Type: Oral
Session: 626. Aggressive Lymphomas: Clinical and Epidemiological: New Prognostic Tools and Treatment Outcomes in Diffuse Large B Cell Lymphoma
Hematology Disease Topics & Pathways:
Research, Lymphomas, Non-Hodgkin lymphoma, Clinical Research, B Cell lymphoma, Diseases, Real-world evidence, Lymphoid Malignancies
Specific cancer therapy exposure can promote expansion of clonal haematopoiesis (CH) in a gene-dependent manner, contributing to myeloid neoplasia post cytotoxic therapy (MN-pCT). Longer term follow-up for chimeric antigen receptor-T cell therapy (CAR-T) has revealed that MN-pCT following CAR-T is relatively common (2-year cumulative incidence of 5-10%), with short latency (<12 months) and is associated with poor survival. This finding warrants specific recognition and surveillance considering the rapid adoption of CAR-T in frontline treatment setting. The study aims to (1) characterize the baseline frequency and natural history of CH variants (vars) detected prior to CAR-T and (2) investigate the relationship between baseline CH and risk of MN-pCT as well as late cytopenia.
Methods
Patients (pts) with large B cell lymphoma (LBCL) treated with CAR-T between April 2019 and December 2023 at Peter MacCallum Cancer Centre and Royal Melbourne Hospital were included. Genomic DNA isolated from blood and/or bone marrow from all patients prior to CAR-T cell infusion were analysed by targeted next-generation sequencing covering the coding regions and flanking splice sites of 80 commonly mutated genes in hematological cancers. VAF cut-off was 0.5%.
Results
In this cohort, 173 pts received CAR-T therapy (63% Axicabtagene ciloleucel, 37% Tisagenlecleucel) for relapsed refractory LBCL. Median pt age was 64 years (range: 22-82, 44% 65 years), 61% were male. Median lines of prior therapy were 2 (range: 1-6) and 32% had an autologous hematopoietic stem cell transplant. At baseline, prior to CAR-T infusion, 91 (66%) of 138 pts with available samples had vars identified. Fifty-nine pts (43%) had CH according to the WHO definition (VAF>=2%). Vars involving DNMT3A, TET2 or ASXL1 (DTA) were found in 54% pts and 49% had vars involving the DNA damage repair (DDR) pathway, such as TP53 or PPM1D. The commonest CH vars at baseline were DNMT3A (49 pts, 54%), TP53 (24 pts, 26%), PPM1D (24 pts, 26%), TET2 (13 pts, 14%) and ASXL1 (7 pts, 8%). Of the total 176 variants, almost half (48%, n=84) were detected at VAF<2%, followed by 35% (n=62) detected between VAF 2-10% and 17% (n=30) with VAF>10%. The median number of vars per pt was 1 (range 1-6), with 1 var detected in 57%, 2 vars in 29% and 3+ vars in 14%. Among pts with TP53 vars, 2 or more TP53 vars were found in 17%.
With a median follow-up of 19.9 months (range: 0.6-62.2) by the cut-off date (31-MAY-2024), 10 (6%) pts have so far developed MN-pCT (5 AML, 5 MDS). The cumulative incidence of MN-pCT was 2% at 1 year, 3% at 2 years and 11% at 3 years, with death from LBCL as a competing risk. Median latency to development of MN-pCT from CAR-T infusion was 24.7 months (range: 3.7-40.7). At MN-pCT, 90% (n=9) had DDR mutations (7 TP53, 1 PPM1D, 1 TP53 & PPM1D), and 60% (n=6) pts had complex karyotype involving del(5q), monosomy 7 and del(17p). 75% DDR mutations detected at time of MN-pCT had the same var identified in tissue prior to CAR-T infusion. For patients with TP53 var detected prior to CAR-T infusion, there is a trend towards increased risk for developing MN-pCT (OR 3.2, 95% CI 0.9-11.3, p=0.07). Overall survival after MN-pCT was poor (median OS of 8.2 months; range 1.2-10.9). Late cytopenias, defined as Gr 3 or higher cytopenias at >90 days, were observed in 18% patients with CH prior to CAR-T (n=16; 6 neutropenia, 10 thrombocytopenia). Presence of DDR CH prior to CAR-T was associated with late thrombocytopenia (OR 3.9, 95% CI 1.1-13.5, p=0.04) based on logistic regression. Serial samples were available from 6 pts with MN-pCT (3 AML, 3 MDS). One patient had baseline TP53 Y220C with VAF 4.2% prior to CAR-T, which expanded to 14.8% at Month 1 post CAR-T and subsequently developed loss of heterozygosity with VAF 90.2% at time of AML pCT 2 years after CAR-T infusion.
Conclusion
Incidental CH var involving the DDR pathway is a frequent finding prior to CAR-T infusion (49%). Baseline DDR var is associated with MN-pCT and late thrombocytopenia. There is an increasing risk of MN-pCT between the 2nd and 3rd year following CAR-T infusion. These findings support consideration of a molecularly-informed risk management plan in patients undergoing CAR-T therapy.
Disclosures: Tiong: Pfizer: Speakers Bureau; Jazz: Honoraria; Novartis: Speakers Bureau. Dowling: Novartis: Consultancy; Kite/Gilead: Consultancy; Abbvie: Patents & Royalties. Scott: Kite/Gilead: Honoraria, Other: Travel funding. O'Leary: Kite/Gilead: Honoraria. van der Linde: Kite: Honoraria. Harrison: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genetech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Haematologix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eusa: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bajel: Glaxo-Smith-Kline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wei: Servier Pharmaceuticals LLC, Shoreline Biosciences: Consultancy; AbbVie Inc, Amgen Inc, Astex Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Janssen Biotech Inc, Novartis, Servier Pharmaceuticals LLC, Syndax Pharmaceuticals: Research Funding; AbbVie Inc, Astellas, Bristol Myers Squibb, Novartis, Servier Pharmaceuticals LLC: Speakers Bureau; AbbVie Inc, Agios Pharmaceuticals Inc, Amgen Inc, Astellas, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Gilead Sciences Inc, Janssen Biotech Inc, MacroGenics Inc, Novartis, Pfizer Inc, Roche Laboratories Inc, Servier Pharmaceuticals LLC, Shoreli: Membership on an entity's Board of Directors or advisory committees.