Fixed-duration first-line ibrutinib-venetoclax improves PFS over chlorambucil-obinutuzumab for CLL

Fixed-duration ibrutinib plus venetoclax (I+V) significantly improved progression-free survival (PFS) over chlorambucil plus obinutuzumab (Clb+O) in the first-line treatment of patients with chronic lymphocytic leukaemia (CLL), primary results of the phase III GLOW trial showed.

“I+V was superior to Clb+O, reducing the risk of progression or death by 78 percent,” presented Professor Arnon Kater from the Amsterdam Medical Center, University of Amsterdam, Amsterdam, Netherlands, at EHA 2021.

Study participants were 211 CLL treatment-naïve adults aged ≥65 years or <65 years with cumulative illness rating scale (CIRS) score >6 or creatinine clearance <70 mL/min, without del(17p) or known TP53 mutations (median age 71 years [34.1 percent age ≥75 years], 57.8 percent male). They were randomized 1:1 to receive I+V (ibrutinib 420 mg/day [3-cycle lead-in], followed by 12 cycles of I+V with venetoclax ramp-up from 20 to 400 mg/day over 5 weeks) or six cycles of standard dose Clb+O (chlorambucil [0.5 mg/kg on day 1 and 15] plus obinutuzumab [1,000 mg on days 1–2, 8, and 15 of cycle 1; day 1 on cycle 2–6]).  

Median CIRS score was 9 and 8 in the I+V and Clb+O arms, respectively, with 69.8 and 58.1 percent, respectively, having CIRS >6. More Clb+O than I+V patients had elevated lactate dehydrogenase levels (48.6 percent vs 33.0 percent).

After a median 27.7-month follow-up, PFS, as per independent review, was significantly improved with I+V vs Clb+O (median not reached vs 21.0 months; hazard ratio [HR], 0.216, 95 percent confidence interval [CI], 0.131–0.357; p<0.0001). [EHA 2021, abstract LB1902]

The PFS results were consistently in favour of I+V over Clb+O across multiple subgroups including CIRS >6 (HR, 0.248) and age ≥65 years (HR, 0.234).

“Patients treated with I+V also achieved deeper and more durable responses vs Clb+O,” Kater said.

Three months after treatment end, undetectable minimal residual disease (uMRD) rates were higher in patients assigned to I+V vs Clb+O in bone marrow (51.9 percent vs 17.1 percent; p<0.0001) and peripheral blood (54.7 percent vs 39.0 percent; p=0.0259). Peripheral blood uMRD rates were maintained in 84.5 percent of I+V recipients at assessment 1 year after treatment end.

Complete response rates were also significantly higher with I+V vs Clb+O (38.7 percent vs 11.4 percent; p<0.0001). More I+V than Clb+O responders maintained response 2 years after first response (90 percent vs 41 percent).

Time to subsequent therapy was longer in the I+V vs Clb+O group (HR, 0.143, 95 percent CI, 0.05–0.41). Treatment duration was longer in I+V than Clb+O recipients (median 13.8 vs 5.1 months).

“Ibrutinib lead-in effectively debulked the tumour; only 2 percent of patients remained at risk for tumour lysis syndrome (TLS) at start of venetoclax dosing,” Kater pointed out.

Overall survival was immature at this primary analysis, with 11 and 12 deaths in the I+V and Clb+O arms, respectively (HR, 1.048).

The most common (≥5 percent) grade ≥3 treatment-emergent adverse events (TEAEs) among I+V recipients were neutropenia (34.9 percent), infections (17.0 percent), diarrhoea (10.4 percent), and hypertension (7.5 percent), while for Clb+O, the most common were neutropenia (49.5 percent), thrombocytopenia (20.0 percent), infections (11.4 percent), and TLS (5.7 percent). Seven and two patients on I+V and Clb+O, respectively, experienced grade 5 AEs.

“Tolerability profiles for I+V and Clb+O were consistent with CLL treatment in elderly comorbid patients,” noted Kater.

“These first randomized data demonstrate the positive clinical profile of fixed-duration I+V in older patients,” said Kater and co-authors.

“[The results of GLOW, along with that of the CAPTIVATE study,] provide experience in >400 patients using this all-oral, fixed-duration I+V therapy across a broad spectrum of patients with previously untreated CLL,” he concluded.