Hodgkin Lymphoma Transformation in Patients Who Received No Prior Chemotherapy for CLL/SLL: Outcomes from a Multicenter Retrospective Study in the Modern Era of Therapy

Introduction:

Richter transformation is the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma, in patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Transformation into Hodgkin lymphoma (HT) is a rare event and outcomes in pts with this complication in the current CLL/SLL therapeutic era of small molecule inhibitors (SMI; e.g., Bruton tyrosine kinase inhibitors [BTKi] and BCL2 inhibitors [BCL2i]) are unknown.

Methods:

We conducted a retrospective study of pts from 12 academic centers. Pts with HT who had not previously received chemotherapy for CLL/SLL-directed treatment (tx) were included. Pt, disease, and tx characteristics were collected. HT was categorized into 3 groups: “Concurrent HT,” defined as HT and CLL/SLL diagnosed simultaneously (within 3 months); “HT without prior CLL/SLL tx,” defined as HT and CLL/SLL diagnosed >3 months apart with the CLL/SLL never treated; and “HT with prior non-chemotherapy tx for CLL/SLL” defined as having received non-chemotherapy CLL/SLL-directed tx prior to the diagnosis (dx) of HT. Overall survival (OS) was measured from HT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS.

Results:

Within a total cohort of 402 pts with Richter transformation (all histologies) without prior chemotherapy, 41 pts with HT (10%) were identified: 12 with concurrent HT, 10 with HT without prior CLL/SLL tx, and 19 with HT with prior non-chemotherapy tx for CLL/SLL. The median age at CLL/SLL dx was 62 years (range 31-96 years) and 73% were male. At CLL/SLL dx, 67% (14/21 evaluated) had unmutated IGHV, and 24% (8/34 evaluated) had TP53 disruption (del(17p) and/or TP53 mutation).

The median age at HT dx was 65 years (range 31-96 years) among all pts. At HT dx, there was no significant difference in highest SUV on PET (median 12.3, range 3-31.1), lactate dehydrogenase (LDH) level (median 242 U/L, range 112-859 U/L), or lymph node longest diameter (median 4.6 cm, range 1.6-25 cm) among the 3 subgroups.

The median time from CLL/SLL dx to HT dx was 5.4 years (range 0.3-16.5 years) in pts with HT without prior CLL/SLL tx and 4.2 years (range 0.5-17.3 years) in pts with HT with prior non-chemotherapy tx for CLL/SLL. The median number of prior non-chemotherapy CLL/SLL-directed tx was 1 (range 1-6) and included BTKi only (n=17) and BTKi and BCL2i sequentially (n=2); no patient had received only prior BCL2i. Among the 19 pts with HT with prior non-chemotherapy tx for CLL/SLL, 18 pts were on active tx at time of dx (17 BTKi, 1 BCL2i).

Initial HT management included: doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; n=16), brentuximab vedotin (BV)-AVD (n=10), radiation only (n=2), other systemic tx (n=11), and supportive cares / hospice (n=2). All but 1 of the 11 other systemic tx were various HL tx regimens. Across all pts with available data (n=32), the overall response rate to 1st line HT tx was 78% (69% complete response rate); 13% had progressive disease and 9% (n=3; all with concurrent HT) died within 6 months without formal response assessment. A total of 11 pts received at least 1 additional line of therapy for HT, which included BV (n=4), an immune checkpoint inhibitor (n=1), or both (n=6) at any point beyond 1^st line HT tx.

Median follow-up from HT dx was 32.8 months (range 2.4-253.8 months). The 36-month OS for the entire cohort was 75% (95% CI: 55-87%). The 36-month OS estimates by subgroups were: 62% (95% CI: 26-84%) in pts with concurrent HT, 100% in pts with HT without prior CLL/SLL tx (no events by 36 months), and 67% (95% CI: 33-87%) in pts with HT with prior non-chemotherapy tx for CLL/SLL.

Exploratory univariable analysis identified TP53 disruption at CLL dx (HR 12.36; 95% CI: 2.55-59.84) and lymph node longest diameter (HR 1.32 per 1 cm increase; 95% CI: 1.12-1.55) and LDH 2-fold increase (HR 3.97; 95% CI 1.24-12.68) at HT dx as prognostic for worse OS. HT subgroup was not prognostic.

