Toxicity limits use, effectiveness of idelalisib-ofatumumab in CLL
Use of idelalisib plus ofatumumab in the frontline treatment of chronic lymphocytic leukaemia (CLL) is effective, yielding high overall response rate (ORR), although this is counterbalanced by significant toxicities, according to efficacy data from a phase II trial.
“The trial was halted [prematurely] due to increased rates of infectious disease-related deaths in other frontline trials of idelalisib, and all patients in our trial ceased [therapy with the drug] at that time,” the authors said.
In the trial, a total of 27 patients (median age 69 years; 78 percent male; 100 percent had ECOG status 0/1) began with 2 months of idelalisib (150 mg twice daily) monotherapy, followed by 6 months of idelalisib plus ofatumumab (300 mg at week 1; 1,000 mg thereafter), followed by idelalisib monotherapy until progression. Five patients (18.5 percent) had del17p/TP53 mutations, four (14.8 percent) had del11q, and 13 (48 percent) had IGHV unmutated disease.
The primary endpoint of best ORR was 89 percent (n=24). There were 22 partial responses (PRs; 81.5 percent), one PR with lymphocytosis (3.7 percent) and one complete response (3.7 percent). Three patients had stable disease, and all of them received <30 days of idelalisib due to either toxicity or trial halt. Median duration of therapy was 8.1 months. [ASH 2017, abstract 1734]
During a median follow-up of 32.2 months, median progression-free survival (PFS) was 22.9 months (95 percent CI, 17.4‒29.9) and 2-year PFS was 42 percent (23‒60). Significant predictors of PFS included ECOG performance status of 1 vs 0 (hazard ratio [HR], 3.33; 95 percent CI, 1.23‒9.03; p=0.018) and del17p mutation (HR, 4.37; 1.11‒17.15; p=0.035).
There were nine patients (44 percent) who had not progressed or died after receiving therapy for a median of 11 months, and 16 (59 percent) who did not require any subsequent treatment for CLL. Median overall survival (OS) was not reached, while the 2-year OS was 92 percent (71‒98).
Toxicity resulting in treatment withdrawal
Therapy was ceased due to toxicity in 15 patients and due to regulatory mandate to discontinue in 12, with none resulting from disease progression. Among the patients who stopped due to mandate, two developed acute tumour flares consisting of fevers, enlarging nodes, and rash shortly after discontinuation and needed to start alternative therapy rapidly.
Hepatotoxicity occurred frequently, as had been previously reported. Fourteen patients (52 percent) developed grade ≥3 transaminitis within a median of 28 days (ie, prior to ofatumumab introduction). [Blood 2016;128:195-203]
The authors noted that while responsive to steroid, the presence of elevated transaminases was severe enough to necessitate idelalisib discontinuation in five patients. “Previously identified risk factors for early hepatotoxicity, including IGHV mutated disease and younger age, were confirmed.”
Other adverse events were diarrhoea/colitis (48 percent; grade ≥3, 15 percent) and pneumonitis (11 percent; grade ≥3, 3.7 percent). Opportunistic infections also occurred, including P jirovecii pneumonia, brain abscess due to an unknown organism (thought likely P jirovecii), Aspergillus pneumonia, cytomegalovirus colitis and herpes simplex virus esophagitis.
Utility of drug combo in CLL limited by toxicity
The present data indicate that “idelalisib plus ofatumumab has a high overall response rate as frontline therapy [for CLL], but the use of the combination in this setting is limited by toxicity,” the authors said. “Event short courses of combination therapy can induce durable remissions. This may have implications for time-limited therapy with novel agents.”
“While the ORR was high, median PFS was shorter than previously reported for the combination of idelalisib plus rituximab as frontline therapy, where median PFS was not reached after a similar length of follow-up,” the authors noted. [Blood 2015 126:2686-94]
They explained that the shorter PFS might be attributed to a limited time on treatment as a result of both frequent therapy interruptions for adverse events in patients who discontinued early and mandated therapy cessation in those doing well.
“The clinical course of responding patients who discontinued therapy due to regulatory mandate is potentially informative for future trials of time-limited therapy with novel kinase inhibitors. Of note, disease flares were seen in some subjects after abrupt discontinuation of idelalisib,” the authors said.
“Future studies of PI3Kδ inhibitors, particularly in the frontline, should routinely employ prophylaxis for opportunistic infections, systematically investigate key toxicities—such as hepatitis, diarrhoea/colitis and pneumonitis—and closely monitor [patients] for disease progression if a limited duration of therapy is investigated,” they added.