Final analysis confirms PROLONGed survival with ofatumumab in relapsed CLL

Ofatumumab proves to be useful in the maintenance treatment of patients with relapsed chronic lymphocytic leukaemia (CLL), according to the final analysis of the phase III PROLONG trial, which has shown that the regimen is well tolerated and substantially extends progression-free survival (PFS).

“The PFS benefit was independent of baseline demographic characteristics, remission status at study entry, prior treatments and immunoglobulin variable heavy-chain gene (IGVH) mutation status,” according to the investigators. “Ofatumumab maintenance was accompanied by an increased risk of grade 3/4 neutropenia and … infections [but] did not increase the risk of Richter transformation nor did it impair the response to next-line treatment.”

The analysis included 480 CLL patients (median age, 64 years; 67 percent male) who had achieved complete or partial remission after second- or third-line treatment. Of these patients, 240 were randomized to receive ofatumumab (300 mg first week, followed by 1,000 mg every 8 weeks for up to 2 years) and the other 240 to undergo observation. Median follow-up duration was 40.9 months.

As already mentioned, ofatumumab was associated with significantly better PFS compared with observation alone (median, 34.2 vs 16.9 months), cutting by half the risk of progression or death (hazard ratio [HR], 0.55, 95 percent confidence interval [CI], 0.43–0.70; p<0.0001). Additionally, the biologic drug prolonged median time to next treatment (TTNT) by about 10 months (37.4 vs 27.6 months; HR, 0.72, 95 percent CI, 0.57–0.91; p=0.0044). [Blood Cancer J 2019;9:98]

Meanwhile, the improvement in PFS did not translate to an increase in overall survival, which was similar in the two treatment arms (median not reached; HR, 0.99, 95 percent CI, 0.72–1.37). PFS after next-line therapy (time from randomization to the second objective disease progression or death) was also comparable (median not reached; HR, 0.88, 95 percent CI, 0.49–1.61). 

There was no significant between-group difference in the rate of grade ≥3 adverse events, occurring in 62 percent of patients in the ofatumumab arm and in 51 percent in the observation arm. The most commonly reported were neutropenia (23 percent and 10 percent, respectively), pneumonia (13 percent and 12 percent) and febrile neutropenia (6 percent and 4 percent).

Ten deaths were recorded up to 60 days after the last treatment: four patients in the ofatumumab arm (none were related to treatment) and six in the observation arm.

“No unexpected toxicity was observed. We have previously shown [in the interim analysis] that no clinically relevant differences in health-related quality of life between the two study arms at any time point during treatment were observed,” the investigators said. [Lancet Oncol 2015;16:1370-1379]

“Although the values are relatively small and our study was not powered to compare these subgroups, the benefit of ofatumumab seems more pronounced in the [subgroup of patients with minimal residual disease at baseline]. This is an important finding because it shows that patients with good response to induction therapy may benefit from additional maintenance therapy,” they pointed out.

The present data, along with that from other phase III trials—some of which involved an anti-CD20 mAb, establish the clinical benefit of administering maintenance treatment in CLL following induction with chemoimmunotherapy. [Med Oncol 2014;31:104; Lancet Haematol 2016;3:e317-e329; Lancet Haematol 2017;4:e475-e486/e534-e543­; Lancet Haematol 2018;5:e82-e94]

“One might argue that our data are less relevant in the present era of promising data on the use of novel agents in CLL, notably Bruton’s tyrosine kinase inhibitors, phosphatidylinositol-3-kinase inhibitors and BCL-2 antagonists,” the investigators noted. “However, at present, the possible role of chemoimmunotherapy in patients relapsing after prior use of (multiple) novel agents is unclear. Thus for relapsed patients, our findings might still be relevant.”