High-Risk Chronic Lymphocytic Leukemia: Insights and Approaches
The current approach to high-risk chronic lymphocytic leukemia (CLL) is characterized by continuous Bruton tyrosine kinase (BTK) inhibition in the front line. At each line of therapy, those with high-risk CLL are more likely to progress, prompting the investigation of newer therapeutic strategies and combinations.
What are your thoughts on strategies for high-risk CLL? Is there any research in this area that seems promising?
John C. Byrd, MD
The Gordon and Helen Hughes Taylor Professor and Chair
“We really need to focus on developing newer therapies and newer combinations because the patients with aberrant TP53 have a high predisposition to progression and, ultimately, death from CLL or associated complications.”
Patients with high-risk CLL are in the specific group that can progress on our currently available therapies, but this occurs in the minority of patients when appropriate targeted therapies are used. High-risk patients are the individuals for whom, in the context of a clinical trial, you may consider upfront combination therapies. We really need to focus on developing newer therapies and newer combinations because the patients with aberrant TP53 have a high predisposition to progression and, ultimately, death from CLL or associated complications.
In defining high-risk, I do not necessarily distinguish between the presence of 17p deletion (del[17p]) at just 1 allele or this together with a TP53 on the other allele in the sense that both groups of patients progress on therapy in the front and second lines. One unclear area is when just a TP53 mutation exists without del(17p) because the literature is somewhat vague. In most treatment studies, there are insufficient numbers of such patients to draw conclusions about their outcomes. For those with TP53 aberrancy, we know from the phase 3 CLL14 trial that the group taking the 12-month treatment with venetoclax plus obinutuzumab does not do as well. You would direct these patients toward a second-generation BTK inhibitor (ie, acalabrutinib or zanubrutinib). You could consider acalabrutinib plus obinutuzumab, which is the approach that is taken for most of these patients in my setting, because the phase 3 ELEVATE-TN study showed that treatment had a trend toward improved progression-free survival (PFS) vs acalabrutinib alone.
Several studies are looking into intermittent therapy and/or periods of treatment discontinuation and are observing patients when they are off therapy. That is a reasonable thing to do, but perhaps not for this high-risk group (ie, if and when the disease comes back, you start therapy again). There is an ongoing study at The University of Texas MD Anderson Cancer Center (NCT04505254) that is testing intermittent acalabrutinib therapy in combination with obinutuzumab in treatment-naive patients. Similar studies involving discontinuation are ongoing at other sites.
Finally, in the high-risk category, some rare genetic features may be associated with progression and/or nonresponse to BTK inhibitor therapy that have been linked to Richter transformation. The significance of these findings is not entirely clear, but Miller et al have shown that near-tetraploidy and complex karyotype may be associated with more aggressive disease, progression, and the development of Richter transformation.
Susan O’Brien, MD
“One of the problems with the study of high-risk CLL in the front line has been limited data. Patients with high-risk mutations usually represent a single-digit percentage of study participants, unless the trial is designed to actively enrich for such patients.”
For patients with TP53 aberrancy, most of us in the field prefer BTK inhibitor therapy over venetoclax plus obinutuzumab. Ibrutinib has been a standard option for the treatment of high-risk and relapsed/refractory CLL; however, ibrutinib is associated with cardiovascular and other adverse effects, which may be attributed to off-target kinase inhibition. Acalabrutinib and zanubrutinib are more selective for BTK inhibition, exhibit less off-target kinase activity than ibrutinib, and have a more favorable cardiovascular risk profile.
One of the problems with the study of high-risk CLL in the front line has been limited data. Patients with high-risk mutations usually represent a single-digit percentage of study participants, unless the trial is designed to actively enrich for such patients. In terms of the frontline treatment of high-risk CLL, the ELEVATE-TN trial provided a direct comparison between acalabrutinib alone and/or in combination with obinutuzumab in treatment-naive individuals. Acalabrutinib with or without obinutuzumab significantly improved PFS compared with chemoimmunotherapy using obinutuzumab plus chlorambucil. For all patients, the PFS with acalabrutinib and obinutuzumab was better than the PFS with acalabrutinib alone. However, when you look at the PFS curves of the high-risk patients, namely those with del(17p) or TP53 mutations, there is no difference between the 2 acalabrutinib curves, which is disappointing. That is, it is disappointing to conclude that the addition of the antibody provided no added benefit in the high-risk patients. We need longer-term data. Outcomes in CLL trials could look one way at 2 years and then look very different at 4 years.
Jennifer R. Brown, MD, PhD
Director, Center for Chronic Lymphocytic Leukemia
“If we are going to pursue time-limited combination therapy for patients with high-risk CLL, I favor an investigative approach of treating to uMRD, monitoring closely thereafter, and perhaps considering retreatment early. Although this approach is currently limited to clinical trials, it is a promising way to improve outcomes for these patients.”
Patients with high-risk CLL in the frontline setting can be described as those having TP53-aberrant disease; the role of complex karyotype in defining high-risk status in the absence of TP53 aberrancy is still unclear. So, for patients with del(17p) or TP53 disruption, the current approach in the front line is continuous BTK inhibitor therapy. Regarding the potential benefit of adding obinutuzumab, I am not completely sure that a benefit might not emerge with longer follow-up. I think that there are a number of datasets out there that hint at the concept that there could be a benefit to deeper remission in this patient population. Hopefully, we will get more data on that over time.
