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Monitoring of measurable residual disease (MRD) can assess depth of response and predict prognosis in patients with chronic lymphocytic leukemia (CLL) treated with immuno-chemotherapy or targeted therapies such as venetoclax monotherapy or venetoclax plus anti-CD20 monoclonal antibodies, which effectively eradicate CLL cells. In the phase 3 MURANO trial comparing venetoclax plus rituximab (VenR) against bendamustine plus rituximab (BR) in patients with relapsed or refractory CLL (rrCLL), patients in the VenR arm had better progression-free survival (PFS) and a higher rate of undetectable MRD (uMRD; less than 1 × 10−4) in peripheral blood (PB) at end of treatment than those receiving BR, regardless of presence of high-risk biomarkers [1]. Moreover, uMRD at the end of treatment in patients in the VenR arm was associated with longer PFS and overall survival compared with patients with high MRD + (≥ 1 × 10−2). Moreover, the median time from MRD conversion to clinical progression was 25.2 months, suggesting that early intervention before clinical progression in patients with MRD conversion might be a clinical option that merits testing in clinical trials. Fixed-duration therapy using venetoclax is being introduced for first-line treatment of CLL. Consequently, monitoring of MRD is increasingly important for CLL management, but reports on MRD monitoring in these patients remain rare in Japan. Here, we report MRD monitoring results of our phase 1/2 study of venetoclax with/without rituximab in patients with rrCLL/small lymphocytic lymphoma (SLL) (M13-834, NCT02265731) [2].
Study design, eligibility criteria, and dosing of M13-834 were as previously reported [2]. In brief, M13-834 was an open-label, multi-center phase 1/2 study of venetoclax monotherapy or combination therapy in Japanese patients with hematological malignancies. Six patients with rrCLL/SLL were enrolled in Arm B (phase 1 study of venetoclax monotherapy) and six with rrCLL only were enrolled in Arm D (phase 2 study of VenR). In both arms, venetoclax was administered with a weekly stepwise ramp-up in dose, followed by a dose of 400 mg/day. In Arm D, rituximab 375 mg/m2 was administered on day 1 of week 6, followed by 500 mg/m2 every 4 weeks until day 1 of week 29. Efficacy was evaluated according to the International Workshop on CLL consensus guidelines.
Samples for MRD measurements were prospectively obtained from PB at baseline (both arms), day 1 of week 24 (Arm B), day 1 of week 30 and every 12 weeks thereafter (Arm D), and within 3 months after complete remission (CR), after CR with incomplete blood count recovery, or when radiographic partial response (PR) criteria were first met (both arms). MRD was measured using the clonoSEQ® assay, a next-generation sequencing-based assay that identifies rearranged IgH, IgK, and IgL receptor gene sequences. The limit of detection and the limit of quantitation of this assay were reported as 1.903 and 2.390 malignant cells [3]. Depending on the amount of genomic DNA input, this assay can detect MRD at least at the 10–6 level (< 1 in 1 million cells). MRD data were available for two patients (Patients 1 and 2) in Arm B and four patients (Patients 3–6) in Arm D. However, PB samples were unavailable for the other six patients due to SLL in two patients, discontinuation of the study because of adverse events and progressive disease in two patients, and unreported reasons in the remaining patients. We evaluated achievement of uMRD or MRD4 as defined by < 1 × 10−4 MRD (< 1 cell/10,000 leukocytes or < 0.01%) [4].
Tumor responses and MRD are presented in Table 1. All four patients receiving VenR achieved CR and uMRD. Meanwhile, two patients receiving venetoclax monotherapy did not achieve CR and uMRD, and their best response was PR. In Patients 3–6, the time to uMRD was 23 (range: 14–40) weeks. This study had several limitations. Because the number of patients with available MRD monitoring data was small, it remains unclear whether uMRD correlated with PFS or other endpoints in this population, or whether these results can be extrapolated to other MRD monitoring methods, such as allele-specific polymerase chain reaction and flow cytometry [4].
