Personalized Treatment for Chronic Lymphocytic Leukemia: Therapeutic Sequencing and Novel Agents
There are important patient- and disease-related factors that are useful for guiding treatment regimen selection in patients with chronic lymphocytic leukemia (CLL).
What is your current approach to personalizing therapy for patients with CLL?
Associate Director for Clinical Science
“Personalized therapy for patients with CLL can take both patient characteristics and disease characteristics into account.”
Personalized therapy for patients with CLL can take both patient characteristics and disease characteristics into account. As relates to disease characteristics, in patients with a 17p deletion or a TP53 abnormality I would be more inclined to use a Bruton tyrosine kinase (BTK) inhibitor. These are the patients who seem to require continuous therapy and a maintenance-type strategy. Additionally, there are hints from the data that appear to support this approach. In a recent analysis presented at the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, data were pooled on patients with 17p/TP53 abnormalities from 4 different clinical trials, and, among 89 patients with 17p deletions or TP53 mutations, progression-free survival (PFS) was 79% and overall survival was 88% after 4 years of follow-up. As relates to venetoclax-based therapy, we do have some data presented at the Virtual Edition of the 25th European Hematology Association Annual Congress last year from the CLL14 trial, which examined fixed-duration venetoclax-obinutuzumab vs chlorambucil-obinutuzumab, with the reporting of TP53 status. And, although no median PFS had been reached with 3 years of follow-up in the fixed-duration venetoclax-obinutuzumab arm, the PFS was approximately 60% in patients with TP53 abnormalities. At that same time point, the PFS for those without a TP53 abnormality was approximately 85%. Again, the data were not mature, and TP53 subsets in frontline trials are small, but these are some of the factors that might be considered.
One can also look at a patient’s comorbidities when personalizing therapy. Given the association of atrial fibrillation with BTK inhibitor administration, I would hesitate to use these agents in patients with a history of atrial fibrillation, particularly if they have recurrent atrial fibrillation, because this can lead to complications such as stroke. Individuals with atrial fibrillation may also need anticoagulation, which can lead to BTK inhibitor–induced bleeding.
Chemoimmunotherapy (CIT) can be an option for young and fit patients with mutated IGHV because of the potential for achieving cure. So, I still offer CIT to these patents, even though this practice is fading in the era of COVID-19 because using highly myelosuppressive chemotherapy is less appealing and there are the risks associated with coming into the clinic for infusions and blood count monitoring.
Professor and D.B. Lane Cancer Research Distinguished Professor
“I am enthusiastic about our new studies of combination targeted therapies and the depth of remission that we observe with the combinations.”
The issue of fixed-duration regimens vs continuous treatment is important when selecting therapy. Most of our newer clinical trials are examining combinations of targeted therapies designed to achieve a deep remission and to get patients off treatment. What I would really like to see in the short-term are data that substantiate the ability to completely get rid of chemotherapy. It will be interesting to see whether we can achieve a plateau with disease progression and survival with venetoclax-based therapy and our combination targeted therapy like we have seen with FCR (fludarabine, cyclophosphamide, and rituximab).
While CIT can produce a functional cure in approximately 50% of patients with mutated IGHV, it has important negative effects. Long-term follow-up data from the CLL14 trial and the MURANO trial that was presented at ASH 2020 showed that the growth kinetics of relapsing disease is more rapid for patients who received CIT either in the frontline setting or in the relapsed setting compared with venetoclax-based treatment. Thus, I think that chemotherapy is not only bad for normal cells and immune function but it may also select for—and even induce—higher-risk clones that are more proliferative and ultimately detrimental to our patient population. So, I am enthusiastic about our new studies of combination targeted therapies and the depth of remission that we observe with the combinations. We see much deeper remissions than we ever did with CIT. I am very optimistic that we will be talking about curative strategies in the near future.
Associate Professor of Medicine
“In terms of BTK inhibitors, I would likely use acalabrutinib instead of ibrutinib in patients with atrial fibrillation at baseline.”
In terms of the ability to functionally cure patients, I think that there is still a role for CIT in the small subset of younger and fitter patients with mutated IGHV, and I still offer FCR to patients who might be interested in achieving a functional cure. However, I agree with the sentiment about trying to develop regimens that are chemotherapy free that may also have the potential for functional cure. Nevertheless, I am not sure that you will be able to achieve a cure with time-limited novel agent–only therapy. As impressive as the CLL14 trial data are, I am not optimistic that it is going to be functionally curative with 1 year of therapy, even for the mutated IGHV patients who seem to be doing extremely well so far. It should be noted, though, that these regimens do not have to be a one-shot treatment. For example, you could get several years of remission from 1 year of treatment with venetoclax plus obinutuzumab, and then you could potentially see response again with another round of the same treatment. So, it seems more likely that this regimen would produce intermittent deep remissions rather than functional cure.
There are also differences between agents within the same class that can be used to personalize treatment for individual patients. For example, in terms of BTK inhibitors, I would likely use acalabrutinib instead of ibrutinib in patients with atrial fibrillation at baseline. A January 2021 press release reporting the results of the ELEVATE-RR trial, which compared acalabrutinib with ibrutinib in patients with previously treated, high-risk CLL, stated that the 2 drugs were similarly effective, but acalabrutinib was associated with a statistically significantly lower risk of atrial fibrillation compared with ibrutinib.
Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukemia (CLL) with 4 years of follow-up in patients with TP53 aberrations (del[17p] or TP53 mutation): a pooled analysis from 4 clinical trials [abstract 2219]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Al-Sawaf O, Bahlo J, Fischer K, et al. Characteristics, treatment, and outcomes of ≥ 80 year old patients with chronic lymphocytic leukemia (CLL) enrolled to prospective trials of the German CLL Study Group [abstract E1025]. Abstract presented at: 22nd Congress of the European Hematology Association; June 22-25, 2017; Madrid, Spain.
Al-Sawaf O, Lilienweiss E, Bahlo J, et al. High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype (CKT) and chronic lymphocytic leukemia (CLL): a prospective analysis from the CLL14 trial [abstract S106]. Abstract presented at: 24th Congress of the European Hematology Association; June 13-16, 2019; Amsterdam, Netherlands.
Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial [abstract 127]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial [abstract S155]. Abstract presented at: Virtual Edition of the 25th European Hematology Association Annual Congress; June 11-21, 2020.
Calquence met primary efficacy endpoint in head-to-head trial against ibrutinib in chronic lymphocytic leukaemia. Press release. AstraZeneca; January 25, 2021. Accessed April 6, 2021. https://www.astrazeneca.com/media-centre/press-releases/2021/calquence-met-primary-endpoint-against-ibrutinib.html
Doyle C. The ASCO Post. Debating the role of chemoimmunotherapy in the first-line setting of CLL. Accessed April 6, 2021. https://ascopost.com/issues/october-25-2019/chemoimmunotherapy-in-first-line-setting-of-cll/
Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (pts) following fixed-duration venetoclax-rituximab (VenR) therapy (Tx) [abstract 125]. Abstract presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020.
Mato AR, Barrientos JC, Ghosh N, et al. Prognostic testing and treatment patterns in chronic lymphocytic leukemia in the era of novel targeted therapies: results from the informCLL registry. Clin Lymphoma Myeloma Leuk. 2020;20(3):174-183.e3. doi:10.1016/j.clml.2019.10.009
Montserrat E, Bauman T, Delgado J. Present and future of personalized medicine in CLL. Best Pract Res Clin Haematol. 2016;29(1):100-110. doi:10.1016/j.beha.2016.08.009