Real World Data on the Outcomes of Richter's Transformation of Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma in the Australian Population: An Australasian Lymphoma Alliance Study
Authors: Walker Stephen K , Harrop Sean , Di Ciaccio Pietro , Lewis Katharine Louise , Boles Rachael , Tedjaseputra Aditya , Hamad Nada , Hodges Georgina , Yannakou Costas K. , Tam Constantine S. , Opat Stephen , Cheah Chan Yoon Y. , Ku Matthew 
Published: November 2021

Abstract
Background
Transformation of Chronic Lymphocytic Leukaemia (CLL) or Small Lymphocytic Lymphoma (SLL) to high-grade disease (Richter's Transformation; RT) carries a poor prognosis. Despite the advent of novel therapies, published data indicates that chemoimmunotherapy remains the standard of care for RT. This project evaluated real-world outcomes in patients with RT across eight Australian centres to validate known prognostic factors, as well as identify new predictors of survival in this cohort of patients. Our aims were also to determine if prior BTK inhibitors (BTKi), BCL 2 inhibitors (BCL2i), or escalation of treatment regimen impacted these patients' outcome.

Methods
This was a retrospective multicentre study conducted by members of the Australasian Lymphoma Alliance in 8 centres across 4 Australian states. Consecutive patients with biopsy proven Diffuse Large B-Cell Lymphoma (DLBCL) or Hodgkin Lymphoma (HL) type RT between 2010 and 2019 were identified using institutional databases. Patients' diagnoses were confirmed by review of local pathology reports. Patients' characteristics, treatment received, and outcomes were recorded and analysed. Univariate comparisons were made using Cox regression analysis. Kaplan Meier curves were used for analysis of overall survival (OS) measured from diagnosis of high-grade disease.
Results
Seventy-eight patients (55 with CLL and 23 with SLL) were included in the analysis. The majority had low Rai stage at diagnosis (stage 0 in 41% of patients, 1 in 39%, 2 in 16%, 3 in 3%, and 4 in 1%). 25% had prior treatment of low-grade disease with a BTKi and 18% with a BCL2i. At the time of low-grade diagnosis, 54/78 (69%) of patients (pts) had had mutational analysis: 24% (13/54) had a 17p deletion, 78% (17/22) were IgHv unmutated, and 33% (6/18) had a TP53 mutation. Median time to transformation from CLL diagnosis was 4.8 years (range 0-24). 42% had received 2 prior lines of treatment for CLL/SLL at the time of transformation (range 0-5). The predominant histology was DLBCL (71 pts with DLBCL; 6 pts with HL, 1 pt had HL and DLBCL concurrently). Majority of the pts had ECOG&lt;2 (0-1, 76%; 2, 23%). 50% had transformed disease in extra-nodal sites, 27% with bone marrow involvement, and 6% had CNS involvement. 15/18 pts (83%) had clonally related disease proven by IgHv testing. 71 pts (91%) received curative intent treatment, with the rest receiving palliative radiotherapy and/or steroids. 54 patients were treated with standard therapy (R-CHOP or similar), 13 pts were treated with an intensive regimen (R-HyperCVAD, OFAR, R-EPOCH14, or R-ICE), and 4 were treated with novel therapies (BTKi + PD1 combination, and BiTEs). There was no significant difference seen between the standard and intensive therapy groups in terms of treatment completion (61% in standard vs 62% in intensive, p=0.82) or CR rates (50% in standard vs 62% in intensive; p=0.80). Overall, 48/76 (64%) of patients died with a median OS of 15 months (median OS 11 months in DLBCL; median OS not reached in HL). Surviving pts had a median follow up of 33 months. There was no difference in OS between pts that received standard or intensive regimens (HR 1.49 CI 0.75-2.94). Patients with prior lines of treatment for CLL (HR 3.71; CI 1.73-7.98), elevated LDH (&gt;1.5x ULN) (HR 3.0; CI 1.6-5.8), 17p deletion (HR 2.34; CI 1.12-4.91), or bone marrow involvement by high grade disease (HR 2.99; CI 1.5-5.9) had an inferior OS. Prior low-grade treatment with a BTKi (HR 1.67; CI 0.88-3.18) or a BCL2i (HR 1.79; CI 0.92-3.45) did not impact outcome following transformation.
Conclusions
This is the largest Australian report on patient outcome following RT. Whilst prior CLL treatment was associated with worse outcome after transformation, prior BTKi or BCL2i use did not seem to have an impact on survival. Furthermore, elevated LDH &gt;1.5 ULN and bone marrow involvement with RT were also predictors of poor patient outcome, with the latter not previously described. Finally, intensive chemotherapy regimens were found not to be superior to R-CHOP chemotherapy, suggesting that RCHOP remains the treatment of choice in this population. The OS for patients with RT is poor, and research into more effective therapies is needed.
Figure 1 Figure 1.

Disclosures
Lewis: Roche: Consultancy, Honoraria; Janssen: Honoraria, Patents & Royalties: Conference attendance; Novartis: Patents & Royalties: Conference attendance; AstraZeneca: Consultancy, Honoraria. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tam: Beigene: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Loxo: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Opat: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, 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; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Sandoz: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Monash Health: Current Employment; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cheah: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Lilly: 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; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy.