High Karyotypic Complexity and Translocations Are Adverse Prognostic Features in Patients with Chronic Lymphocytic Leukemia without TP53 Aberrations Treated with Venetoclax-Based Time-Limited Combinations

Abstract

Background: The presence of ≥3 (complex karyotype, CKT) and specifically ≥5 (high-CKT, hCKT) chromosomal aberrations (CA) is associated with a poor prognosis in patients (pts) with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT). Studies on the prognostic impact of CKT with targeted agents are not only heterogeneous in size and methodologies but also conflicting, with reports on both negative impact (venetoclax [ven] + rituximab [RVe] and ibrutinib monotherapy) and no impact (ven + obinutuzumab [GVe], ven + ibrutinib, idelalisib + rituximab) on progression-free (PFS) and overall survival (OS). Here, we prospectively evaluate the impact of CKT in a large cohort of pts treated with ven-based time-limited combinations within the GAIA/CLL13 trial. Methods: The phase 3 GAIA/CLL13 trial compared 3 different time-limited ven-based combinations against CIT in fit, treatment-naïve pts with CLL. Pts with TP53 aberrations were excluded. Pts were randomized to CIT (FCR in pts ≤65y; BR in pts >65y), RVe, GVe, or GVe plus ibrutinib (GIVe). Chromosome banding analyses were performed following IL-2/CpG-stimulation, karyotypes were analyzed according to ISCN 2020. No CKT (nCKT) was defined as ≤2, CKT as ≥3, intermediate CKT (iCKT) as 3-4 and hCKT as ≥5 CA. Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10 000 leukocytes measured by 4-color flow cytometry. Results: Chromosome analysis was successfully performed at baseline in 895 of 926 pts. Of these, 672 (RVe: 231; GVe: 218; GIVe: 223) were in the pooled ven population (pooled ven) and 223 in the CIT arm. nCKT was present in 79.4%, 81.0%, 83.5%, and 87.9%, iCKT in 13.5%, 14.7%, 11.5%, 9.4% and hCKT in 7.2%, 4.3%, 5.0% and 2.7% of pts treated with CIT, RVe, GVe and GIVe, respectively. Male gender, del(11q), del(6q) and trisomy 12 were associated with CKT. No correlation was observed between IGHV status or CLL-IPI and CKT. With CIT, uMRD rates in peripheral blood at month 15 were lower in pts with CKT compared with nCKT (37.0% vs 57.1%; OR 0.44, p=0.016). In none of the ven arms, uMRD rates were significantly different between pts with CKT and nCKT (RVe: 52.3% vs 56.7%, GVe: 86.1% vs 86.3%, GIVe: 92.6% vs 92.3%). Across all treatment arms, pts with ≥5 CA had significantly shorter PFS than pts with <5 CA (Figure 1). With CIT, also iCKT was associated with shorter PFS (vs nCKT: HR 2.49, p=0.003), while in none of the ven arms there was a significant PFS difference between iCKT and nCKT (RVe: HR 1.35, p=0.376; GVe: HR 0.94, p=0.912; GIVe: HR 0.38, p=0.341). Pts harboring translocations (TL) (CIT: n=52 [23.4%], pooled ven: n=160 [24.1%]) had inferior PFS compared to pts without TL irrespective of the treatment arm (Figure 2). Focusing on the ven-treated population, this difference was mostly driven by unbalanced TL (vs no TL: HR 3.83, p<0.001) however balanced TL still conferred inferior PFS compared to pts without any TL (HR 1.66, p=0.035). Pts with CKT but without TL had comparable PFS to nCKT (HR 0.53, p=0.217) whereas pts with CKT and TL had significantly shorter PFS (HR 2.79, p<0.001). In pooled ven, particularly pts with TL involving 8q (n=22) or 18q (n=29) showed significantly shorter PFS (HR t(8q;x) 3.94, p<0.001; HR t(18q;x) 2.48, p=0.006), while with CIT numbers were too small for reliable conclusions (n=5 and n=6, respectively). In a multivariate analysis, CKT was identified as an independent prognostic factor for PFS with CIT, while in pooled ven, only hCKT and TL were identified as independent adverse factors for PFS. OS was shorter for CKT vs nCKT with CIT (HR 3.25, p=0.044), but not in the ven arms. At progression (PD), karyotyping data was available in 88 of 161 (54.7%) pts. With CIT, 7 of 20 (35.0%) pts with nCKT at baseline acquired CKT at PD, in the pooled ven group this fraction was substantially smaller (6/45, 13.3%). With CIT, the number of CA increased between baseline and PD (mean, 2.0 to 3.4) while it remained stable after ven (2.1 to 2.0). Conclusions: In pts lacking TP53 aberrations, hCKT (≥5 CA) but not iCKT (3-4 CA) was associated with shorter PFS following treatment with time-limited ven combinations. While this study confirms the adverse impact of CKT with CIT, it identifies hCKT as an adverse prognostic factor in the context of ven-based combination treatment in CLL. Presence of translocations was associated with inferior PFS in all treatment arms. Karyotyping at relapse shows increased genomic complexity after CIT as opposed to ven-based treatments. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal