Acalabrutinib, venetoclax and obinutuzumab in relapsed CLL: Phase 2 CLL2-BAAG trial results from the German CLL Study Group

[AussieNeil]

Some very encouraging news for those with unmutated IGHV and/or TP53 aberrations, who are wondering how they will fare with a subsequent treatment. This phase 2 trial of 44 relapsed patients included 34 (75.6%) who had unmutated IGHV and 14/44 (31.8%) who had TP53 aberrations. A Measurable Residual Disease (MRD) guided treatment approach was used to stop therapy early for those with good responses, while guiding extending treatment for those with persisting disease. Circulating tumor (ct)DNA testing (currently only available in research lab studies), was used in addition to MRD testing to improve detection of recurrence of MRD.

MedPage Today reported the results of this study as follows:

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

— Undetectable disease rate over 90%, ctDNA also promising for earlier detection of recurrence

medpagetoday.com/hematology...

"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."

Of note is the optional inclusion of Bendamustine for debulking* and the MRD guided protocol "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."

ashpublications.org/blood/a...

Key Points

- Time-limited acalabrutinib, venetoclax and obinutuzumab induced deep and ongoing remissions in patients with relapsed/refractory CLL

- The addition of ctDNA-based analyses to conventional flow cytometry appears to improve early detection of molecular and clinical relapses

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

The median number of previous treatments was 1 (range 1-4), 18 patients (40%) had received a BTK inhibitor (BTKi) and/or venetoclax prior to inclusion, 14/44 (31.8%) had TP53 aberrations, 34 (75.6%) had unmutated IGHV. With a median observation time of 36.3 months and all patients off treatment for a median of 21.9 months, uMRD <10^-4 in PB (Peripheral Blood) was achieved in 42/45 patients (93.3%) at any time point, including 17/18 (94.4%) previously exposed to venetoclax/BTKi and 13/14 (92.9%) with TP53 aberrations. The estimated three-year progression-free and overall survival rates were 85.0% and 93.8%.

:

"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."

:

"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]."

That last sentence is particularly encouraging, given the higher risk of adverse events from adding additional drugs. However what's most interesting is whether this triplet therapy will ever become mainstream. Guided therapy treatment should result in longer remissions, but will the extended remissions justify the additional expense? Richard Larson, MD, of the University of Chicago, stated. '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". 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."' (My emphasis)

*As reported in The Lancet in August 2022, "This multicentre, open-label, investigator-initiated, phase 2 study evaluates a sequential treatment consisting of a debulking with two cycles of bendamustine for patients with a higher tumour load (70 mg/m^2 intravenously on days 1 and 2, repeated after 28 days), followed by an induction and a maintenance with obinutuzumab (1000 mg intravenously on days 1–2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2–6 and every 12 weeks in the maintenance phase), acalabrutinib (100 mg orally twice daily continuously from induction cycle 2 day 1 onwards) and venetoclax (starting in induction cycle 3 with 20 mg per day with a weekly dose ramp-up over 5 weeks to the target dose of 400 mg per day)"

thelancet.com/journals/lanh...

Neil, with thanks to cujoe for prompting me to post about this study.

[HelloCLL]

Thank you for the hope ❤️🧡

[craterlake]

Hi Neil , thanks for the info ..great results if you can stand the side effects and like the article says it would be expensive ..they would be billing my medicare at least $55,000... per month and i am not sure what my copay would be but by my estimation i would need 2 grants simultaneously and a part time job 2 afford it ... i spoke with my doc. about my xray friday night and am headed to the dentist tomorrow to see if they can save some of my bad teeth .. question and update coming this week ... 😊 blessings , james

[Yvbb]

very interesting. Surprised by the optional use of Bendamustine for debulking. Also for the tp 53 included patients?

[Beattiem-UK]

Thank you for bringing our attention to this Neil. I'm always cheered by studies that show good results for those of us with TP53 concerns.

B

[mrsjsmith in reply to Beattiem-UK]

Me too Beattie.

[avzuclav]

Thanks for posting. It's also interesting that the German CLL study group is running the very similar CLL2-BZAG (swapping acalabrutinib with zanubrutinib). dcllsg.de/en/trial/cll2-bza...

The Lancet article "Interpretation" stresses the need for doublet vs triplet comparisons, for which we'll eventually have your ACE-CL-311 (AMPLIFY) study results. And MAJIC for the doublets head-to-head. Looking forward to the data!

[Floxxy]

Thank you Neil. Very promising. X

[Lavinia-Blue]

That is good news.

I just had an interesting result from Clonoseq. I was on acalabrutinib, venetoclax for a little over 2 yrs and went off the acal this past May and vento this past Jan after the result was 39 per million, didn’t make remission, but decided on a break nevertheless. I just had another test after 3 months off the meds and the result was 18 per million, and I hit remission status. Go figure.