Conclusions:

This is the largest report of outcomes in pts with CLL/SLL who develop HT following SMI tx without any prior chemotherapy, representing a contemporary cohort. Prior CLL/SLL tx status was not associated with OS; however, cautious interpretation is required given the sample size. Our findings support the use of appropriate HL-directed treatment in the setting of HT; however, OS estimates remain worse than would be expected in an older adult de novo HL cohort (Cheng Blood Adv 2022).

Allan:ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy; Janssen: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Research Funding; Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Bhat:AstraZeneca: Consultancy, Research Funding. Bond:Incyte: Research Funding; BMS: Research Funding; Kite/Gilead: Research Funding; GenMab: Research Funding; ADC Therapeutics: Consultancy; AstraZeneca: Research Funding; Nurix Therapeutics: Consultancy, Research Funding; Accutar: Research Funding; Novartis: Consultancy, Research Funding. Brander:BeiGene: Consultancy, Other: site PI clinical trial (grant paid to institution); Catapult: Other: site PI clinical trial (grant paid to institution); DTRM: Other: site PI clinical trial (grant paid to institution); Genentech: Consultancy, Other: site PI clinical trial (grant paid to institution); Juno/Celegene/BMS: Other: site PI clinical trial (grant paid to institution); NeWave: Other: site PI clinical trial (grant paid to institution); Nurix: Other: site PI clinical trial (grant paid to institution); Pharmacyclics: Consultancy, Other: site PI clinical trial (grant paid to institution); TG therapeutics: Other: site PI clinical trial (grant paid to institution); BMS: Other; 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). Chavez:Janssen: Honoraria; Lilly: Honoraria, Speakers Bureau; AstraZeneca: Consultancy; Cellectis: Consultancy; GenMab: Consultancy, Research Funding; Abbvie: Consultancy; Allogene: Consultancy; Kite, a Gilead Company: Consultancy; Novartis: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Merck: Research Funding. Chong:AstraZeneca: Consultancy, Research Funding; Nurix: Research Funding; Genentech/Roche: Research Funding; CARGO: Research Funding; AbbVie: Research Funding; Beigene: Consultancy; Genmab: Research Funding. Danilov:Cyclacel: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; ADCT: Consultancy; MEI Pharma: Research Funding; Takeda: Research Funding; Bayer: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Incyte: Consultancy; MorphoSys: Consultancy; Nurix: Consultancy, Research Funding; Genentech: Consultancy; BeiGene: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; GenMab: Consultancy, Research Funding; Janssen: Consultancy. Davids:Ascentage Pharma: Consultancy, Research Funding; Adaptive Biosciences: Consultancy; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Genmab: Consultancy; Merck: Consultancy; Surface Technology: Research Funding; BMS: Consultancy; MEI Pharma: Research Funding; Novartis: Research Funding; Janssen: Consultancy; AbbVie: Consultancy, Research Funding; Eli Lilly: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding. Matasar:Genentech: Consultancy, Honoraria, Research Funding; BMS/Celgene: Honoraria; Epizyme: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; IMV Therapeutics: Honoraria; Regeneron Pharmaceuticals, Inc.: Honoraria; GM Biosciences: Consultancy, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Takeda: Honoraria; AstraZeneca: Honoraria; ADC Therapeutics: Honoraria; Immunovaccine Technologies: Research Funding; Allogene: Membership on an entity's Board of Directors or advisory committees; Merck: Current equity holder in publicly-traded company; Kite: Honoraria; Johnson & Johnson: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Parikh:Merck: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MingSight: Consultancy; Amgen: Consultancy; Kite: Consultancy; Pharmacyclics: Consultancy; Novalgen Limited: Consultancy; Genentech: Consultancy, Research Funding; BeiGene: Consultancy; Janssen: Consultancy, Research Funding; AbbVie: Consultancy. Rogers:Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees; 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. Shouse:Abbvie: Consultancy; Astra Zeneca: Honoraria; Beigene, Inc: Consultancy, Honoraria, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Stephens:AstraZeneca, Beigene, Novartis: Research Funding; Abbvie, AstraZeneca, Beigene, BMS, Celegene, Eli Lilly, Genentech, Janssen, Pharmacyclics: 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:AbbVie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Schrodinger: Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy; Loxo Lilly: Consultancy; Merck: Consultancy; Janssen: Research Funding; Morphosys: Research Funding; Newave: Consultancy; Genentech, Inc.: Consultancy. Kittai:AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Eli-Lilly: Consultancy; BMS: Consultancy; Abbvie: Consultancy; BeiGene: Consultancy, Research Funding, Speakers Bureau.