High Deep-Remission Rate With Triple Regimen for Relapsed/Refractory CLL

Time-limited treatment with a three-drug combination for relapsed/refractory chronic lymphocytic leukemia (CLL) produced long-term undetectable residual disease in more than 90% of patients, updated results from a prospective study showed.

After a median follow-up of 36.3 months, 42 of 45 patients achieved undetectable measurable residual disease (uMRD) in peripheral blood (PB) at any time point with the combination of acalabrutinib (Calquence), venetoclax (Venclexta), and obinutuzumab (Gazyva). Estimated 3-year overall survival (OS) was 93.8%. Subgroups with uMRD status exceeding 90% included patients previously treated with venetoclax and those with TP53 mutations.

At last follow-up, patients had been off treatment for a median of 21.9 months. COVID-19 was responsible for all three fatal adverse events in the study, reported Moritz Fürstenau, MD, of the University of Cologne in Germany, and coauthors in Blood.

Their report also showed that monitoring circulating tumor (ct)DNA in addition to flow cytometry at least doubled early detection of MRD recurrences.

"Prolonged maintenance treatment in patients with persistent MRD led to deepening responses with achievement of uMRD in the majority of patients, with a best uMRD rate of 93.3% in PB," the authors wrote of their findings. "Extensive ctDNA-based analyses suggest an improvement in the early detection of molecular relapses when combining cell-based and cell-free approaches. No new safety signals were identified in an updated analysis of AEs [adverse events]."

"In this diversely treated population, uniform treatment approaches like continuous monotherapies or fixed-duration combinations might result in overtreatment with unnecessary toxicities and acquisition of resistance mutations or undertreatment with persisting disease at the end of treatment," they added. "The presented MRD-guided treatment approach takes the different treatment requirements into account by stopping therapy early for those with good responses and extending treatment for those with persisting disease."

Intriguing ctDNA Results

Given that three MRD recurrences were detected by flow cytometry alone, ctDNA should not be used as a standalone method for MRD detection, the authors said. Currently, cell-free methods for detecting MRD recurrence should be used only to complement flow cytometry.

The updated results, with longer follow-up, are consistent with those of an earlier report showing high uMRD response rates after 6 months. The ctDNA data were particularly interesting to Richard Larson, MD, of the University of Chicago.

"We haven't seen much data previously on ctDNA in CLL, so that's an up-and-coming technology," Larson, who is an expert for the American Society of Hematology, told MedPage Today. "I think this is one of the largest reports of a series of patients who have been monitored with ctDNA. Clearly, as the authors point out, it's not flawless. There were a couple of patients who did not have detectable ctDNA but did have progression by flow cytometry, a more standardized, widely available technology. That's still the standard of care, but we will have to see where ctDNA eventually ends up."

"Right now [ctDNA] is really only in research laboratories," he added. "It's not something that clinical labs in the community, or even most academic medical centers, would have available."

The three-drug "is certainly potent" in a diverse, high-risk patient population and was "pretty impressive in terms of inducing undetectable measurable residual disease," Larson said. The findings will likely add to an ongoing debate about how best to use currently available therapies for CLL.

"It begs the question of whether using your best three drugs simultaneously or concurrently is better than using them sequentially," he said. "That's a question that hasn't really been addressed very well for any combination regimen. You might wonder how many of the patients would have responded to just the venetoclax or just the acalabrutinib, leaving something in reserve for patients who didn't respond."

"Certainly, it's not standard treatment in the United States," Larson added. "It would be a very expensive regimen to give these three drugs in combination, particularly over 2 and a half years, which was the full treatment period, although many patients were able to stop treatment once they developed undetectable measurable residual disease."

Key Findings

The multicenter phase II CLL2-BAAG trial involved 45 patients with relapsed/refractory CLL treated with at least one prior regimen (range of one to four). The study population included 18 patients who had received a Bruton's tyrosine kinase (BTK) inhibitor and/or venetoclax. All patients received the MRD-guided triple combination, and 18 received optional debulking with bendamustine prior to induction, which consisted of six 28-day cycles of the triple combination and a maximum of eight 84-day maintenance cycles. Maintenance stopped when a patient achieved a complete response and uMRD in peripheral blood on two consecutive measurements, developed intolerable toxicity, or completed maintenance cycles.

MRD samples were obtained monthly during induction and every 3 months during maintenance. Samples were assessed by conventional four-color flow cytometry and ctDNA by digital droplet PCR. Undetectable MRD was defined as <10^-4 and recurrence as detectable ctDNA or MRD ≥10^-4.

The updated results showed that 93.3% of patients attained uMRD status at some point during follow-up. The overall response results included 17 of 18 patients with prior BTK/venetoclax exposure and 13 of 14 patients with TP53 mutations. The estimated 3-year progression-free survival was 85%, in addition to the 3-year OS of 93.8%.

MRD analysis included 585 paired flow cytometry/ctDNA samples, which showed 18 recurrences (five without clinical progression) after treatment ended. Recurrence was initially detected by ctDNA in 12 cases, by flow cytometry in three, and by both methods simultaneously in three.

The 12 MRD recurrences detected by ctDNA appeared to be associated with higher-risk, more aggressive disease, including unmutated immunoglobulin heavy-chain variable region gene in 10 cases, del(11q) in five, and complex karyotype in five of nine evaluable patients.

Comment