E1912 extended follow-up: Sustained survival benefit with Ibrutinib + rituximab in CLL patients

A combination therapy of ibrutinib + rituximab continues to yield superior survival benefits compared with standard chemoimmunotherapy for treatment-naïve patients aged ≤70 years with chronic lymphocytic leukaemia (CLL), according to data from extended follow-up of the large ECOG 1912 (E1912) trial presented at ASH 2019 Meeting.

In the previous release of the interim results at ASH 2018, the combination regimen was hailed as “practice-changing and immediately establish ibrutinib and rituximab as the new standard of care for the initial treatment of CLL in patients age 70 and younger” by lead investigator Dr Tait Shanafelt of Stanford University in Stanford, California, US.

The initial results showed that ibrutinib + rituximab was superior to the standard chemoimmunotherapy in terms of progression-free survival (PFS) and overall survival (OS) in patients with previously untreated CLL after a median follow-up of 33.4 months. The current analysis was on an extended median follow-up of 48 months, and provided new safety and efficacy data on patients who had completed ibrutinib + rituximab and who continued receiving ibrutinib for as long as it was effective.

After an extended follow-up for a median of 48 months, 73 percent of the patients initially randomized to ibrutinib + rituximab remained on ibrutinib, with a median time on treatment of 43 months (range, 0.2–61 months). [ASH 2019, abstract 33]

During the 48 months of follow-up, PFS continued to favour ibrutinib + rituximab vs standard chemoimmunotherapy (hazard ratio [HR], 0.39; p<0.0001). The median PFS after discontinuing ibrutinib was 23 months.

Superior OS benefit was also sustained with ibrutinib + rituximab over the standard chemoimmunotherapy (HR, 0.34; p=0.010). 

When the analysis was stratified by immunoglobulin heavy chain variable region (IGHV) mutation status, the PFS benefit with ibrutinib + rituximab was particularly prominent and met statistical significance in IGHV unmutated patients (HR, 0.28; p<0.0001). However, the difference between treatments was not significant in IGHV mutated patients (HR, 0.42; p=0.086).

According to Shanafelt, FCR* therapy has previously been shown to be particularly effective in patients with IGHV mutated CLL. “Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy,” he said.

Participants in the phase III study were 529 patients aged ≤70 years with previously untreated CLL who were randomized 2:1 to ibrutinib + rituximab for six cycles** or standard chemoimmunotherapy with FCR for six cycles. Patients who completed six cycles of ibrutinib + rituximab continued receiving ibrutinib until disease progression. The study excluded patients with 17p deletion mutation.

Treatment-related adverse events (AEs) of grade ≥3 occurred in more patients on standard chemoimmunotherapy than ibrutinib + rituximab arm (80 percent vs 70 percent; odds ratio [OR], 0.56; p=0.013).

“Although less than 7 percent of ibrutinib treated patients progressed while on therapy, roughly one in five patients have discontinued ibrutinib for a reason other than progression or death,” said Shanafelt.

Seventy-two patients discontinued ibrutinib for a reason other than progression or death: 48 (14 percent of patients in the ibrutinib arm) were due to AE or complication and 24 (7 percent) were due to withdrawal of consent or other reasons. The median time on ibrutinib among these patients was 15.1 months (range 0.2–58.2 months).

Of the various potential baseline predictors tested, only CIRS*** score was significantly associated with discontinuing ibrutinib for a reason other than progression or death (HR, 1.13 per unit increase; p=0.009).

“With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL,” concluded Shanafelt.