S149 FIXED‐DURATION VENETOCLAX PLUS OBINUTUZUMAB IMPROVES PROGRESSION‐FREE SURVIVAL AND MINIMAL RESIDUAL DISEASE NEGATIVITY IN PATIENTS WITH PREVIOUSLY UNTREATED CLL AND COMORBIDITIES
Authors: Fischer K. , Al‐Sawaf O. , Bahlo J. , Fink A.‐M. , Tandon M. , Dixon M. , Robrecht S. , Warburton S. , Humphrey K. , Samoylova O. , Liberati A.M. , Pinilla‐Ibarz J. , Opat S. , Sivcheva L. , Le DÛ K. , Maria Fogliatto L. , Utoft Niemann C. , Weinkove R. , Robinson S. , Kipps T.J. , Boettcher S. , Tausch E. , Schary W.L. , Eichhorst B. , Wendtner C.‐M. , Langerak A.W. , Kreuzer K.‐A. , Goede V. , Stilgenbauer S. , Mobasher M. , Ritgen M. , Hallek M. 
Published: June 2019

Background:

The multinational, open‐label, phase 3 CLL14 trial (NCT02242942) compared fixed‐duration targeted venetoclax plus obinutuzumab (VenG) treatment with chlorambucil‐obinutuzumab (ClbG) treatment in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.

Aims:

We present endpoint analyses with particular emphasis on progression‐free survival (PFS) and minimal residual disease (MRD)‐negativity.

Methods:

Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles of standard Clb or Ven 400 mg daily in combination with G for the first 6 cycles. The primary endpoint was PFS. MRD‐negativity in peripheral blood (PB) or bone marrow (BM) 3 months after treatment completion was a key secondary endpoint. MRD was analyzed serially from Cycle 4 every 3 months by an allele‐specific oligonucleotide polymerase chain reaction assay (ASO‐PCR; cut‐off, 10−4) and by next generation sequencing (NGS; cut‐offs, 10−4, 10−5, 10−6).

Results:

In total, 432 pts were enrolled; 216 in each treatment group (intent‐to‐treat population). Median age, total CIRS score, and CrCl at baseline were 72 years, 8, and 66.4 ml/min respectively. After 29 months median follow‐up, superior PFS was observed with VenG vs ClbG (Figure 1a). Median PFS was not reached in either group: at Month 24, PFS rates were 88% with VenG and 64% with ClbG (hazard ratio [HR] 0.35; 95% confidence interval [CI] 0.23–0.53; P < 0.0001). MRD‐negativity by ASO‐PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P < 0.0001]) and BM (57% vs 17% [P < 0.0001]) 3 months after treatment completion. Overall, 75% of VenG MRD‐negative pts in PB were also MRD‐negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD‐negativity was associated with longer PFS. MRD‐negativity rates were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD‐negative 12 months after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off‐treatment: 19 months) (Figure 1b). MRD‐negativity rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD‐negative status at <10−4, 35% vs 15% at ≥10−6–<10−5 and 31% vs 4% at <10−6, respectively.

Summary/Conclusion:

Fixed‐duration VenG induced deep, high (<10−4 in 3/4 of pts and <10−6 in 1/3 of pts), and long lasting MRD‐negativity rates (with a low rate of conversion to MRD‐positive status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS.

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