A Multi-Center Retrospective Study on Complex Karyotype in Patients with Richter Transformation Who Received No Chemoimmunotherapy for Their CLL

Introduction:

Complex karyotype (CK, ≥3 chromosome (chr) abnormalities (abn)) is an important adverse prognostic indicator in chronic lymphocytic leukemia (CLL). CK at diagnosis (dx) of CLL, particularly with major structural chr abn (i.e. unbalanced translocation, add, marker, ring chr), called type-2 CK (CK2), has been associated with an increased risk of Richter transformation (RT) (Visentin Haematologica 2022). RT is defined as development of aggressive lymphoma, most often large B-cell lymphoma, in the setting of CLL. In patients (pts) with relapsed/refractory CLL treated with ibrutinib, CK as a continuous variable and the presence of polyploidy were independent predictors for RT. CK is a common finding at the time of RT, and high-CK (≥5) has been associated with short survival in RT, although previous studies predominantly included pts with prior chemoimmunotherapy (CIT) administration for their CLL. The prognostic significance of CK in pts with RT whose prior CLL-directed therapies include only non-CIT, as is the current standard of care for CLL, has not been evaluated.

Methods:

We conducted a multicenter, retrospective analysis of pts from 14 academic centers. Pts with RT diagnosed between 6/2011 to 6/2023, who had CLL-directed treatment that did not include prior CIT, with stimulated karyotype data available, were included. Pts who did not receive treatment for their CLL prior to developing RT were not included. Baseline pt, disease, and cytogenetics data were collected via chart review at time of CLL diagnosis and at the development of RT. Karyotype abn up to 20 were counted on both CLL tissue (peripheral blood or bone marrow) and RT tissue using IWGMC guidelines (Chun Leuk Res 2010). CK was categorized as CK1 (balanced abn, deletion, aneusomies) or CK2. Polyploidy was defined as ≥58 chrs. Karyotype was considered evolved if one or more chr abn were seen in a follow-up sample of CLL tissue that were not seen at CLL dx.TP53 disruption was defined as presence of del(17p) or TP53 mutation. Overall survival (OS) was measured from RT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS.

Results:

A total of 64 eligible pts were identified. Median age at RT dx was 65 years (range 40-89) and 71.9% of pts were male. Of those evaluated (n=49), 79.6% had unmutated IGVH. Median number of therapies for CLL prior to RT was 1 (range 1-5) and included BTK inhibitor (n=37), BCL2 inhibitor (n=3), both (n=18), or other non-CIT treatment (n=6).

At CLL diagnosis, 54.7% of pts had a CK, and the median number of chr abn was 3 (range 0-20). Of those with CK, 96.9% had a CK2, and 6.3% had a polyploid subclone. TP53 disruption was found in 46% of pts.

At time of RT, chr analysis of CLL tissue was available for 38 pts and showed 78.9% had a CK, and the median number of chr abn was 8 (range 0-20). Polyploidy was found in 29.6%. TP53 disruption (46 pts evaluated) was found in 52.2%. Karyotype evolution from dx (35 pts evaluated) occurred in 74.3% of pts.

In RT tissue, of those evaluated (n=29), 96.6% were clonally related to the preceding CLL. MYC translocation (45 pts evaluated) occurred in 17.8%. CK (20 pts evaluated) was found in 70%, with a median number of chr abn of 8 (range 0-20). Of those with CK, 33.3% had a polyploid subclone. With a median follow-up of 17.8 months (range 2.1-83.0) there were 42 deaths, with a median OS of 14.3 months (range 6.9-29.1).

For this subset of patients with karyotype data available who would go on to develop RT, an exploratory univariable analysis for OS from RT found that increasing number of chr abn as a continuous variable at CLL dx was associated with worse OS (HR 1.10, 95% CI 1.02-1.19, p=0.01). Similarly, at RT, increasing number of chr abn in CLL tissue (HR 1.09, 95% CI 1.02-1.16, p=0.01) and in RT tissue (HR 1.09, 95% CI 1.01-1.18, p=0.03) was also prognostic of survival. Karyotype evolution in CLL tissue at RT (HR 3.02, 95% CI 1.02-8.94, p=0.05) was borderline significant for worse OS.

