Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease

Author(s): Matthew S. Davids, MD, MMSc¹, Christine E. Ryan, MD¹, Benjamin L. Lampson, MD, PhD¹, Yue Ren, MS², Svitlana Tyekucheva, PhD², Stacey M. Fernandes, BS¹, Jennifer L. Crombie, MD¹, Austin I. Kim, MD¹, Matthew Weinstock, MD³, Josie Montegaard, NP¹, Heather A. Walker, MPH¹, Claire Greenman, BA¹, Victoria Patterson, RN¹, Caron A. Jacobson, MD, MMSc¹, Ann S. LaCasce, MD, MMSc¹, Philippe Armand, MD, PhD¹, David C. Fisher, MD¹, Steve Lo, MD⁴, Adam J. Olszewski, MD⁵, Jon E. Arnason, MD³, Inhye E. Ahn, MD¹, Jennifer R. Brown, MD, PhD¹;

Source: https://doi.org/10.1200/JCO-24-02503

Dr. Anjan Patel's Thoughts

Triple therapy for CLL, AVO, is highly active and has very high MRD-negative rates compared to other studies using Ven+Obi or BTKi therapy alone. The battle between indefinite BTKi therapy vs more intense combination therapy will continue as we don’t know if one paradigm is better from a bigger picture.

PURPOSE

The AMPLIFY trial recently established fixed-duration acalabrutinib, venetoclax, and obinutuzumab (AVO) as a new standard-of-care option for patients with previously untreated chronic lymphocytic leukemia (CLL) with wild-type TP53; however, due to the chemoimmunotherapy control arm, AMPLIFY excluded patients with high-risk TP53 aberration, for whom current standards of care are continuous Bruton tyrosine kinase inhibitor therapy or alternatively fixed-duration venetoclax-based doublets. AVO has not previously been evaluated in patients with CLL with TP53 aberration.

METHODS

This investigator-sponsored, multicenter, phase II study enrolled patients with treatment-naïve CLL enriched for high-risk CLL, defined by TP53 aberration (ClinicalTrials.gov identifier: NCT03580928). Patients received acalabrutinib, obinutuzumab, and then venetoclax, with each treatment introduced sequentially and in combination, with the duration guided by measurable residual disease (MRD). Patients who achieved undetectable MRD (uMRD) after either 15 or 24 cycles could discontinue treatment. The primary end point was complete remission (CR) with bone marrow uMRD (BM-uMRD) at the start of cycle 16.

RESULTS

Seventy-two patients were accrued, including 45 patients with TP53 aberration. The CR with BM-uMRD rates at the start of cycle 16 were 42% in patients with TP53 aberration and 42% in all-comers, and the BM-uMRD rates were 71% and 78%, respectively. Hematologic toxicities were mainly low grade, and cardiovascular toxicities and bleeding complications were infrequent. After a median follow-up of 55.2 months, 10 patients had progressed, including four with transformation, and three patients died. Four-year progression-free survival and overall survival for patients with or without TP53 aberration were 70%/96% and 88%/100%, respectively.

CONCLUSION

AVO was highly active and well tolerated in patients with previously untreated high-risk CLL, supporting its use as a new standard-of-care treatment option.

Author Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; ² Department of Data Science, Dana-Farber Cancer Institute, Boston, MA; ³ Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA; ⁴ Stamford Hospital, Stamford, CT; ⁵ Brown University Health, Providence, RI

A phase 2 trial of CHOP with anti-CCR4 antibody mogamulizumab for older patients with adult T-cell leukemia/lymphoma Available to Purchase

The phase 2 trial of Moga-CHOP (CHOP + mogamulizumab) in older patients with aggressive adult T-cell leukemia/lymphoma (ATL) demonstrated a significant improvement in 1-year PFS (36.2% vs 16% historical control), with a 1-year OS of 66.0% and a CR rate of 64.6%. The overall response rate (ORR) was high at 91.7%, and the median overall survival (OS) reached 1.6 years. Notably, CCR4 mutations and Moga-associated cutaneous AEs correlated with better OS, and the regimen was generally tolerable with no unexpected toxicities. Bottom line: Moga-CHOP is now a strong first-line option for older, transplant-ineligible ATL patients, and it’s encouraging to see these survival gains in a population with historically poor outcomes.

Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia

The phase 3 FLAIR trial compared MRD-guided ibrutinib–venetoclax (I+V) to ibrutinib (I) alone and FCR in previously untreated chronic lymphocytic leukemia (CLL). I+V achieved undetectable minimal residual disease (MRD) in bone marrow at 2 years in 66.2% of patients, versus 0% with I and 48.3% with FCR. At 5 years, PFS was 93.9% with I+V, 79.0% with I, and 58.1% with FCR; OS was 95.9%, 90.5%, and 86.5%, respectively. These data suggest that MRD-guided I+V not only deepens remissions but also translates to superior long-term outcomes—this could be a real game-changer for our frontline CLL management, especially for those with unmutated immunoglobulin heavy chain variable (IGHV).

Phase III Trial of Pirtobrutinib Versus Idelalisib/Rituximab or Bendamustine/Rituximab in Covalent Bruton Tyrosine Kinase Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (BRUIN CLL-321)

Pirtobrutinib improved progression-free survival (PFS) to 14 months compared to 8 months with Idelalisib/Rituximab or Bendamustine/Rituximab (IdelaR/BR), with a hazard ratio of 0.54, in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had previously been treated with covalent BTK inhibitors (cBTKi). It also demonstrated favorable tolerability. With acalabrutinib and venetoclax emerging as preferred first-line therapies, Pirtobrutinib represents a strong second-line option for eligible patients.

Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration

It does not seem that all NPM1 mutations are created equally. Type A and B mutations had favorable outcomes and type D mutations do much worse, something to consider when risk stratifying in patients with AML.

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia

This study was done with and without obinutuzumab, both arms beat obinutuzumab and chlorambucil. There were more deaths in the obinutuzumab arm even though it was superior because of COVID, so it is immunosuppressive.