Complex Karyotype Subtypes at Chronic Lymphocytic Leukemia Diagnosis Refine the Risk of Developing a Richter Syndrome. the Richter Syndrome Scoring System
Authors: Visentin Andrea , Rigolin Gian Matteo , Mauro Francesca Romana , Martines Annalisa , Frezzato Federica , Imbergamo Silvia , Pravato Stefano , Romano Gargarella Leila , Bardi Maria Antonella , Nanni Mauro , Piazza Francesco , Facco Monica , Foà Robin , Semenzato Gianpietro , Bonaldi Laura , Cuneo Antonio , Trentin Livio 
Published: February 2021

INTRODUCTION. Richter syndrome (RS), the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, is a rare but a life threatening complication. Complex karyotype (CK), defined by the presence of ≥3 chromosomal lesions, is a heterogeneous cytogenetic category associated with a shorter survival in CLL, but its impact on the evolution into a RS has not been investigated. Among CK cases, those with≥5 lesions (highCK) and those with major structural abnormalities [type-2 CK (CK2)] display a more aggressive clinical course. The aim of this study was to assess the impact of CK subtypes on the risk of CLL evolution into a RS.
METHODS. We performed a retrospective study in 3 Italian CLL centers. Stimulated cytogenetic with CpG+IL2 was performed in 540 patients within the first year after CLL diagnosis. CK cases with unbalanced translocations, additions, insertions, derivative or marker chromosomes were classified as type-2 CK (CK2). Instead, high-CK cases were those presenting at least 5 chromosome abnormalities. An IGHV gene sequence homology ≥98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). TP53 disruptions (TP53dis) included deletions and/or mutations. Time to Richter syndrome (TTRS) was calculated from CLL diagnosis to either histologically confirmed diffuse large B-cell lymphoma transformation or last known follow-up visit. Survival curves were compared with the log-rank test and p&lt;0.05 was considered as significant. Hazard ratio (HR) was calculated by multivariate analysis.
RESULTS. Among the 540 patients, the median age at diagnosis was 63±12 years, 61% were males, 76% were at Binet stage A, 52% were U-IGHV, 11% had TP53dis, 20% harbored a CK. According to the qualitative classification of CK subtypes, 78/107 (73%) were CK2, whereas, with regards to the number of chromosome lesions, 52/107 (49%) were classified as high-CK. High-CK was present in 63% of CK2 patients. Seventeen % of patients died and 5% developed a RS over a median follow-up of 7 years.
Overall, the rate of RS after 5 and 10 years from the diagnosis of CLL was 2.6% and 12%. We observed that patients who developed a RS were more commonly at a more advanced Binet stage at CLL diagnosis (46% vs 23%, p=0.0113) and displayed more frequently an U-IGHV status (79% vs 56%, p=0.0191), TP53 abnormalities (32% vs 10%, p=0.0043), CK2 (46% vs 13%, p&lt;0.0001) and a high-CK (39% vs 8%, p&lt;0.0001) profile, as compared to patients who did not developed RS.
By univariate and multivariate analysis, the presence of a CK (overall), of a CK2 and of a high-CK subtypes were all significantly associated with a shorter TTRS, together with U-IGHV status, TP53dis, 11q- by FISH and Binet stage B-C. Patients with a CK2 (HR=5.6 p&lt;0.0001) and/or a high-CK (HR=6.9 p&lt;0.0001) harbored the highest risk of developing a RS, with a 10-year TTRS of 38% and 41%, respectively, vs 8% of patients without a CK. Other variables associated with TTRS at univariate and multivariate analysis were Binet stage B-C, U-IGHV, 11q-, TP53 dis.
By integrating the statistically significant variables, we developed a hierarchical model based on HR values (Figure 1): 15% of patients were classified as high-CK and/or CK2, for whom the 10-year TTRS was 31% and the HR 13; 45% were U-IGHV/TP53dis/11q-/Binet B-C and showed a 10-year TTRS of 12% and the HR 3; 40% were M-IGHV without CK and TP53 wild-type, the 10-year TTRS was only 3%. This model was confirmed in multivariate analysis and internally validated (p&lt;0.0001). Moreover, our RS scoring system prove to better forecast the risk to develop RS that the hierarchical FISH score, the CLL-IPI and the Barcelona-Brno score, based both lower prediction error and Akaike index.
CONCLUSIONS. We herein identified variables associated with a higher risk of developing a RS and recapitulated them into a RS scoring system. Remarkably, patients harboring a CK subtype at CLL diagnosis have the highest risk of developing a RS and should be carefully monitored during the clinical follow-up.
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Disclosures
Visentin: Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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, Speakers Bureau. Rigolin:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro:Octopharma: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jannsen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Foà:Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trentin:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria.