VenR in Relapsed CLL: 4-Year Results and Evaluation of Impact of Genomic Complexity and Gene Mutations from MURANO 3 study

[Jm954]

This is an important evaluation and insight into how your CLL profile affects your response to VR in relapsed and refractory CLL. Sadly it looks like bad genetics is still relatively bad news in terms of PFS even on VenR.

"In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory CLL. At the 4-year follow-up, they report long-term outcomes, response to subsequent therapies and the predictive value of molecular and genetic characteristics."

"Undetectable MRD at the end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity and high MRD positivity. Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with higher genomic complexity (GC) than in those without GC; higher genomic complexity (GC) was associated with shorter PFS. Higher levels of MRD positivity rates were seen with BIRC3 and BRAF mutations at EOCT and with TP53, NOTCH1, XPO1, and BRAF mutations at EOT."

'Clinically relevant biomarkers predictive of poor response to CIT include unmutated immunoglobulin heavy chain (IGHV) gene, del(17p), mutated TP53, and cytogenetic or genomic complexity (GC).8-11 Targeted therapies overcome the adverse impact of IGHV status, but the identification of biomarkers for targeted therapies is required to guide clinical practice. Specific biomarkers that might have predictive value with targeted agents as well as CIT are certain recurrent mutations and GC. How to define GC is currently under debate. It was recently found that presence of five or more, but not three or more, chromosomal aberrations is an independent prognostic factor with adverse outcome in CLL after chemotherapy. Whether this also holds true for targeted agents is currently unknown.

They concluded that

"The data shows a sustained long-term benefit for fixed-duration VenR in R/R CLL and suggest that extended therapy would be unlikely to prevent early progression. Data for next-line therapy indicate the potential of either ibrutinib or venetoclax re-treatment as a treatment option after progression on VenR. The clinical relevance of the biomarker findings requires validation in further studies.

Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS"

Much more detail here: ascopubs.org/doi/full/10.12...

Jackie

[avzuclav]

Good one!

"The benefits of fixed-duration VenR versus BR were sustained after a median follow-up of 48 months, confirming this fixed-duration treatment strategy as broadly effective. There has been some doubt as to whether drug cessation is the optimal approach for patients with high MRD positivity at 24 months, because of high rates of early progression in this population. However, the data presented here show that nearly all of these patients already had increasing MRD while on venetoclax therapy. Although this indicates emerging disease resistance and a probable lack of benefit from ongoing single-agent venetoclax, it is possible that treatment slowed the MRD increase, a hypothesis currently under investigation. The enduring PFS benefit and progressively greater OS benefit of VenR, despite subsequent high rates of novel agent use after progression in the BR arm, support the early use of targeted therapies such as VenR in patients with R/R CLL and indicate that treatment benefits are durable. "

[Jm954 Administrator in reply to avzuclav]

I nearly included that paragraph but felt the post was getting too long. Thanks for posting it as not everyone will read the full paper.

Jackie

[Agiledog in reply to Jm954]

Thanks Jackie. I have some difficulty ferreting the results’ particular meaning for me. I am 11q, unmutated. Treated 6 cycles FCR 1/12 - 6/12. Now 45 months into acala dosing trial at NIH. Have had steady, uncomplicated improvement in ALC to the point of best Yet 4.00 at last labs. No hiccups. But I am planning for the future. Your thoughts on a future tx strategy when I relapse on Acala? As always, your posts are tops! Bud

[Jm954 Administrator in reply to Agiledog]

Hi there Bud, firstly, thank you for those kind words which are much appreciated by me today.

I am also 11q del and unmutated so your question is very pertinent to me. However, I'm not really thinking about my next treatment as things are changing so fast. I'm keeping up to date with the evidence and treatment availability so that when/if the time comes, I can have an informed discussion with my doctor.

I would think that you should have many years with Acalabrutinib and I wouldn't be surprised if there isn't something new, a new combination or even CAR-NK/T for relapsed CLL in the near future. Price might be an issue of course and the other important thing is to keep as fit and well as you can so that you can tolerate future treatments.

You take care, best wishes

Jackie

[Agiledog in reply to Jm954]

Thanks, Jackie. You have become a go-to source over the years here. I have wondered if, when I relapse, it will be due to some subset of cells that we never very responsive to acala from the getgo, or new mutated clones getting going. In either case, the I+V combo would seem to be a possibility given its early trial results. Let acala keep doing what it can, and add V for bigger impact on circulating cells. I have really had smooth sailing in the acala trial. I really appreciate hearing from you that reasonable expectations are for a long run.

Best to, friend

Bud

[mrsjsmith in reply to Agiledog]

Bud,

I totally agree with you and we are so lucky to have someone with Jackie’s extensive knowledge and experience of Haematology.

Colette x

[DebKat999 in reply to mrsjsmith]

I so agree Colette, we are very lucky.

Debbie x