FCR plus ibrutinib in fit patients
Ibrutinib-based treatment has been shown to prolong survival compared to FCR in CLL patients with unmutated IGHV . It was hypothesized that combining ibrutinib with FCR (iFCR) as initial therapy would lead to high CR rates with uMRD in the bone marrow in a broad population of younger, fit CLL patients. The phase II study launched in 2014 enrolled a total of 85 patients at 7 US sites with a median age of 55 years. After a 1-week lead-in with ibrutinib alone, iFCR was administered for up to 6 cycles, followed by ibrutinib maintenance for 2 years. Patients who achieved uMRD at the end of this period discontinued therapy, while those who did not continued treatment until progression. Retreatment with ibrutinib was allowed in patients who relapsed. The primary endpoint of the trial was the CR rate with uMRD in the bone marrow 2 months after iFCR completion.
According to the first analysis published in 2019, the primary endpoint was met after a median follow-up of 16.5 months, with 33 % of patients achieving CR as defined above . The best uMRD rate in the bone marrow by intent-to-treat (ITT) was 84 % at that time, which was higher than results obtained with any prior CIT or novel-agent–based regimen for initial CLL therapy.
Deepening of remissions
The updated efficacy analysis reported at ASH 2021 showed that the best CR rate with uMRD in the bone marrow by ITT had increased to 55 % with ibrutinib maintenance . Complete remissions had deepened with ibrutinib maintenance from 34 % 2 months after FCR to 81 % as best rate; for patients with mutated IGHV, increases had occurred from 41 % to 88 %, and for those with unmutated IGHV, from 28 % to 76 %. The best rate of uMRD in the bone marrow by ITT remained at 84 %. In the 81 patients with TP53 wildtype, the best MRD-negative rate by ITT in the bone marrow amounted to 91 %.
Two years after the end of treatment, 86.5 % of patients achieved MRD 10-4 in the peripheral blood by flow cytometry; by NGS, this was 91.0 %. Dynamic BH3 profiling suggested that increased CLL cell BCL-2 dependence after 1 week of ibrutinib treatment might predict deeper clinical responses. PFS and overall survival were promising, with rates of 97 % and 99 %, respectively, at a median follow-up of 40.3 months. All of the few patients who experienced recurrence responded to re-treatment with ibrutinib monotherapy.
Compared to the previous report, the updated safety analysis showed increases in the rates of grade 3/4 neutropenia (from 35 % to 40 %), febrile neutropenia (from 9 % to 12 %), and atrial fibrillation (from 3.5 % to 8 %). Grade 3/4 thrombocytopenia and anemia remained unchanged (32 % and 11 %, respectively). No Richter’s syndrome has been observed to date. Overall, the safety profile was consistent with individual toxicities of ibrutinib and FCR. The authors concluded that iFCR warrants exploration in comparative studies in a broad population of younger, fit CLL patients with intact TP53 who desire functional cure with time-limited treatment approaches.
FLAIR: FCR vs. ibrutinib/rituximab
The frontline comparison of FCR (n = 385) with ibrutinib/rituximab (IR; n = 386) in patients considered fit for FCR was at the heart of the randomized NRCI FLAIR trial. Rituximab was administered for 6 cycles, while ibrutinib was taken orally for a maximum of 6 years or until sustained MRD negativity. The MRD status was assessed every 6 months based on blood.
After a median follow-up of 52.7 months, the primary endpoint of the FLAIR trial was met: IR was superior compared to FCR regarding PFS (not reached vs. 66.53 months; HR, 0.44; p < 0.001; Figure 2) . PFS was significantly prolonged in the experimental arm in patients with unmutated IGHV (HR, 0.40; p < 0.001), whereas a non-significant improvement resulted in IGHV-mutated disease (HR, 0.68; p = 0.197). Moreover, significant PFS advantages emerged with IR in patients harboring 11q deletion and normal karyotype but not in those with trisomy 12 and 13q deletion. Three months after the end of treatment, greater proportions of FCR-treated patients showed CR (60.5 % vs. 21.0 %) and MRD negativity in the bone marrow (55.3 % vs. 3.9 %). Overall survival had not been reached yet in either arm, with superimposable curves (HR, 1.01); however, it must be noted that almost all patients relapsing after FCR received either ibrutinib or venetoclax plus rituximab.
Among the most frequent AEs reported within one year of randomization, anemia, nausea and decreased white blood cell counts were more common with FCR than with IR, as well as infusion-related reactions and grade ≥ 3 decreases of white blood cells, while diarrhea was substantially more common with IR. Twenty-nine and 30 patients died in the FCR and IR arms, respectively. Deaths in the FCR arm were predominantly due to secondary hematological malignancies, Richter’s transformation, and infections. Those in the IR arm, on the other hand, were mostly related to cardiac causes and non-hematological malignancies. Sudden unexplained death or cardiac death occurred more commonly with IR than with FCR (8 vs. 2); most of these patients (7 of 8) had hypertension or a prior history of cardiac disorder requiring therapy at trial entry. The authors noted that FLAIR is not an outlier for sudden unexplained or cardiac deaths in ibrutinib-containing arms and is consistent with other phase III trials assessing ibrutinib-based regimens in CLL.