A prospective, single-center, single-arm clinical trial of zanubrutinib monotherapy and zfcg combined therapy was given sequentially for the treatment of primary symptomatic CLL/SLL (Stop Trial)

Abstract Background: Although Bruton tyrosine kinase (BTK) inhibitor monotherapy yields an overall response rate (ORR) of 80–90% and prolongs survival in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), its complete response (CR) rate remains suboptimal (<10%). Even after 7–8 years of continuous treatment, the CR rate only improves to around 30%. More critically, achieving undetectable minimal residual disease (uMRD) is infrequent, compelling patients to undergo long-term BTK inhibitor therapy. To address these limitations, our trial investigated a time-limited combination immunochemotherapy strategy in treatment-naïve CLL patients, aiming to deepen remission, achieve uMRD, and enable treatment cessation to enhance quality of life. Methods: Eligible pts were treatment-naïve CLL/SLL patients aged ≤65 years. The regimen consisted of zanubrutinib (Z) monotherapy (160 mg twice daily) for 12 cycles, followed by four cycles of combination therapy with fludarabine (F, 25 mg/m² IV D1-3 cycles 13-16), cyclophosphamide (C, 250 mg/m² IV D1-3 cycles 13-16), and obinutuzumab (G, 1000 mg IV D0,7,14 cycle 13; 1000 mg IV D0 cycles 14-16) (ZFCG regimen). After cycle 16, response and MRD status in peripheral blood (PB) and bone marrow (BM) were assessed by four-color flow cytometry. Patients achieving CR/CRi with uMRD in both PB and BM could stop treatment; others could choose to continue or stop zanubrutinib monotherapy.（NCT05287984） Results: As of April 1, 2025, 59 pts initiated therapy. Thirty pts completed combination therapy; 3 withdrew (1 due to COVID-19 impact, 2 due to disease progression：one in zanubrutinib monotherapy phase, the other post the ZFCG phase). Baseline characteristics: median age 58 years (range 33-65); 67.8% male. High-risk and very-high-risk CLL-IPI scores were present in 20.3% and 3.4% of pts, respectively. IGHV was unmutated in 38.3%. Cytogenetic abnormalities included TP53 deletion (del) (1.7%), ATM del (15.3%), RB1 del (22.0%), and trisomy 12 (20.3%). TP53 mutation was detected by NGS in 3.4%. All 59 patients received zanubrutinib monotherapy, with 41 progressing to the ZFCG phase. Among the 30 patients who completed 4 cycles of ZFCG and underwent efficacy assessment, after 12 cycles of zanubrutinib monotherapy alone, the CR rate was 13.3% (4/30), and only 1 patient (3.3%) achieved CR with uMRD in both PB and BM. After 2 cycles of ZFCG, 18 patients (60%) achieved both CR and CR with PB+BM uMRD. Upon completion of 4 cycles of ZFCG, the proportion of patients achieving CR and CR with PB+BM uMRD increased to 76.7% (23/30) and 73.3% (22/30), respectively. Additionally, 100% of patients (30/30) achieved PB uMRD, and 96.7% (29/30) achieved BM uMRD. All 30 patients met the criteria for treatment cessation after completing 16 cycles of therapy. With a maximum treatment-free interval of 20 months, 29 patients maintained CR with uMRD without treatment. However, 1 patient experienced disease progression, characterized by the reappearance of a pulmonary mass noted at diagnosis, 7 months post-cessation, although the BM remained in CR with uMRD at recurrence. During the ZFCG phase, the most common grade ≥3 adverse events (AEs) were thrombocytopenia (32.5%), neutropenia (27.5%), and leukopenia (25%). Grade ≥3 non-hematological AEs included lung infection (15%) and febrile neutropenia (5%). Conclusion: The ZFCG regimen demonstrated high rates of CR with uMRD in treatment-naïve CLL patients after 4 cycles of combination therapy, accompanied by excellent uMRD rates in PB and BM. All patients who completed 16 cycles of therapy fulfilled the criteria for treatment cessation. With a median follow-up of nearly 1 year (max 20 months) post-treatment, 29 out of 30 patients maintained continuous CR with uMRD. However, longer follow-up is required to determine the durability of treatment-free remission. These preliminary findings from the Stop Trial indicate that ZFCG is an effective, time-limited treatment option for treatment-naïve CLL patients.