Open AccessS149 FIXED‐DURATION VENETOCLAX PLUS OBINUTUZUMAB IMPROVES PROGRESSION‐FREE SURVIVAL AND MINIMAL RESIDUAL DISEASE NEGATIVITY IN PATIENTS WITH PREVIOUSLY UNTREATED CLL AND COMORBIDITIES
Author(s) -
Fischer K.,
AlSawaf O.,
Bahlo J.,
Fink A.M.,
Tandon M.,
Dixon M.,
Robrecht S.,
Warburton S.,
Humphrey K.,
Samoylova O.,
Liberati A.M.,
PinillaIbarz 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.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000558816.91319.ce
Subject(s) - medicine , minimal residual disease , gastroenterology , venetoclax , hazard ratio , clinical endpoint , obinutuzumab , population , surrogate endpoint , progression free survival , oncology , surgery , confidence interval , randomized controlled trial , chronic lymphocytic leukemia , bone marrow , leukemia , chemotherapy , environmental health
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.