Conclusions:

Our multi-center study identified increasing number of chr abn at CLL diagnosis and at time of RT, and clonal evolution in the CLL tissue, are associated with worse OS in pts with RT whose CLL was treated without CIT. Limitations include incomplete cytogenetics data across the cohort and potential variability across institutions in cytogenetics laboratory practices. This provides further evidence for the clinical utility of chr analysis in the modern era of CLL therapy.

Allan:TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Research Funding; Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau. Bhat:AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy; Aptitude Health: Honoraria. Bond:Nurix Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; GenMab: Research Funding; Accutar: Research Funding; ADC Therapeutics: Consultancy; Novartis: Consultancy, Research Funding; Incyte: Research Funding; Kite/Gilead: Research Funding. Brander:BMS: Other; TG therapeutics: Other: site PI clinical trial (grant paid to institution); Pharmacyclics: Consultancy, Other: site PI clinical trial (grant paid to institution); Nurix: Other: site PI clinical trial (grant paid to institution); NeWave: Other: site PI clinical trial (grant paid to institution); Juno/Celegene/BMS: Other: site PI clinical trial (grant paid to institution); Genentech: Consultancy, Other: site PI clinical trial (grant paid to institution); DTRM: Other: site PI clinical trial (grant paid to institution); Catapult: Other: site PI clinical trial (grant paid to institution); BeiGene: Consultancy, Other: site PI clinical trial (grant paid to institution); AstraZeneca/Acereta: Other: site PI clinical trial (grant paid to institution); ArQule/Merck: Other: site PI clinical trial (grant paid to institution); AbbVie: Consultancy, Other: site PI clinical trial (grant paid to institution). Byrd:Vincerx Pharma, Eilean Therapeutics, and Kurome Therapeutics: Current equity holder in private company; Abbvie, AstraZeneca, and Syndax: Consultancy. Chavez:ADC Therapeutics: Consultancy; Cellectis: Consultancy; GenMab: Consultancy, Research Funding; Abbvie: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Merck: Research Funding; Janssen: Honoraria; Lilly: Honoraria, Speakers Bureau; Allogene: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Chong:AstraZeneca: Consultancy, Research Funding; CARGO: Research Funding; Genentech/Roche: Research Funding; AbbVie: Research Funding; Nurix: Research Funding; Beigene: Consultancy; Genmab: Research Funding. Danilov:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; BeiGene: Consultancy; Genentech: Consultancy; Nurix: Consultancy, Research Funding; MorphoSys: Consultancy; Incyte: Consultancy; TG Therapeutics: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Takeda: Research Funding; MEI Pharma: Research Funding; ADCT: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; Cyclacel: Research Funding; GenMab: Consultancy, Research Funding; Janssen: Consultancy. Dowling:Novartis: Consultancy; Abbvie: Patents & Royalties; Kite/Gilead: Consultancy. Islam:Disc Medicine: Consultancy. Matasar:Genmab: Membership on an entity's Board of Directors or advisory committees; GM Biosciences: Consultancy, Research Funding; Merck: Current equity holder in publicly-traded company; Genentech: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Immunovaccine Technologies: Research Funding; ADC Therapeutics: Honoraria; AstraZeneca: Honoraria; BMS/Celgene: Honoraria; Kite: Honoraria; Epizyme: Honoraria; IMV Therapeutics: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria. Parikh:BeiGene: Consultancy; AbbVie: Consultancy; Novalgen Limited: Consultancy; Pharmacyclics: Consultancy; Kite: Consultancy; Amgen: Consultancy; Merck: Consultancy, Research Funding; MingSight: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Rhodes:Johnson and Johnson: Consultancy; Acerta: Research Funding; Genentech: Consultancy; Epizyme: Consultancy; VelosBio: Research Funding; Oncternal