Encouraging results from venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen

[AussieNeil]

We've heard that re-treatment with venetoclax is possible. Per the attached image, here's some encouraging evidence showing a good response to a second venetoclax treatment, from a trial of 46 CLL patients who relapsed after their initial venetoclax treatment.

The overall rate of response (ORR) to Ven2 with retreatment was 79.5% with a Complete Response (CR) of 33% after Ven1 treatment giving an ORR of 95%.

Most of the Ven1 group were relapsed/refractory CLL, so treatment naive patients should do better. The median time to progression from Ven1->Ven2 was 26 months. Median progression free survival on Ven2 was 25 months. (SD is stable disease; the CLL was not progressing.)

ashpublications.org/bloodad... (Select PDF to read the abstract.)

The abstract concludes:-

We report the largest experience of the venetoclax re-treatment strategy in patients with CLL. The results of this study have substantial clinical relevance as more patients will require treatment of CLL following time-limited venetoclax-based therapy. 14 The high ORR and durability of observed remissions support the clinical practice of venetoclax re-treatment and the development of future studies to prospectively validate venetoclax re-treatment in patients with CLL.

This is an unlocked post

Neil

[Justasheet1]

Neil,

Do you have the rest of the article? This is potentially great news.

Jeff

[alpek in reply to Justasheet1]

If you click on the "pdf" tab the article is viewable

[Sushibruno]

👍👍

[Fran57]

Great news… thanks NeilStay safe,

Fran 😷

[casanova]

Reassuring news for those who may need re-treatment. Thanks for posting Neil.

Maureen UK

[Newdawn Administrator]

A subject close to my heart so reassuring to read.

Newdawn

[johnliston]

Neil, were both Ven1 and Ven 2 time limited treatments? If so, how long was the treatment ?

john

[AussieNeil Partner Administrator in reply to johnliston]

Yes, per the PFD, the median exposures were 18 months and 10 months for Ven 1 and Ven 2 respectively.

[spi3]

Thank you with all my heart for your update/article. My husband is in a Dana-Farber study, newly diagnosed with Cll and last week he ramped up to 400 on 16 June. Prior months he started with Acalabrutinib and then the next few months with Obinutuzuimab Iv. So now he's on all three. His,study is time limited. Wondering when the article states that "venetoclax 2" can start after 18 months. . Means

[AussieNeil Partner Administrator in reply to spi3]

The relevant section of the study report is:-

"There was a median of 16 months between the completion of Ven1 and the start of Ven2 (range 3-52 months; 84.8% of patients with ≥ 6 month interval; 58.7% ≥ 12 month interval). The majority of patients (84.8%) did not have another line of therapy between Ven1 and Ven2. Reasons for initiation of Ven2 were iwCLL progression of disease (93.0% of 43 cases with available data) and MRD-positive relapse without clinical progression (7.0%). Ven 2 was administered as: monotherapy (45.7%) or in combination with rituximab (28.2%), obinutuzumab (10.9%), ibrutinib (4.4%) or other (10.9%)."

The 18 months is in regard to the median exposure for the first venetoclax treatment. Keep in mind that venetoclax was only FDA approved for CLL in May 2019, only 3 years ago! Dana-Faber were the first to establish an A+V+O time limited combination treatment protocol, so the study patients had a range of different treatments incorporating venetoclax.

I've underlined the section which covers why the patients in the study were again treated with venetoclax. Note also the wide range in remission times - 3 to 52 months. Also, as I noted in my post, this study group is mostly comprised of relapsed/refractory patients, who had previous treatments before their first venetoclax treatment.

I'm fairly familiar with this trial, because I entered an AVO clinical trial in December 2019 which was rewritten to be time limited and has almost the same protocol. Like me, your husband was treatment naive before starting AVO, so should do much better than what was reported in that study. I achieved uMRD and (hopefully healthy) B cells have only just begun to appear in my blood tests this year at very low levels.

By the way, it would help if you updated your husband's bio per healthunlocked.com/profile/... Also, I gather that you've become the researcher and community contributor for your husband who has CLL, so it would help if you made that clearer. Incidentally, you have plenty of company here in providing that support role. Your husband is fortunate to have you doing that for him. He is of course welcome to also join if he wishes!

Neil

[spi3 in reply to AussieNeil]

Thank you so much and yes I will update his bio (hubby is new to computers and websites) - I love this group many times the stories shared and results have put my fears to rest, given us hope and unity. Thank you so much too for explaining this study --God bless you for all you do

[SofiaDeo]

Yay, this is my current plan, glad to know there is some support for it being a good one!

[JustAGuy]

2 years of PFS seems not enough, unless I’m not understanding properly.

I see the cohort were not treatment naïve so Ven2 I suppose could have been a third (or more) treatment for them.

Can we expect longer PFS in treatment naïve for some Venetoclax combination treatment such as OV? Also I suppose that CLL progression after first treatment does not mean immediate re-treatment does it, or is there a potential for years of additional W&W during post treatment disease progression?

Do I have this straight?

Thanks everyone!

[AussieNeil Partner Administrator in reply to JustAGuy]

According to the iWCLL, with my emphasis, "Progression-free survival is defined as the interval between the first treatment day (in phase 3 trials: day of randomization for intent-to-treat analysis) to the first sign of disease progression or death from any cause." So yes, you could continue on watch and wait for some time after your progression free survival period came to an end.

You generally get your longest remission from your first treatment, with the important proviso that it was the best choice for your particular markers. (That wouldn't be possible for unmutated IGHV patients treated before targeted therapies became available!)

As I've mentioned recently, I've seen studies where relapsed/refractory patients have had over 10 previous lines of treatment. This study included patients going back over 4 years ago and per the PDF, notes with respect to the Ven1 patient history, with my emphasis, "In most cases (91.3%) Ven1 was administered in the relapsed and/or refractory setting. The median number of prior therapies was 2 (0-10), and 40.0% of patients had received a Bruton’s tyrosine kinase inhibitor (BTKi) prior to Ven1 (unknown prior BTKi status, n=1). Ven1 was commonly administered in combination with anti-CD20 antibody therapy (rituximab 47.8%, obinutuzumab 4.3%) or as monotherapy (37.0%)." So up to 60% of the Ven 1 patients would have had chemoimmunotherapy (most likely FCR or BR, with perhaps a few just having immunotherapy, which would most likely be monotherapy with rituximab or maybe obinutuzumab. Relapsed/refractory patients with a long treatment history are more likely to be enrolled in clinical trials with new drugs - simply because established drugs no longer work for them and a clinical trial is their only hope. In this study, this would almost certainly include patients with 17p del or mutated TP53, given chemoimmunotherapy selects sub-clones with these markers. These are harder to treat patients, even with targeted therapies. Importantly, you don't get the same strong selection for these in patients who have been previously treated with targeted therapies. Hence I would expect longer PFS times for patients who were treatment naïve or had previously been treated with a targeted therapy.

Neil