Authored by Brian Koffman, MDCM (retired), MSEd
The Bottom Line:
Acalabrutinib combined with venetoclax, with or without obinutuzumab, could lead to the FDA approval of the first all-oral frontline CLL therapy. The AMPLIFY clinical trial demonstrated that this combination therapy is very effective and well tolerated. The addition of the IV monoclonal antibody obinutuzumab (Gazyva) improves efficacy but at the cost of increased infection risk for those with chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL).
Who Performed the Research and Where Was it Presented:
Dr. Jennifer Brown from Dana Farber, Boston, MA, led an international group of investigators in this large registration (for therapy approval) trial. She gave an oral presentation of the research at ASH, the American Society of Hematology Annual Meeting and Exposition, held in San Diego, CA, in December 2024.
Background:
AMPLIFY, a phase 3 clinical trial, looked at fixed-duration acalabrutinib plus venetoclax (A+V) alone or combined with obinutuzumab (AVO) versus chemoimmunotherapy (CIT) for frontline CLL patients who did not have high-risk characteristics that would prohibit the ethical use of chemotherapy. The trial was largely conducted during the COVID-19 pandemic.
The oral medications, Bruton tyrosine kinase inhibitors or BTKi (ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib) along with the only currently approved B-cell lymphoma 2 or more commonly, BCL2 blocker, venetoclax have drastically improved outcomes for those with CLL / SLL. The addition of the anti-CD20 monoclonal antibody, obinutuzumab, has resulted in deep and durable remission with other limited-duration combination therapies. While other countries have approved the combination of ibrutinib plus venetoclax (I+V), and obinutuzumab is widely used in combination with venetoclax as a fixed-duration therapy, there is no approved all-oral therapy in the USA. Moreover, much preclinical and clinical evidence suggests that combinations of A+V and AVO would work synergistically and not have any significant overlapping toxicities. This trial was designed to seek FDA approval for doublet or triplet therapy.
Methods and Participants:
- Over 1,100 patients were screened, and 857 entered the trial.
- Approximately 63% came from Europe.
- The average age was 61 and 64.5% were male.
- 58.6% had unmutated IGHV, and 15% had a complex karyotype, both of which are unfavorable markers. All those with TP53 aberrations or del 17p were excluded due to the inclusion of the two CIT arms, as these would be ineffective and unethical treatment options.
- The CIT arms were split roughly 50/50 between FCR and BR, totaling 290 patients.
- 291 received A+V, while 286 received AVO for a total of 14 cycles of 28 days each.
Results:
| A+V | AVO | FCR/BR | |
| 3 Year Progression Free Survival (PFS) | 76% | 83% | 66% |
| Overall Response Rate (ORR) | 93% | 93% | 75% |
| COVID-19 Deaths | 10 | 25 | 21 |
| Total Deaths | 18 | 37 | 42 |
- Low neutrophil count was the most common serious side effect seen in all arms.
- In the non-CIT arms, the rate of known problems with BTKi and venetoclax, namely tumor lysis syndrome (TLS), atrial fibrillation (AF), and serious hypertension, were very low.
Conclusions:
This is a potentially practice-changing study.
Acalabrutinib combined with venetoclax, not surprisingly, proved to be significantly better than chemoimmunotherapy in terms of PFS and ORR. If approved, which appears likely based on the results of this study, it will offer CLL patients, regardless of whether they have previously received therapy, with their first all-oral, limited-duration treatment. Adding obinutuzumab improved the depth and duration of responses but came with an increased risk of dying, mainly from the excessive COVID-19 mortality. There is good reason to believe that the risk is much lower post-pandemic. Still, adding obinutuzumab to A+V will involve carefully balancing the increased risks versus the increased benefits.
This will likely be the first of many combinations to increase the options for CLL / SLL patients. Similar doublets are being studied with zanubrutinib, pirtobrutinib, and a new experimental BCL2 blocker, sonrotoclax. The MAJIC trial is comparing acalabrutinib plus venetoclax versus venetoclax plus obinutuzumab.
The future increasingly seems focused on limited-duration combination therapies and appears very promising.
Links:
The full ASH 2024 abstract can be accessed at Fixed-Duration Acalabrutinib Plus Venetoclax with or without Obinutuzumab Versus Chemoimmunotherapy for First-Line Treatment of Chronic Lymphocytic Leukemia: Interim Analysis of the Multicenter, Open-Label, Randomized, Phase 3 AMPLIFY Trial.
Watch CLL Society’s interview with Dr. Jennifer Brown below.
