Combination of Ibrutinib Plus Venetoclax with MRD-Driven Duration of Treatment Results in a Higher Rate of MRD Negativity in IGHV Unmutated Than Mutated CLL: Updated Interim Analysis of FLAIR Study

Munir, Talha; Pitchford, Alexandra; Bloor, Adrian; Pettitt, Andrew R.; Patten, Piers E.M.; Forconi, Francesco; Schuh, Anna; Fox, Christopher P.; Gatto, Simona; Kennedy, Ben; Gribben, John G.; Pemberton, Nicholas; Sheehy, Oonagh; Preston, Gavin; Howard, Dena; Hockaday, Anna; Cairns, David A.; Jackson, Sharon; Greatorex, Natasha; McWhirter, Nichola; Shingles, Jane; Cwynarski, Kate; Paneesha, Shankara; Allsup, David; Rawstron, Andrew; Hillmen, Peter

doi:10.1182/blood-2022-170463

Cited by 11 publications

(17 citation statements)

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“…However, if U-MRD4 was achieved at EOT+3, U-MRD4 was sustained in 80% of uIGHV patients and 76.9% of mIGHV patients (50). In the ClbO arm, just 12.2% of patients sustained U-MRD4 at EOT+18 (51). These findings reflect the durable responses seen in CLARITY, where 75% of the cohort had uIGHV (47), and demonstrate that while the addition of venetoclax increases U-MRD4 responses, the BTKi base still holds the preference for response in uIGHV disease.…”

Section: Mrd Outcomesmentioning

confidence: 61%

“…Of those in U-MRD4 at 6 months, this was sustained at either 26 or 38 months. Of note, 75% of this cohort had uIGHV disease, and the good rates of U-MRD4 and the durability of remission for U-MRD4 patients with IV have also been reflected in uIGHV patients in the later GLOW and FLAIR trials (47,50,51).…”

Section: Mrd Outcomesmentioning

confidence: 81%

“…Further interesting results from FLAIR 2 years postrandomization were presented at ASH 2022 (51) for the IV arm, demonstrating a higher rate of U-MRD4 in uIGHV than mIGHV disease. The arms were well balanced for other disease variables when stratified by IGHV mutational status.…”

Section: Mrd Outcomesmentioning

confidence: 95%

“…Furthermore, GLOW has reported on residual disease kinetics after the EOT stratified by IGHV mutational status (50). In theory, uIGHV disease should respond well to ibrutinib-based therapies due to the dependence of this disease on BCR signaling (51), and this has been demonstrated in single-agent ibrutinib trials (54, 55). In the IV arm, the U-MRD4 rates at cycle 6 (6 months of treatment) in uIGHV disease were 52.2%, with EOT+3 U-MRD4 59.7%, and 77.6% of these patients retaining U-MRD4 at EOT plus 18 months (EOT+18).…”

Section: Mrd Outcomesmentioning

confidence: 98%

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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 Outcomesmentioning

confidence: 61%

Section: Mrd Outcomesmentioning

confidence: 81%

Section: Mrd Outcomesmentioning

confidence: 95%

Section: Mrd Outcomesmentioning

confidence: 98%

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

et al. 2023

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“…In treatment arms combining ibrutinib with rituximab or obinutuzumab, the PFS seems to be shorter in the IGHV unmutated than mutated subgroup, but direct comparisons are missing and results on the combination of acalabrutinib and obinutuzumab did not suggest a prognostic impact of the IGHV status ( 5 – 7 , 9 ). With regards to venetoclax-based fixed-duration therapy, unmutated IGHV status retained prognostic significance and one can speculate that as IGHV unmutated patients achieved high response rates and MRD negativity, shorter PFS may reflect the more proliferative nature of IGHV unmutated CLL cells potentially leading to a faster re-growth of the CLL clone after end of treatment ( 10 , 38 – 40 ).…”

mentioning

confidence: 99%

Opinion: What defines high-risk CLL in the post-chemoimmunotherapy era?

Edelmann¹,

Malčíková²,

Riches³

2023

Front. Oncol.

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The definition of high-risk chronic lymphocytic leukemia (CLL) was relatively simple in the chemoimmunotherapy era, as it was defined by only one genomic marker, TP53 alteration, along with poor responses to purine-analogue based treatment (1). While other biomarkers such as unmutated IGHV, del(11q), high ZAP70 expression and high CD38 expression were associated with inferior prognosis, TP53 deficiency by mutation and/or del (17p) remained the only biomarker that clearly guided treatment decisions (2).The emergence of targeted compounds has rendered chemoimmunotherapy virtually obsolete for CLL treatment, with it remaining an option only for patients with a mutated IGHV, normal TP53 and a non-complex karyotype (3). Instead, non-chemotherapeutic targeted treatment has now become the standard of care. Approved treatment options in firstand second-line include continuous treatment with a covalent BTK inhibitor (e.g. ibrutinib, acalabrutinib) plus/minus anti-CD20 monoclonal antibody (4-9), fixed duration therapy with the BCL2 inhibitor venetoclax plus anti-CD20 monoclonal antibody (10, 11), fixed duration therapy with venetoclax plus ibrutinib (12, 13), and for TP53 altered cases, continuous monotherapy with venetoclax (14). Moreover, clinical trials are currently evaluating triple drug regimens that combine BTK and BCL2 inhibitors with anti-CD20 treatment (15-18). Looking forward, non-covalent BTK inhibitors (e.g. pirtobrutinib and nemtabrutinib) (19, 20), BTK degraders (e.g. NX-2127) (21), and second-generation BCL2 inhibitors (e.g. Lisaftoclax) ( 22) are promising alternatives in clinical development, along with immunotherapeutic approaches such as CAR T-cells and bispecific antibodies.The paradigm shift from chemoimmunotherapy to targeted therapy and the everincreasing number of treatment options has meant that defining high-risk CLL is less straight-forward. This is mainly because BTK and BCL2 inhibitors have been demonstrated to markedly improve progression-free and overall survival (PFS and OS) in TP53-deficient and IGHV unmutated CLL patients (4,5,7,9, 10,14,(23)(24)(25). Limited data from clinical trials evaluating ibrutinib first-line and acalabrutinib have even raised the possibility that BTKinhibition may overcome the adverse effects of TP53 deficiency (5,6,9,26). Although resultsFrontiers in Oncology frontiersin.org 01

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