Therapeutics: Research Funding; Verastem: Consultancy; TG Therapeutics: Consultancy; Seagen: Consultancy; ADC Therapeutics: Consultancy; Beigene: Consultancy; AbbVie: Consultancy, Research Funding; Loxo Oncology: Research Funding; Janssen: Research Funding; MorphoSys: Consultancy; Pharmacyclics: Consultancy, Research Funding. Roeker:Ascentage: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; AbbVie: Consultancy, Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; Aptose Biosciences: Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Dava Oncology: Honoraria, Speakers Bureau; Dren Bio: Research Funding; Genentech: Research Funding; Janssen: Consultancy; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; Medscape: Honoraria, Speakers Bureau; PeerView: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy; Qilu Puget Sound Biotherapeutics: Research Funding; Curio: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy. Rogers:AstraZeneca Pharmaceuticals LP.: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc, BeiGene Ltd, Genentech, a member of the Roche Group, Janssen Biotech Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company, Pharmacyclics LLC, an AbbVie Company: Consultancy; AbbVie Inc, Genentech, a member of the Roche Group, Novartis: Research Funding; Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees. Skarbnik:Celgene: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; SeaGen: Consultancy, Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau; Acerta Pharma: Research Funding; Kite: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Lilly: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Speakers Bureau; Verastem: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau. Scott:Kite/Gilead: Honoraria, Other: Travel funding. Shadman:BMS (spouse): Current Employment; Abbvie, Genentech, AstraZeneca, Janssen, Beigene, Bristol Myers Squibb, Morphosys/Incyte, Kite Pharma, Eli Lilly, Mustang Bio, Fate therapeutics, Nurix, Merck: Consultancy; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Mustang Bio, Genentech, AbbVie, Beigene, AstraZeneca, Genmab, Morphosys/Incyte, Vincerx: Research Funding. Shouse:Beigene, Inc: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy; Astra Zeneca: Honoraria; Kite Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Stephens:AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: Consultancy. Thompson:Clinical Care Options: Honoraria; Nurix Therapeutics: Other: Reimbursed travel, Research Funding; Genentech: Research Funding; Mashup Media LLC: Honoraria, Other: Reimbursed Travel; Dava Oncology: Honoraria, Other: Reimbursed travel; BeiGene: Consultancy, Research Funding; Genmab: Other: Reimbursed travel, Research Funding; Peerview Institute for Medical Education: Honoraria; AbbVie: Consultancy, Research Funding; Pharmacyclics/Janssen Pharmaceuticals: Consultancy; Loxo Oncology at Lilly: Consultancy; AstraZeneca: Consultancy, Research Funding. Thompson:Abbvie: Consultancy, Honoraria; Adaptive biotechnologies: Honoraria, Research Funding; Ascentage: Consultancy, Honoraria; AstraZeneca: Honoraria; Beigene: Consultancy, Honoraria; Eli Lilly and Company: Consultancy, Honoraria; Genentech: Honoraria; Janssen: Consultancy, Honoraria; Merck: Honoraria; Roche: Consultancy. Wang:Kite: Honoraria; Eli Lilly, LOXO Oncology, TG Therapeutics, Incyte, InnoCare, Kite, Jansen, BeiGene, AstraZeneca, Genmab, AbbVie: Other: Advisory Board; InnoCare, AbbVie: Consultancy; Incyte, InnoCare, LOXO Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck: Research Funding. Woyach:Merck: Consultancy; AbbVie: Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy; Morphosys: Research Funding; Genentech, Inc.: Consultancy; Janssen: Research Funding; Newave: Consultancy; Loxo Lilly: Consultancy; Pharmacyclics: Consultancy, Research Funding; Schrodinger: Research Funding. Kittai:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Eli-Lilly: Consultancy; BMS: Consultancy; BeiGene: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy.