S106 HIGH EFFICACY OF VENETOCLAX PLUS OBINUTUZUMAB IN PATIENTS WITH COMPLEX KARYOTYPE (CKT) AND CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): A PROSPECTIVE ANALYSIS FROM THE CLL14 TRIAL
Authors: Al‐Sawaf O. , Lilienweiss E. , Bahlo J. , Robrecht S. , Fink A.‐M. , Patz M. , Tandon M. , Humphrey K. , Jiang Y. , Schary W.L. , Porro Lurà M. , Ritgen M. , Tasch E. , Stilgenbauer S. , Eichhorst B. , Fischer K. , Hallek M. , Kreuzer K.‐A. 
Published: June 2019

Background:

CKT, defined as presence of ≥3 chromosomal aberrations, is associated with poor prognosis in CLL. Depending on age and prior therapy exposure, 10–30% of CLL patients (pts) exhibit CKT. In the CLL14 trial, treatment‐naïve, elderly, unfit CLL pts were randomized 1:1 to receive chlorambucil plus obinutuzumab (ClbG, n = 216) or venetoclax plus obinutuzumab (VenG, n = 216) for 12 cycles. After median follow‐up of 29 months, longer progression‐free survival (PFS), and higher overall response rate (ORR) and rate of minimal residual disease (MRD) negativity were seen with VenG vs ClbG.

Here, we present for the first time, data of a prospective evaluation of CKT in pts treated with a fixed‐duration, chemotherapy‐free regimen of VenG.

Aims:

To prospectively evaluate prevalence of CKT in a homogenously treated population of treatment‐naïve, elderly, unfit CLL pts, to investigate the prognostic role of CKT, and to compare it with established risk factors, as well as to evaluate the influence of CKT on a standard (ClbG) and experimental (VenG) therapy.

Methods:

Metaphase spreads were produced after IL‐2/CpG‐stimulation and analyzed according to ISCN 2013. ORR, PFS, overall survival (OS) and MRD rates were evaluated according to the presence of CKT alone and in combination with TP53 aberrations. PFS and OS were estimated using the Kaplan–Meier method, calculated from randomization. Survival times were compared by non‐stratified log‐rank tests. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression modelling.

Results:

Chromosome analysis was successfully performed in 397/432 (92%) randomized pts. CKT and non‐CKT (NCKT) were found in 34 (17%) and 166 (83%) VenG pts, respectively, and 30 (15%) and 167 (85%) ClbG pts, respectively. Del(17p)/TP53mut was detected in 11/34 (33%) VenG CKT pts and in 9/29 (31%) ClbG CKT pts. Most pts with CKT were graded as high or very high risk according to the CLL‐International Prognostic Index (CLL‐IPI; 79% and 82%, respectively). In the VenG arm, ORR was 82% in CKT and 87% in NCKT pts; the MRD negativity rate 3 months (mo) after treatment completion did not differ between groups in peripheral blood (PB; 79% vs 77%, respectively) and bone marrow (BM; 59% and 58%, respectively). No difference in PFS or OS was observed between CKT and NCKT pts (median not reached [NR]; HR 1.909 [95% CI 0.806–4.520] and HR 1.511 [95% CI 0.496–4.600], respectively; Figure 1). For ClbG, ORR was 50% in CKT and 78% in NCKT pts; the MRD negativity rate was lower in CKT vs NCKT pts, both in PB (20% vs 40%, respectively) and BM (0% vs 22%, respectively). Median PFS was 19 mo in ClbG CKT pts and NR in NCKT pts (HR 2.790 [95% CI 1.631–4.772], p < 0.001). Likewise, OS was significantly shorter in CKT vs NCKT pts (median NR, HR 3.736 [95% CI 1.357–10.287], p = 0.006).

In CKT pts, presence of del(17p)/TP53mut did not significantly alter PFS compared with pts without del(17p)/TP53mut in the VenG (HR 1.419 [95% CI 0.317–6.353]) or ClbG groups (HR 2.103 [95% CI 0.795–5.567]).

Summary/Conclusion:

CKT can be frequently observed in older, treatment‐naïve CLL pts. While CKT correlates well with CLL‐IPI high/very high risk, 2/3 of these pts do not show TP53 aberrations. Presence of CKT in pts treated with ClbG is associated with shorter PFS and OS, including pts without TP53 aberrations. In contrast, VenG is able to overcome the adverse risk associated with CKT. These findings support the clinical importance of chromosome analysis before choosing frontline therapy, and underline the particular value of VenG in CLL CKT pts.

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