Orelabrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (OFCG) for First-Line Treatment of Chronic Lymphocytic Leukemia: A Multicenter, Investigator-Initiated Study (cwCLL-001 Study)

Background: A phase II trial has shown, that first-line treatment with iFCG (ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab) led to a bone marrow (BM) undetectable minimal residual disease (uMRD) rate of 98% (44/45) as the best response in patients with chronic lymphocytic leukemia (CLL) with mutated immunoglobulin heavy⁃chain variable region gene (IGHV) and without TP53 aberrations. A phase II trial was initiated to evaluate the efficacy and safety of the second-generation BTK inhibitor orelabrutinib (O) plus FCG (OFCG) in younger, fit patients with previously untreated CLL/small lymphocytic lymphoma (SLL) without restriction by del(17p)/TP53 aberrations and/or IGHV mutation status (cwCLL-001 study, NCT05322733).

Methods：This is a multicenter, open-label, non-randomized phase II study for previously untreated patients with CLL/SLL without restriction by del(17p)/TP53 aberrations and/or IGHV mutation status. Eligible patients were 18-65 years old with adequate renal function. A 7-day lead-in period with single-agent oral orelabrutinib (150 mg daily) was given in all patients, followed by OFCG regimen for three 28-day cycles. Patients who achieved undetectable MRD (uMRD at 10^-4) in BM assessed by flow cytometry (FCM) discontinued FC and received 3 cycles of orelabrutinib plus obinutuzumab (OG). Otherwise, the patients received an additional 3 cycles of OFCG. Patients who achieved BM-uMRD after 6 cycles discontinued obinutuzumab and others received an additional six cycles of OG. Patients who achieved BM-uMRD by FCM after 12 cycles discontinued all treatments, otherwise, they continued orelabrutinib for a further 1 year. MRD in the BM and peripheral blood was evaluated by a next-generation sequencing (NGS) assay of immunoglobulin gene rearrangements with a sensitivity of up to 10⁻⁶. The primary endpoint is the rate of BM-uMRD after 6 cycles by FCM (at 10^-4 sensitivity). The secondary endpoints are the rates of uMRD in BM and peripheral blood (PB) at other key time points by FCM, best overall response rate (ORR), complete response rate (CRR), progression-free survival (PFS), 2- and 3-year PFS rates, duration of response (DOR), overall survival (OS), 3-year OS rate as well as safety.

Results: From 30 May 2022 to 30 Jun 2023, 25 patients were enrolled. The median age was 49 years (range, 23-62). Unmutated IGHV, del(17p), TP53 mutation, and del(11q) were detected in 63% (15/24), 8% (2/25), 13% (3/24), and 24% (6/25) of patients, respectively. At the data cut-off (July 24^th, 2024), the median follow-up was 21.4 months (range 7.3-25.7 months). 2 patients were off the study due to willingness, and 23 patients completed 3 cycles of OFCG. One patient who received only one cycle of FCG was also evaluated for PB-MRD after cycle 3. After 3 cycles, the rates of PB-uMRD and BM-uMRD by FCM were 71% (17/24) and 57% (13/23), respectively, and the ORR and CR/CRi (CR with incomplete hematologic recovery) rates were 100% (22/22) and 32% (7/22), respectively. One patient died after cycle 5 due to COVID-19 infection. Twenty-two patients completed 6 cycles of treatment. After cycle 6, the rates of PB-uMRD and BM-uMRD by FCM were 95% (20/21) and 86% (19/22), respectively, and the rate CR/CRi was 59% (13/22). A total of 22 patients completed 12 cycles of treatment. After cycle 12, the rates of PB-uMRD by FCM, BM uMRD by FCM, and CR/CRi were 95% (21/22), 91% (20/22), and 77% (17/22), respectively. Twelve of 21 patients and 11 of 20 patients achieved BM-uMRD at 10⁻⁶ sensitivity by NGS after cycle 6 and cycle 12, respectively. Mutated IGHV was significantly associated with higher rates of BM-uMRD by NGS after cycle 6 and cycle 12 (C6: IGHV mutated 100% [9/9] vs. 25% [3/12], p=0.0011; IGHV mutated 88% [7/8] vs. 33% [4/12], p=0.0281). The 2-year PFS was 96%. Adverse effects were mainly hematological. Grade 3-4 neutropenia occurred in 20 (80%) patients at any time during the treatment (G4, n =13). Grade 3-4 thrombocytopenia was present in 13 (52%) patients (G4, n=2). Grade 3-4 neutropenia and thrombocytopenia were reported in 17 (68%) and 12 (48%) patients during the OFCG cycles, respectively. Neutropenic fever occurred in four patients (16%, all in the OFCG cycles). No patients developed atrial fibrillation or flutter.

Conclusion: The OFCG regimen leads to a rapid and deep molecular remission with a manageable safety profile in previously untreated CLL patients including those with unfavorable characteristics.

No relevant conflicts of interest to declare.

Previous studies have evaluated the ibrutinib combined with fludarabine, cyclophosphamide, and rituximab (or obinutuzumab; iFCR or iFCG) in patients with CLL/SLL as first-line therapy and achieved a favorable remission. Orelabrutinib is a newly developed BTK inhibitor with high selectivity. High kinase selectivity,persistent BTK target occupancy, potent anti-tumor activity, and the safety profile support orelabrutinib combined FCG could achieved deeper remission.