Kathleen A. Dorritie, MD
As upfront treatment approaches in chronic lymphocytic leukemia (CLL) become increasingly less reliant on standard chemotherapy agents in favor of BTK inhibitor–based regimens, it is even more crucial to understand and identify the appropriate strategies for patients with newly diagnosed vs relapsed/refractory disease, according to Kathleen A. Dorritie, MD.
Two studies that have helped move the needle in treatment-naive CLL are the phase 3 AMPLIFY (NCT03836261) and ELEVATE-TN (NCT02475681) trials, Dorritie noted. In the AMPLIFY trial, at a median follow-up of 40.8 months, the estimated 36-month progression-free survival (PFS) was 76.5%, 83.1%, and 66.5% for patients with newly diagnosed CLL treated with acalabrutinib (Calquence) plus venetoclax (Venclexta) vs acalabrutinib plus venetoclax/obinutuzumab (Gazyva) vs chemoimmunotherapy, respectively.1 Respective overall survival rates were 94.1%, 87.7%, and 85.9%.
In ELEVATE-TN, after 6 years of follow-up, the median PFS was not reached with acalabrutinib/obinutuzumab or acalabrutinib monotherapy; in contrast, the median PFS was 27.8 months in the chlorambucil/obinutuzumab arm (P < .0001).2 The estimated 72-month overall PFS rates in these respective arms were 78.0%, 61.5%, and 17.2%. Notably, acalabrutinib/obinutuzumab improved PFS vs acalabrutinib monotherapy (HR, 0.58; P = .0229).
“AMPLIFY and ELEVATE-TN both showed that patients who received targeted therapy had improved outcomes compared with those who received standard chemoimmunotherapy,” Dorritie explained during an interview with OncLive®.
In the interview, Dorritie expanded on 2 case studies of patients with CLL, both of which she presented as chair of a recent State of the Science Summit™ on hematologic malignancies. Dorritie also highlighted differences in treatment strategies for patients with newly diagnosed vs relapsed/refractory CLL, and the shift towards chemotherapy-free regimens in CLL.
Dorritie is a hematologist/oncologist at the University of Pittsburgh Medical Center Hillman Cancer Center in Pennsylvania.
OncLive: What clinical case scenarios were discussed at the Summit?
Dorritie: In a clinical case scenario,[we have to consider:] what is the optimal approach for newly diagnosed CLL, particularly for young patients. The SOC is changing to the point where it’s almost chemotherapy-free regimens for all. One of the case studies I presented in the newly diagnosed setting was asking whether we are ready for triplet combination therapy or are not quite there yet.
In the other case study, we focused on an older patient who had had some exposure to prior targeted agents and had relapsed multiple times, and [we identified] what the best option might be in the relapsed/refractory setting.
How does treatment decision-making differ for patients who are newly diagnosed vs those who have received multiple lines of therapy?
In the newly diagnosed setting, [the SOC] has really changed with the results from studies like AMPLIFY and ELEVATE-TN, [both of which assessed a] treatment-naive patient population. Evidence from both AMPLIFY and ELEVATE-TN has directed the incorporation of BTK inhibitors and the BCL2 inhibitor venetoclax in the upfront treatment setting. [These are] the new SOC, and there are very few patients for whom we would choose a chemotherapy regimen upfront.
In the relapsed/refractory setting, we also discussed how we sequence therapies, which comes down to what patients had been previously treated with. How did they respond to those therapies? Were there certain toxicities that they [encountered with] a specific therapy? That helps guide what our next choice is regarding that line of treatment.
How are chemotherapy-free regimens shifting the CLL treatment paradigm?
[Historically,] in certain younger patients who were fit, we may still opt for a regimen like fludarabine, cyclophosphamide, and rituximab [Rituxan], for example, or even bendamustine/rituximab [BR]. However, now we have multiple studies [showing that] the outcomes of PFS were better in patients who received the more targeted therapy. [This] includes AMPLIFY, which looked at the combination of acalabrutinib and venetoclax [with or without] obinutuzumab; the ELEVATE-TN study, which looked at acalabrutinib [with or without] obinutuzumab vs chlorambucil [plus] obinutuzumab; and the [phase 3] SEQUOIA study [NCT03336333] which compared zanubrutinib [Brukinsa] vs BR. [Additionally,] we’ve taken chemoimmunotherapy off the table for the vast majority of patients with CLL, which is a great and huge paradigm shift.
References
- Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804
- Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. Published online April 8, 2025. doi:10.1182/blood.2024024476