN prior to apheresis, making it possible for a better triage of those who will proceed with CAR-T and those who might benefit from other strategies.

Methods: A retrospective analysis was conducted in NHL patients who received commercial CAR-T products between January 2018 and March 2024 at Mayo Clinic Rochester, Arizona and Florida. Clinical and laboratory data including age, hemoglobin (Hb), absolute neutrophil count (ANC), platelet (PLT), ferritin, and LDH, obtained at the initial CAR-T evaluation, typically within 1 week of leukapheresis, were used for analysis. Prior lines of therapies including autologous stem cell transplant (ASCT) were collected. Prolonged cytopenias were defined as Hb < 8 g/dL, ANC < 0.5 x 10⁹/L, and/or PLT < 50 x 10⁹/L at 3 months after CAR-T. t-MN was diagnosed per WHO 2016.

For prolonged cytopenia, the optimal cutoff points for continuous variables were determined by maximizing the sum of sensitivity and specificity. Logistic regression was then used to determine the factors associated with cytopenia at 3 months post-CAR-T. For t-MN, maximally selected log-rank statistics was used to determine the optimal cutoffs. We used competing risk analysis to determine the factors associated with development of t-MN. Death without t-MN was considered a competing risk. For both analyses, the factors with P < 0.1 in univariate analysis (UVA) were included in multivariate analysis (MVA).

Results: Among the 387 NHL patients, with a median follow-up of 11 months (95% CI 8.7 - 12.2 months), 56 (14.4%) developed (41, 10.5% with 1 cytopenia; 14, 3.6% with 2 and 1, 0.2% with cytopenia in all 3 lineages), 20 (5.2%) developed and 315 (81.2%) did not have either.

Factors associated with prolonged cytopenia: were age >, PLT ≤ 150, ferritin ≥ 600, and LDH ≥ 250. Univariate analysis identified baseline Hb, ANC, PLT and ferritin to be significantly associated with prolonged cytopenia. MVA identified Hb ≤ 11 (HR = 1.98; 95% CI 1.03-3.85, P = 0.042) and PLT ≤ (HR = 2.56; 95% CI 1.39-4.78; P = 0.003) to be associated with the development of prolonged cytopenia.

Factors associated with t-MN:were age > 65 years, Hb ≤ 9 g/dl, ANC < 3.8, PLT ≤ 80, Univariate analysis identified age, Hb, ANC, PLT, ferritin, and ≥ 3 prior lines of treatment to be significantly associated with t-MN. On MVA, age ≥ 65 (HR = 3.91; 95% CI 1.52-10.03; P = 0.004), Hb ≤ 9 (HR = 3.49; 95% CI 1.38-8.85; P = 0.008), ferritin ≥ 300 (HR = 3.06 ; 95% CI 1.08-8.67; P = 0.035) and ≥ 3 prior lines of therapy (HR = 3.25; 95% CI 1.33-7.94 ; P = 0.010) were associated with t-MN development.

Association of prolonged cytopenia with t-MN development: Prolonged cytopenia was noted in 45% of patients who developed t-MN and 15% of those who did not (P = 0.002). Cumulative incidence of t-MN at 1 year was 3.3% and the presence of prolonged cytopenia was associated with a higher 1of t-MN (HR 8.93, 95% CI 2.15 - 37.1, P = 0.003).

Conclusions: Readily accessible clinical and lab data such as blood count and inflammatory markers at the time of CAR-T evaluation were associated with the development of prolonged cytopenias. Similarly, advanced age, anemia, high ferritin levels and history of ≥3 lines of therapy were associated with the development of t-MN. These findings, when validated in larger dataset, can be used for patient counseling and therapy selection by identifying patients at high-risk of developing hematotoxicity and/or t-MN development.

Bansal:Kite Pharma: Other: Travel Support. Rosenthal:RMEI, Curio Science, Targeted Oncology, OncLiveU: Other: Educational Workshop Speaker Role. Kharfan-Dabaja:Novartis: Research Funding; Kite Pharma: Honoraria; Pharmacyclics: Research Funding; Bristol Myers Squibb: Research Funding. Ansell:Takeda: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Pfizer: Research Funding; SeaGen: Research Funding; Regeneron Pharmaceuticals, Inc.: Research Funding. Kapoor:Janssen: Membership on an entity's Board of Directors or advisory committees; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Loxo Pharmaceuticals: Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; Ichnos: Research Funding; Karyopharm: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Regeneron: Research Funding; Bristol Myers Squibb: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; CVS Caremark: Consultancy; Keosys: Consultancy. Gertz:Alexion: Honoraria; Johnson & Johnson: Other: personal fees; Astra Zeneca: Honoraria; Dava Oncology: Honoraria; Ionis/Akcea: Honoraria; Alnylym: Honoraria; Janssen: Other: personal fees; Abbvie: Other: personal fees for Data Safety Monitoring board ; Prothena: Other: personal fees; Sanofi: Other: personal fees; Medscape: Honoraria. Kumar:Oncopeptides: Other: Independent review committee participation; Merck: Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Roche: Research Funding. Dingli:Sorrento: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; Genentech: Consultancy; K36 Therapeutics: Research Funding; Alexion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Apellis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria. Villasboas Bisneto:Aptose: Research Funding; CRISPR: Research Funding; Enterome: Research Funding; Epizyme: Research Funding; Genentech: Research Funding; Regeneron: Research Funding. Kenderian:Novartis, Humanigen, MustangBio,: Patents & Royalties; Novartis, Kite/Gilead, Juno/BMS, Capstan, Humanigen, Carisma: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Novartis, Carisma, Juno/BMS, Humanigen, Luminary: Consultancy; Novartis, Kite/Gilead, Juno/BMS, Lentigen, Humanigen, Morphosys, Tolero, LeahLabs, InCyte, Viracta: Research Funding. Lin:Genentech: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Caribou: Membership on an entity's Board of Directors or advisory committees; Legend: Consultancy; NexImmune: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Janssen: Consultancy, Research Funding. Wang:Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding; Kite: Honoraria; InnoCare, AbbVie: Consultancy; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board.