As Dr Byrd alluded to, there is some research that is evaluating time-limited regimens for these patients. In the German CLL2-GIVe trial, obinutuzumab, ibrutinib, and venetoclax therapy was tested in previously untreated patients with del(17p) and/or TP53 mutation. Most participants stopped therapy at 15 months, and the 3-year PFS was still 80%.
Here at our institution, we conducted a phase 2 triple-drug study using acalabrutinib instead of ibrutinib (ie, acalabrutinib, venetoclax, and obinutuzumab [AVO]) in treatment-naive patients with and without TP53 aberration. After 16 months of treatment, we found that the rates of undetectable minimal residual disease in the bone marrow (BM-uMRD) were actually comparable between the group with TP53 aberrancy (83% BM-uMRD) and all patients (86% BM-uMRD). In this study, patients with BM-uMRD may elect to discontinue therapy and undergo MRD monitoring every 3 months with the option to re-treat at early MRD recurrence. This is the way to do it; if we are going to pursue time-limited combination therapy for patients with high-risk CLL, I favor an investigative approach of treating to uMRD, monitoring closely thereafter, and perhaps considering retreatment early. Although this approach is currently limited to clinical trials, it is a promising way to improve outcomes for these patients.
Allan JN, Shanafelt T, Wiestner A, et al. Long-term efficacy of first-line ibrutinib treatment for chronic lymphocytic leukaemia in patients with TP53 aberrations: a pooled analysis from four clinical trials. Br J Haematol. 2022;196(4):947-953. doi:10.1111/bjh.17984
ClinicalTrials.gov. Acalabrutinib and obinutuzumab for the treatment of chronic lymphocytic leukemia. Updated March 14, 2023. Accessed May 4, 2023. https://clinicaltrials.gov/ct2/show/NCT04505254
ClinicalTrials.gov. A study of zilovertamab vedotin (MK-2140) (VLS-101) in participants with hematologic malignancies (MK-2140-001). Updated January 17, 2023. Accessed May 4, 2023. https://clinicaltrials.gov/ct2/show/NCT03833180
Davids MS, Lampson BL, Tyekucheva S, et al. Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL). Blood. 2020;136(suppl 1):20-21. doi:10.1182/blood-2020-139864
Edelmann J. NOTCH1 signalling: a key pathway for the development of high-risk chronic lymphocytic leukaemia. Front Oncol. 2022;12:1019730. doi:10.3389/fonc.2022.1019730
Hillmen P, Eichhorst B, Brown JR, et al. Zanubrutinib versus ibrutinib in relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma: interim analysis of a randomized phase III trial. J Clin Oncol. 2023;41(5):1035-1045. doi:10.1200/JCO.22.00510
Hing ZA, Walker JS, Whipp EC, et al. Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter's transformation. Nat Commun. 2023;14(1):97. doi:10.1038/s41467-022-35778-1
Huber H, Edenhofer S, von Tresckow J, et al. Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia. Blood. 2022;139(9):1318-1329. doi:10.1182/blood.2021013208
Huber H, Tausch E, Schneider C, et al. Final analysis of the prospective multicenter CLL2-GIVe trial of obinutuzumab, ibrutinib, and venetoclax in untreated patients with CLL with 17p deletion/TP53 mutation [abstract 343]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Kittai AS, Huang Y, Beckwith KA, et al. Patient characteristics that predict Richter's transformation in patients with chronic lymphocytic leukemia treated with ibrutinib. Am J Hematol. 2023;98(1):56-65. doi:10.1002/ajh.26755
Mansouri L, Thorvaldsdottir B, Sutton L-A, et al. Different prognostic impact of recurrent gene mutations in chronic lymphocytic leukemia depending on IGHV gene somatic hypermutation status: a study by ERIC in HARMONY [published correction appears in Leukemia. 2023;37(2):504]. Leukemia. 2023;37(2):339-347. doi:10.1038/s41375-022-01802-y
Mato AR, Tang B, Azmi S, et al. A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib. Haematologica. 2022;107(11):2630-2640. doi:10.3324/haematol.2021.280376
Miller CR, Ruppert AS, Heerema NA, et al. Near-tetraploidy is associated with Richter transformation in chronic lymphocytic leukemia patients receiving ibrutinib. Blood Adv. 2017;1(19):1584-1588. doi:10.1182/bloodadvances.2017007302
Ryan CE, Lampson BL, Tyekucheva S, et al. Updated results from a multicenter, phase 2 study of acalabrutinib, venetoclax, obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease [abstract 642]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
Thompson PA, Keating MJ, Ferrajoli A, et al. Venetoclax consolidation achieves durable off-treatment remissions in patients with high-risk CLL who have been on ibrutinib more than a year [abstract 96]. Abstract presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA.
van der Straten L, Hengeveld PJ, Kater AP, Langerak AW, Levin M-D. Treatment approaches to chronic lymphocytic leukemia with high-risk molecular features. Front Oncol. 2021;11:780085. doi:10.3389/fonc.2021.780085
Zenz T, Kröber A, Scherer K, et al. Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. Blood. 2008;112(8):3322-3329. doi:10.1182/blood-2008-04-154070