Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial

Michallet, Anne‐Sophie; 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; Orsini, Frédérique; Banos, Anne; Carassou, P.; Cartron, Guillaume; Fornecker, Luc Mathieu; Ysebaert, Loïc; Dartigeas, Caroline; Graczyk, Małgorzata; Vilque, Jean Pierre; Aurran, Thérèse; Cymbalista, Florence; Leprêtre, Stéphane; Lévy, Vincent; Nguyen‐Khac, Florence; Garff‐Tavernier, Magali Le; Aanei, Carmen Mariana; Ticchioni, Michel; Letestu, Rémi; Feugier, Pierre

doi:10.1016/s2352-3026(19)30113-9

Cited by 20 publications

(20 citation statements)

References 31 publications

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“…As our study required patients to complete up to 6 cycles of FCR if tolerated, we also do not know whether some patients may have derived similar efficacy with less toxicity with fewer cycles of FCR, as has been suggested by prior retrospective studies of FCR alone [19]. As a single-arm study, we also cannot know how DFCR compares to other promising frontline novel-agent plus chemoimmunotherapy regimens such as ibrutinib + FCR [20] or ibrutinib + FC + obinutuzumab [21,22]. Unlike ibrutinib-based regimens, DFCR was not associated with any significant cardiovascular toxicity or bleeding risk.…”

Section: Discussionmentioning

confidence: 94%

A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients

et al. 2020

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Fludarabine, cyclophosphamide, and rituximab (FCR) is highly effective initial therapy for younger patients with chronic lymphocytic leukemia (CLL); however, most eventually relapse. Duvelisib is a delta/gamma PI3K inhibitor approved for relapsed/refractory CLL. We conducted an investigator-initiated, phase 1b/2 study of duvelisib + FCR (DFCR) as initial treatment for CLL patients aged ≤65. A standard 3 + 3 design included two dose levels of duvelisib (25 mg qd and 25 mg bid). Duvelisib was given for 1 week, then with standard FCR added for up to six 28-day cycles, then up to 2 years of duvelisib maintenance. Thirty-two patients were enrolled. The phase 2 dose of duvelisib was identified as 25 mg bid. Hematologic toxicity was common, and all-grade non-hematologic toxicities included transaminitis (28%), febrile neutropenia (22%), pneumonia (19%), and colitis (6%). The best overall response rate by ITT was 88% (56% CR/CRi and 32% PR). The best rate of bone marrow undetectable minimal residual disease (BM-uMRD) by ITT was 66%. The rate of CR with BM-uMRD at end of combination treatment (primary endpoint) was 25%. Three-year PFS and OS are 73 and 93%, respectively. DFCR is active as initial therapy of younger CLL patients. Immune-mediated and infectious toxicities occurred and required active management.

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Section: Discussionmentioning

confidence: 94%

A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients

et al. 2020

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“…An interesting phase II study attempted to use time-limited therapy with frontline ibrutinib-obinutuzumab with the goal of stopping therapy with uMRD and thus avoiding CIT. 75 Patients received 6 months of the regimen followed by 3 months of ibrutinib alone at which time those in a CR with uMRD went on to receive an additional 6 months of ibrutinib while all others received four cycles of iFCG. Unfortunately, only 12% of patients in this study were able to avoid CIT.…”

Section: Something Borrowed: Does Anti-cd20 Monoclonal Antibody Help?mentioning

confidence: 99%

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

Gordon

Danilov

2021

Therapeutic Advances in Hematology

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Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.

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“…Anderson et al showed that a CK (n = 16 out of 38, 42%) was associated with a shorter PFS in patients with R/R CLL treated with the BCL2 inhibitor venetoclax (median follow‐up: 23 months 2‐46 ). 55 In contrast, an analysis performed after a shorter follow‐up time (median [IQR]: 7 months [0;1‐38;4]), found that a CK (n = 52 out of 130, 26.8%) was not associated with a shorter PFS in cases of treatment‐naïve and R/R CLL 56 .…”

Section: Prognostic Value Of the Ck In Cllmentioning

confidence: 99%

“…It remains to be determined whether the presence of a CK with major structural aberrations corresponds to a subset of cases with particularly aggressive disease. Overall, a CK is observed in 11% to 18% of treatment‐naïve patients with CLL and in up to 40% of patients with relapsed/refractory (R/R) CLL 38‐42 …”

Section: The Ck: Definition and Frequencymentioning

confidence: 99%

The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations

et al. 2020

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Chromosomal abnormalities are frequently observed in patients with chronic lymphocytic leukemia (CLL) and have prognostic value. Deletions of the short arm of chromosome 17 (and/or mutations TP53) predict resistance to chemoimmunotherapy and shorter progression-free survival after targeted therapies. Although the complex karyotype (CK) is strongly predictive of a poor prognosis in hematologic malignancies such acute myeloid leukemia or myelodysplastic syndrome, its value in CLL is subject to debate. Here, we review the literature on the CK in CLL and examine its prognostic value with different treatments. We also propose a standardized method for defining a CK in all types of hematopoietic neoplasm.

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Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial

Cited by 20 publications

References 31 publications

A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients

A phase 1b/2 study of duvelisib in combination with FCR (DFCR) for frontline therapy for younger CLL patients

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

The complex karyotype and chronic lymphocytic leukemia: prognostic value and diagnostic recommendations

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