In conclusion, MRD monitoring using the clonoSEQ® assay is feasible in Japanese patients with rrCLL who received venetoclax. uMRD was achieved in all patients treated with VenR with available MRD data.
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References
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Medical writing support was provided by Shinichi Kaiho (ASCA Corporation) in the development of this publication and funded by AbbVie GK.
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AbbVie, Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, review, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
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Koji Izutsu: clinical trial contracts with AbbVie, AstraZeneca, Beigene, Celgene, Chugai Pharmaceutical, Janssen, Novartis and Yakult; and honoraria for lectures from Janssen, AbbVie, Novartis, Celgene, AstraZeneca and Chugai Pharmaceutical. Kazuhito Yamamoto: grants from IQVIA/Genmab, Ono Pharmaceutical, Solasia Pharma, Yakult and Incyte; grants and personal fees from AbbVie, Astra-Zeneca, Bristol-Myers Squibb/Celgene, Chugai Pharmaceutical, Eisai, Meiji Seika Pharma, Nippon Shinyaku, Novartis, Otsuka Pharmaceutical, Takeda and Zenyaku; personal fees from SymBio, HUYA/IQVIA Services Japan, Janssen, Kyowa Kirin, Micron/Daiichi-Sankyo, MSD, Sanofi, Nippon Kayaku and Astellas. Koji Kato: consulting fees from AbbVie, AstraZeneca, Celgene, Chugai Pharmaceutical, Eisai, Janssen, Daiichi Sankyo, Ono Pharmaceutical and Novartis; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Celgene, Dainippon-Sumitomo, Janssen, Kyowa Kirin, MSD, Mundipharma, Ono Pharmaceutical, Takeda, AbbVie, Daiichi Sankyo, Eisai and Chugai Pharmaceutical. Takayuki Ishikawa: grants from AbbVie. Noriko Fukuhara: research grants from AbbVie, Bayer, Chugai Pharmaceutical, Celgene, Genmab and Incyte; and honoraria from AstraZeneca, BMS, Chugai Pharmaceutical, CSL Behring, Dainippon Sumitomo, Eisai, Janssen, Kyowa Kirin, Nippon Shinyaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Sanofi, Symbio, Takeda and Zenyaku; and data safety monitoring board for HUYA Japan; and advisory board for AstraZeneca, AbbVie, Eli Lilly, Genmab and Novartis. Yasuhito Terui: consultant/adviser/honoraria from Celgene, Janssen, Eisai, Ono Pharmaceutical, Chugai Pharmaceutical, Symbio and AbbVie; and research grants from AbbVie, Bristol Myers Squibb; and scholarship funds from Ono Pharmaceutical, Eisai and Takeda. IIseung Choi: grants from AbbVie. Sumiko Okubo, Natsumi Ogawa, Mizu Sakai, Yasuko Nishimura, Brenda J Chyla, and Yan Sun: Employees of AbbVie and possible ownership of stocks or options. Dai Maruyama: honoraria from Ono Pharmaceutical, Celgene, Takeda, Janssen, Mundipharma, Eisai, Chugai Pharmaceutical, Kyowa Kirin, MSD, Zenyaku, Bristol Myers Squibb, AstraZeneca, Nippon Shinyaku, AbbVie, Sanofi and SymBio; research grants from Amgen Astellas Biopharma, Celgene, Kyowa Kirin, Novartis, Chugai Pharmaceutical, Ono Pharmaceutical, Takeda, Janssen, Sanofi, MSD, Otsuka Pharmaceutical, Bristol Myers Squibb, Astellas, Eisai and AbbVie; and scholarship funds from Taiho, Chugai Pharmaceutical, Ono Pharmaceutical, Kyowa Kirin and Eisai.
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Izutsu, K., Yamamoto, K., Kato, K. et al. Measurable residual disease in Japanese patients with relapsed or refractory chronic lymphocytic leukemia treated with venetoclax. Int J Hematol 118, 526–528 (2023). https://doi.org/10.1007/s12185-023-03646-3
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DOI: https://doi.org/10.1007/s12185-023-03646-3