Early treatment for high risk CLL

[ikahan]

Is recommended by this randomized controlled clinical trial.

hematologyadvisor.com/home/...

Ileana

[SofiaDeo]

I think you put a different link than stated?

[ikahan]

Sorry wrong link

hematologyadvisor.com/home/...

[AussieNeil Administrator]

This CLL12 clinical trial (ClinicalTrials.gov Identifier: NCT02863718) is a very important study by the German CLL Study Group, which notes:-

At the data cutoff, the OS (overall survival) results were still immature.

With respect to safety, the frequency of any-grade adverse events (AEs) was similar in the ibrutinib arm (82.2%) and the placebo arm (84.8%). The most frequent AEs leading to treatment interruption in the ibrutinib group compared with the placebo group were arrhythmias (18 vs 0 patients), bleeding (8 vs 1 patient), diarrhea (4 vs 3 patients), and neoplasia (4 vs 3 patients). Treatment was discontinued by 34.1% of patients in the ibrutinib arm compared with 45.9% in the placebo arm. AEs (n = 53) were the main reason for discontinuation in the ibrutinib group, but disease progression (n = 45) was more common in the placebo group.

Did you mean to include another reference? (You can correct your post by selecting 'Edit' from the options available when you select "More v" below your post.

The conclusion of Reference 1 from your referenced paper, (published February 2021 from Mayo Clinic and which examines the outcomes of early intervention trials), states in its summary:-

Previous clinical trials of treatments for patients with early-stage CLL did not extend into routine clinical practice owing to the excessive toxicity and/or ineffectiveness of the treatments and a lack of robust prognostic models for appropriate patient selection. We have now reached an exciting era in which a plethora of effective anti-CLL therapies are available that have fewer toxic effects on bone marrow reserve and immune status than did past therapies. The parallel improvement in prognostic tools for disease progression has created a new opportunity to reassess the role of early treatment in patients with asymptomatic (or minimally symptomatic) disease who are at high risk for disease progression. Several ongoing clinical trials will ultimately pave the way for the adoption of an early-treatment approach in patients with high-risk asymptomatic CLL, and we strongly support enrolling appropriate patients with early-stage CLL in rationally designed trials. However, until the mature results of such trials become available, we continue to follow the 2018 iwCLL guidelines for starting therapy in patients with newly diagnosed, early-stage CLL.

After initial diagnosis, the risk for progression to symptomatic disease is highly variable. As a result, optimal patient selection is a key component of efforts to evaluate the benefits of early intervention. Prognostic models used for risk stratification have progressed from the early Rai and Binet staging system to current models that incorporate clinical, genomic, and biological factors. While these models were created mainly to predict OS, in terms of early intervention, the best risk model is one that accurately predicts time to first therapy.

At present, 4 such models exist, which include the MD Anderson Cancer Center (MDACC), German Chronic Lymphocytic Leukemia Study Group (GCLLSG), CLL International Prognostic Index (CLL-IPI), and the CLL prognostic model (CLL-PM).

From the above, I would say that this research highlights the importance of having a reliable model which can identify patients who are likely to need treatment soon, plus treatment(s) that have a sufficiently low risk of Adverse Events, are necessarily requirements before early treatment can be recommend. In that regard, confirmation that second generation BTK inhibitors and the new combination treatments do have significantly lower Adverse Event profiles, will be needed before we can save some of us from the stress of Watch and Wait (and Worry). I note that there is a full publication of Early-Intervention Studies in Asymptomatic CLL in the Clinical Advances in Hematology & Oncology.

Neil

[ikahan in reply to AussieNeil]

Thanks Neil I corrected the link in my original post

[ikahan in reply to ikahan]

In terms of being able to identify patients that are going to need treatment Dr Byrd said that unmutated IGHV will need treatment sooner (5 years ) to later ( 10 years ). However waiting when your DNA is more labile can also cause clonal evolution.

[Smakwater]

ikahan,

What is better, a managed forest, or a controlled burn with high winds in the forecast?

I like the idea of looking for the answer to the origin.

Keep these coming.

JM

[cajunjeff]

That’s an interesting article if I read the right one. It confirms my understanding that they are looking at whether the watch and wait paradigm should be reconsidered in light of the newer drugs.

I just did not read where it said early treatment is currently “recommended “ as opposed to being studied. Is there some part of the article that says early treatment is now recommended? It looks to me like they are saying to follow the current guidelines.

[ikahan in reply to cajunjeff]

You are right, the study didn't 'recommend' anything, but it did find that the ibrutinib group had longer progression free survival (PfS) and event free survival than the placeobe group. the trial subjects had high risk CLL but were otherwise on watch and wait. Median event free survival for the ibrutinib group had not been reached by the end of the trial, whereas in the placebo group the median time to for a medical event related to CLL (eg pneumonia) was 4 years. similarly, median progression free survival ( PFS ) was not reached in the ibrutinib group but was reached after 14.8 months in the placebo group.

[cajunjeff in reply to ikahan]

The way I read the article was that it recommended doctors continue to follow the iwCLL guidelines, which means watch and wait is still the practice. It does suggest that in the future early treatment might become the standard of care for high risk Cll.

[CLLerinOz Administrator Volunteer in reply to cajunjeff]

That’s my reading of it, too. It predicts that earlier treatment for certain high risk patients may be more likely in future but that, until further trial data provides more surety, iwCLL guidelines should be followed.

The longer paper linked in the summary article concluded:

“Several ongoing clinical trials will ultimately pave the way for the adoption of an early-treatment approach in patients with high-risk asymptomatic CLL, and we strongly support enrolling appropriate patients with early-stage CLL in rationally designed trials. However, until the mature results of such trials become available, we continue to follow the 2018 iwCLL guidelines for starting therapy in patients with newly diagnosed, early-stage CLL.”