S145: The Combination of Ibrutinib Plus Venetoclax Results in a High Rate of MRD Negativity in Previously Untreated Cll: The Results of the Planned Interim Analysis of the Phase Iii Ncri Flair Trial

Hillmen, Peter; Pitchford, Alexandra; Bloor, Adrian; Pettitt, Andrew R.; Patten, Piers; Forconi, Francesco; Schuh, Anna; Fox, Chris P; Elmusharaf, N.; Gatto, S.; Kennedy, Ben; Gribben, John G.; Pemberton, Nicholas; Sheehy, Oonagh; Preston, Gavin; Howard, D.; Hockaday, Anna; Cairns, David A.; Jackson, Sharon; Greatorex, Natasha; Webster, N.; Dalal, S.; Shingles, J.; Cwynarski, Kate; Paneesha, Shankaranarayana; Allsup, D.; Rawstron, A.; Munir, Tahla

doi:10.1097/01.hs9.0000843472.57904.29

Cited by 6 publications

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“…The rates of U-MRD4 in ELEVATE-TN were similar in PB and BM in the patients with CR/CRi in the AO and ClbO arms (Table 6). Only one patient in the acalabrutinib monotherapy group had U-MRD4 in peripheral blood by flow cytometry, which is consistent with what has been described for other BTKis (61). Interestingly, there are similar rates of U-MRD4 in the two primary groups in patients achieving CR within each group, though a higher number of patients achieved CR in the AO arm.…”

Section: Mrd Outcomessupporting

confidence: 87%

“…Monitoring MRD levels may provide a means of potential safe treatment de-escalation or cessation but is potentially of limited value in single-agent BTKi regimens where U-MRD4 is expected to occur rarely. These regimens can still achieve good ORR and PFS rates even without obtaining a high U-MRD rate (59,61). Conversely, MRD retains its potential utility when BTK inhibitors are administered in combination with another CLL-directed therapy with a high U-MRD4 rate, as part of a fixed-duration regimen or one with MRD-driven stopping rules.…”

Section: Clinical Decisions With Mrd Results and Patient's Experiencementioning

confidence: 99%

“…Interim of the first 274 patients on I or IV reported a similar ORR at 9 months, but with a higher CR of 59.6% versus 8% favoring IV. Extending this to 24 months, 93.4% on IV were in CR (Table 6) and 39.7% had stopped treatment as per the MRD stopping rules (61).…”

Section: Treatment-naive Continuous Therapy Trialsmentioning

confidence: 99%

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The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials

et al. 2023

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Measurable residual disease (MRD) status in chronic lymphocytic leukemia (CLL), assessed on and after treatment, correlates with increased progression-free and overall survival benefit. More recently, MRD assessment has been included in large clinical trials as a primary outcome and is increasingly used in routine practice as a prognostic tool, a therapeutic goal, and potentially a trigger for early intervention. Modern therapy for CLL delivers prolonged remissions, causing readout of traditional trial outcomes such as progression-free and overall survival to be inherently delayed. This represents a barrier for the rapid incorporation of novel drugs to the overall therapeutic armamentarium. MRD offers a dynamic and robust platform for the assessment of treatment efficacy in CLL, complementing traditional outcome measures and accelerating access to novel drugs. Here, we provide a comprehensive review of recent major clinical trials of CLL therapy, focusing on small-molecule inhibitors and monoclonal antibody combinations that have recently emerged as the standard frontline and relapse treatment options. We explore the assessment and reporting of MRD (including novel techniques) and the challenges of standardization and provide a comprehensive review of the relevance and adequacy of MRD as a clinical trial endpoint. We further discuss the impact that MRD data have on clinical decision-making and how it can influence a patient’s experience. Finally, we evaluate how upcoming trial design and clinical practice are evolving in the face of MRD-driven outcomes.

