Improving Treatment Options for Patients with Double Refractory CLL - patients who progressed after treatment with both cBTKis and BCL2i

[AussieNeil]

Abstract

The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton's tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL.

Authors, Ryan Jacobs , William Wierda

pubmed.ncbi.nlm.nih.gov/399...

[manzelka]

I found this an interesting read this morning.

Thank you.

[DoNorth]

In the middle of this now. P+O gave me a much needed lifeline. Started last month and saw fairly dramatic improvement in just under a month. Am now moving onto BTK degrader trial for a few years hopefully and then CAR-T.

[Stewie_1968 in reply to DoNorth]

Hi DoNorth

Great news about the results, how long are you planning to stay on P and O for the just a few months

Stewie

[Teagle47 in reply to DoNorth]

DoNorth. I am on Pirto now and slowly relapsing. For some family reasons I cannot start a degrader until April/May. At what point did they add O? What were your counts and/or B symptoms, because it looks like that may be my option as well. Which degrader did you chose?

Terry

[DoNorth in reply to Teagle47]

Hi, my ALC was around 23K, platelets around 14K and Hgb around 9. I had ITP in the past so thought it might be still an issue but was unsure. My BMB showed 80% CLL (perhaps the V+I was keeping lymphocytes in the peripheral blood artificially low) so the specialist figured Obintuzumab to treat the CLL (and ITP if it was still an issue) plus Pirtobrutinib was the prudent move. I started both the same day. Platelets recovered to 70K within a month and are still rising. ALC dropped to about 10K as of Thursday. Hgb is slower to recover. I knew PFS on Pirtobrutinib is typically short so am opting to move on to the NX-5948 sooner rather than later. My doctor wanted to get me to a stable position for the trial and I think we accomplished that this week. B symptoms were mostly fatigue, large lymph nodes in neck and armpits and some GI issues. Pathologist suspected Richters but my specialist more or less ruled it out and thinks it is aggressive P53 mutated CLL

[DoNorth in reply to Teagle47]

How long have you been on Pirtobrutinib?

[Teegolf47 in reply to DoNorth]

Started in June 2023, but based on the Flow we noticed the beginning of relapse in August 2024, so we knew it was coming. My flow is now at 62%, but ALC is only 7.9. Platelets and Hgb all in normal range. As of yet no B symptoms. I was approved for NX-5948 on paper but they wanted to start the screening next week, and start the drug after that, but we are going Europe at the end of March and that would be right at the beginning of the trial, so I am having to delay it a bit and hope there are slots available when I get back. If there aren't available then I will have to wait until Phase 2 opens in June or July and hope I remain stable till then. But they think they can just give me a round or 2 of Obin to keep me stable if I rapidly progress. I will definitely want to follow your progress.

[DoNorth]

about 3 months. Screening for the degrader trial begins in March and if all goes well, I would begin first dose in April