A fixed-duration, measurable residual disease–guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial

Michallet, Anne‐Sophie; Letestu, Rémi; Garff‐Tavernier, Magali Le; Aanei, Carmen Mariana; Ticchioni, Michel; Dilhuydy, Marie-Sarah; Subtil, Fabien; Rouille, Valérie; Mahé, Béatrice; Laribi, Kamel; Villemagne, Bruno; Salles, Gilles; Tournilhac, Olivier; Delmer, Alain; Portois, Christelle; Pégourie, Brigitte; Leblond, Véronique; Tomowiak, Cécile; Guibert, Sophie de; Piocelle, Frédérique Orsini; Banos, Anne; Carassou, P.; Cartron, Guillaume; Fornecker, Luc‐Matthieu; Ysebaert, Loïc; Dartigeas, Caroline; Truchan-Graczyk, Malgorzata; Vilque, Jean-Pierre; Aurran, Thérèse; Cymbalista, Florence; Leprêtre, Stéphane; Lévy, Vincent; Nguyen‐Khac, Florence; Feugier, Pierre

doi:10.1182/blood.2020008164

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…The ICLL-07 study design ( supplemental Figure 1 ), inclusion/exclusion criteria ( supplemental Data ), and methodology are published. 35 , 36 Supplemental Figure 2 shows the patient-care flow. Briefly, between 27 October 2015 and 16 May 2017, a total of 135 previously untreated, medically fit patients with CLL were enrolled from 27 FILO centers.…”

Section: Methodsmentioning

confidence: 99%

“… 32 , 33 , 34 However, several phase 2 trials are now providing evidence to support the alternative approach of combining targeted agents with immunochemotherapy. 35 , 36 , 37 , 38 …”

Section: Introductionmentioning

confidence: 99%

“…The phase 2 ICLL-07 trial by the French Innovative Leukemia Organization (FILO) evaluated a fixed-duration (15-month) combination of ibrutinib plus obinutuzumab-based immunochemotherapy in previously untreated, medically fit patients with CLL. 35 , 36 Patients underwent obinutuzumab and ibrutinib induction for 9 months, then an MRD-guided strategy for 6 additional months, in which all patients received ibrutinib, and immunochemotherapy (≤4 cycles of FCG) was given only to those in partial response and/or with BM MRD ≥0.01%. MRD was measured using an 8-color flow cytometry technique with sensitivity of 10 -6 .…”

Section: Introductionmentioning

confidence: 99%

“… 35 The follow-up at median 37 months from the start of the treatment showed a persistent PB MRD benefit beyond the end of treatment, high survival rates, and low long-term toxicity. 36 …”

Section: Introductionmentioning

confidence: 99%

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A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

et al. 2023

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In previously untreated, medically fit patients with chronic lymphocytic leukemia, research is focused on developing fixed-duration strategies to improve long-term outcomes whilst sparing patients from serious toxicities. The ICLL-07 trial evaluated a fixed-duration (15-month) immunochemotherapy approach where, following obinutuzumab-ibrutinib induction for 9 months, patients (n=10) in complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) <0.01% continued only ibrutinib 420 mg/day for 6 additional months (I arm), whereas the majority (n=115) received up to 4 cycles of fludarabine/cyclophosphamide-obinutuzumab 1000 mg alongside the ibrutinib (I-FCG arm). Primary analysis at month 16 showed that 62.2% (84/135) of all patients enrolled achieved CR with BM MRD <0.01%. Here we report follow-up at median 63 months. PB MRD was assessed 6 monthly beyond end of treatment using a highly-sensitive (10-6) flow cytometry technique. In the I-FCG arm, the PB MRD <0.01% rate (low-level positive <0.01% or undetectable with limit of detection ≤10-4) in evaluable patients was still 92.5% (74/80) at month 40 and 80.6% (50/62) at month 64. No differences in PB MRD status were apparent according to the IGHV mutational status. In the overall population, 4-year progression-free and overall survival rates were 95.5% and 96.2%, respectively. Twelve deaths occurred overall. Fourteen serious adverse events occurred beyond the end of treatment. Thus, our fixed-duration immunochemotherapy approach produced deep and sustained PB MRD responses, high survival rates, and low long-term toxicity. A randomized trial is needed to compare our immunochemotherapy approach with a chemotherapy-free strategy. This trial was registered at www.clinicaltrials.gov as #NCT02666898.

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Section: Methodsmentioning

confidence: 99%

“… 32 , 33 , 34 However, several phase 2 trials are now providing evidence to support the alternative approach of combining targeted agents with immunochemotherapy. 35 , 36 , 37 , 38 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“… 35 The follow-up at median 37 months from the start of the treatment showed a persistent PB MRD benefit beyond the end of treatment, high survival rates, and low long-term toxicity. 36 …”

Section: Introductionmentioning

confidence: 99%

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A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

et al. 2023

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“…In contrast, those with partial response will receive four cycles of additional CIT (fludarabine, cyclophosphamide, and obinutuzumab) [ 151 ]. This strategy led to high PFS and ORR in three years with manageable long-term AEs [ 151 , 152 ]. Based on the promising results, ibrutinib–obinutuzumab combination has been approved for the management of TN CLL patients in 2019.…”

Section: Btk Inhibitors In Hematological Malignanciesmentioning

confidence: 99%

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Alu

Han

et al. 2022

J Hematol Oncol

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Bruton’s tyrosine kinase (BTK) is an essential component of multiple signaling pathways that regulate B cell and myeloid cell proliferation, survival, and functions, making it a promising therapeutic target for various B cell malignancies and inflammatory diseases. Five small molecule inhibitors have shown remarkable efficacy and have been approved to treat different types of hematological cancers, including ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and orelabrutinib. The first-in-class agent, ibrutinib, has created a new era of chemotherapy-free treatment of B cell malignancies. Ibrutinib is so popular and became the fourth top-selling cancer drug worldwide in 2021. To reduce the off-target effects and overcome the acquired resistance of ibrutinib, significant efforts have been made in developing highly selective second- and third-generation BTK inhibitors and various combination approaches. Over the past few years, BTK inhibitors have also been repurposed for the treatment of inflammatory diseases. Promising data have been obtained from preclinical and early-phase clinical studies. In this review, we summarized current progress in applying BTK inhibitors in the treatment of hematological malignancies and inflammatory disorders, highlighting available results from clinical studies.

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Flow Cytometric MRD Detection in Selected Mature B-Cell Malignancies

Engelmann,

Böttcher

2024

Methods in Molecular Biology

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A fixed-duration, measurable residual disease–guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial

Cited by 12 publications

References 22 publications

A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

A fixed-duration immunochemotherapy approach in CLL: 5.5-year results from the phase 2 ICLL-07 FILO trial

BTK inhibitors in the treatment of hematological malignancies and inflammatory diseases: mechanisms and clinical studies

Flow Cytometric MRD Detection in Selected Mature B-Cell Malignancies

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