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Section: Mrd Outcomessupporting

confidence: 87%

Section: Clinical Decisions With Mrd Results and Patient's Experiencementioning

confidence: 99%

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The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials

et al. 2023

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“…The primary endpoint of this study, the CR rate at the EOT, was met with a 76% CR rate, which compares favorably with that reported in fit patients treated with FCR chemoimmunotherapy in the CLL10 trial (40%) and the ECOG1912 study (30.3%) 9,36 , and also in the CLL14 trial in unfit patients treated with Ven plus obinutuzumab (49.5%) [21][22][23] . High CR rates were also described with ibrutinib and Ven in the Flair trial (59.6%) 38 and the MRD and the fixed duration cohorts of the Captivate trial (46% and 52.2%) [37][38][39] .…”

Section: Discussionmentioning

confidence: 85%

High rate of durable responses with undetectable minimal residual disease with front-line venetoclax and rituximab in young, fit patients with chronic lymphocytic leukemia and an adverse biological profile: results of the GIMEMA phase II LLC1518 – VERITAS study

et al. 2023

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The GIMEMA phase II LLC1518 VERITAS trial investigated the efficacy and safety of frontline, fixed-duration venetoclax and rituximab (VenR) combination in young (≤65 years) and fit patients with chronic lymphocytic leukemia (CLL) and unmutated IGHV and/or TP53 disruption. Treatment consisted of the Ven ramp-up, six-monthly courses of the VenR combination, followed by six monthly courses of Ven single agent. A centralized assessment of measurable minimal residual disease (MRD) was performed on the peripheral blood (PB) and bone marrow (BM) by ASO-PCR at the end of treatment (EOT) and during the follow-up. The primary endpoint was the complete remission (CR) rate at the EOT. Seventy-five patients were enrolled; the median age was 54 years (range 38-65), 96% had unmutated IGHV, 9 (12%) had TP53 disruption, and 4% were IGHV mutated with TP53 disruption. The overall response rate (ORR) at the EOT was 94.7%, with a CR rate of 76%. An undetectable (u) MRD was recorded in 69.3% of patients in the PB and 58.7% in the BM. The 12-month MRD-free survival in the 52 patients with uMRD in the PB at the EOT was 73.1%. After a median follow-up of 20.8 months, no disease progressions were observed. Three patients have died, two due to Covid-19 and 1 to tumor lysis syndrome. The first report of the VERITAS study shows that frontline VenR was associated with a high rate of CRs and durable responses with uMRD in young patients with CLL and unfavorable genetic characteristics.

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“…Contrarily, the BCL2 inhibitor venetoclax, in combination with anti-CD20 antibody, has shown durable MRD negativity and a promising long-lasting progression-free survival in relapsed and refractory patients ( 7 ). Furthermore, the combination of BTK and BCL2 inhibitors (ibrutinib and venetoclax) achieves even deeper MRD negativity, and it has a favorable prognostic profile in terms of PFS, but it is now available only in few clinical trials ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Measurable residual disease in chronic lymphocytic leukemia

et al. 2023

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Measurable residual disease (MRD) is defined as the presence of residual cancer cells after treatment in patients with clinically undetectable disease, who would otherwise be considered in complete remission. It is a highly sensitive parameter which indicates the disease burden and predicts survival in this setting of patients. In recent years, MRD has gained a role in many hematological malignancies as a surrogate endpoint for clinical trials: undetectable MRD has been correlated to longer progression free survival (PFS) and overall survival (OS). New drugs and combinations have been developed with the aim to achieve MRD negativity, which would indicate favorable prognosis. Different methods to measure MRD have also been devised, which include flow cytometry, polymerase chain reaction (PCR) and next generation sequencing (NGS), with different sensitivity and accuracy in evaluating deep remission after treatment. In this review, we will analyze the current recommendations for the detection of MRD, with particular focus on its role in Chronic Lymphocytic Leukemia (CLL), as well as the different detection methods. Moreover, we will discuss the results of clinical trials and the role of MRD in new therapeutic schemes with inhibitors and monoclonal antibodies. MRD is not currently used in the clinical practice to evaluate response to treatment, due to technical and economical limitations, but it’s gaining more and more interest in trials settings, especially since the introduction of venetoclax. The use of MRD in trials will likely be followed by a broader practical application in the future. The aim of this work is to provide a reader-friendly summary of the state of art in the field, as MRD will soon become an accessible tool to evaluate our patients, predict their survival and guide physician’s therapeutic choices and preferences.

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S145: The Combination of Ibrutinib Plus Venetoclax Results in a High Rate of MRD Negativity in Previously Untreated Cll: The Results of the Planned Interim Analysis of the Phase Iii Ncri Flair Trial

Cited by 6 publications

References 0 publications

The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials

The evolving use of measurable residual disease in chronic lymphocytic leukemia clinical trials

High rate of durable responses with undetectable minimal residual disease with front-line venetoclax and rituximab in young, fit patients with chronic lymphocytic leukemia and an adverse biological profile: results of the GIMEMA phase II LLC1518 – VERITAS study

Measurable residual disease in chronic lymphocytic leukemia

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