The landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treatment has been significantly transformed by new data from a pivotal Phase III trial and emerging therapeutic approaches. The AMPLIFY trial has established new benchmarks for first-line treatment, while innovative immunotherapy options show promise for relapsed/refractory disease.
AMPLIFY Trial Demonstrates Superiority of Novel Combinations
The Phase III AMPLIFY trial has revealed compelling evidence for the superiority of acalabrutinib-based regimens over traditional chemoimmunotherapy in previously untreated CLL/SLL patients. At a median follow-up of 41 months, both the doublet (acalabrutinib plus venetoclax) and triplet (acalabrutinib, venetoclax, and obinutuzumab) combinations demonstrated statistically significant improvements in progression-free survival compared to chemoimmunotherapy (hazard ratios of 0.65 and 0.42, respectively).
The results were particularly striking in patients with unmutated IGHV, where the triplet regimen achieved an impressive 82% three-year progression-free survival rate, compared to 68% with the doublet and 56% with chemoimmunotherapy. The acalabrutinib plus venetoclax combination also showed a trending overall survival benefit over chemoimmunotherapy (HR = 0.33, nominal P < .0001).
Safety Considerations and COVID-19 Impact
While efficacy data strongly favored the novel combinations, safety monitoring revealed important considerations. The triplet therapy showed the highest incidence of grade ≥3 COVID-19 infections (6%) and COVID-19 pneumonia (11%). Serious adverse events leading to death were most frequent in the triplet arm at 6%, primarily due to COVID-19 complications. Notably, cardiac events and hypertension remained below 3% across all treatment arms, with bleeding events mainly confined to the acalabrutinib-containing regimens.
Promising Results for Relapsed/Refractory Disease
In parallel developments, the novel CD3 × CD20 bispecific antibody epcoritamab has shown encouraging results in heavily pretreated CLL/SLL patients. In the EPCORE CLL-1 trial, epcoritamab demonstrated complete response rates of 43% in the expansion cohort and 60% in the optimization cohort, with a median progression-free survival of 12.8 months.
The optimization cohort successfully eliminated grade ≥3 cytokine-release syndrome through an adapted step-up dosing schedule, while maintaining efficacy. This represents a significant advance for patients who have exhausted other treatment options, particularly those who have become refractory to both BCL2 and BTK inhibitors.
Clinical Implications and Future Directions
These findings establish acalabrutinib-based combinations as potential new standards for first-line CLL/SLL treatment in fit patients without del(17p) or TP53 mutation. The choice between doublet and triplet therapy will likely depend on individual patient factors, particularly considering the increased risk of COVID-19 complications with the triplet regimen.
The emergence of epcoritamab as a viable option for relapsed/refractory disease adds another valuable tool to the therapeutic arsenal, particularly given its manageable safety profile and the ability to administer it subcutaneously. These developments collectively represent significant progress in the treatment of CLL/SLL, though long-term follow-up data will be crucial for determining the durability of responses and long-term safety profiles.
