CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia

Tresckow, Julia von; Cramer, Paula; Bahlo, Jasmin; Robrecht, Sandra; Langerbeins, Petra; Fink, Anna‐Maria; Al‐Sawaf, Othman; Illmer, Thomas; Klaproth, Holger; Estenfelder, Sven; Ritgen, Matthias; Fischer, Kirsten; Wendtner, Clemens‐Martin; Kreuzer, Karl‐Anton; Stilgenbauer, Stephan; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

doi:10.1038/s41375-018-0313-8

Cited by 43 publications

(40 citation statements)

References 20 publications

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“…The Illuminate study tested Clb‐G against a combination of ibrutinib and obinutuzumab in elderly and comorbid patients . This combination had previously shown promising results with MRD‐negative responses . The Illuminate study produced a significant PFS benefit for the combination of ibrutinib and obinutuzumab vs Clb‐G.…”

Section: Treatment Of Cllmentioning

confidence: 99%

“…Moreover, combinations of all available drugs, as well as novel strategies to prevent clonal evolution of CLL need to be investigated in order to achieve long‐lasting remissions or even cure for CLL patients. So far, results obtained by these combination therapies appear promising, in particular when combining anti‐CD20 antibodies with targeted agents . While ibrutinib has been tested in combination with anti‐CD20 antibodies and yielded high response rates, the choice of the antibody clearly has an impact on the efficacy.…”

Section: Current Challenges and Uncertaintiesmentioning

confidence: 99%

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Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment

2019

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Disease overview Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B‐cells. Diagnosis The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B‐lymphocytes, which identify a clonal B‐cell population carrying the CD5 antigen, as well as typical B‐cell markers. Prognosis The two similar clinical staging systems, Rai and Binet, create prognostic information by using results of physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del [17p]) and/or mutations of the TP53 gene, predict resistance to chemoimmunotherapy and a shorter time to progression, with most targeted therapies. A comprehensive, international prognostic score (CLL‐IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients. Therapy Only patients with active or symptomatic disease, or with advanced Binet or Rai stages require therapy. When treatment is indicated, several options exist for most CLL patients: a combination of venetoclax with obinutuzumab, ibrutinib monotherapy, or chemoimmunotherapy. For physically fit patients younger than 65 (in particular when presenting with a mutated IGVH gene), chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab remains a standard therapy, since it may have curative potential. At relapse, the initial treatment may be repeated, if the treatment‐free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del (17p) or TP53 mutation are a different, high‐risk category and should be treated with targeted agents. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del (17p), or patients that are refractory to inhibitor therapy. Future Challenges Targeted agents (ibrutinib, idelalisib, venetoclax, obinutuzumab) will be increasingly used in combination to allow for short, but potentially definitive therapies of CLL. It remains to be proven that they generate a superior outcome when compared to monotherapies with inhibitors of Bruton tyrosine kinase, which can also yield long‐lasting remissions. Moreover, the optimal sequencing of drug combinations is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.

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Section: Treatment Of Cllmentioning

confidence: 99%

Section: Current Challenges and Uncertaintiesmentioning

confidence: 99%

Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment

2019

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show abstract

“…Therefore, the Illuminate study tested Clb‐G against a combination of ibrutinib and obinutuzumab in elderly and comorbid patients . This combination had previously shown promising results with MRD‐negative responses . The Illuminate study produced a significant PFS benefit for the combination of ibrutinib and obinutuzumab versus Clb‐G.…”

Section: Long‐term Monotherapy Versus Fixed‐duration Combination Treamentioning

confidence: 99%

“…Moreover, we are actively investigating combinations of all available drugs, as well as novel strategies to prevent clonal evolution of CLL in order to achieve long‐lasting remissions or even cure for CLL patients. So far, results obtained by these combination therapies appear very promising, in particular when combining anti‐CD20 antibodies with targeted agents . While ibrutinib has been tested in combination with anti‐CD20 antibodies and yielded high response rates, the choice of the antibody clearly has an impact on the efficacy.…”

Section: Second‐line Therapy: Intensification or Optimal Sequencing?mentioning

confidence: 99%

How to approach CLL in clinical practice

Hallek

Fürstenau

2019

Hematological Oncology

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“…Down-regulation of CD20 on CLL cells by ibrutinib has additionally been described in co-culture systems and may be interpreted as a potential antagonistic mechanism (24,25). However, combination therapy of ibrutinib and anti-CD20 antibody has proven to be clinically highly effective especially for unfit patients with CLL (26,27).…”

Section: Introductionmentioning

confidence: 99%

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

Barbarino

Henschke

Blakemore

et al. 2020

Preprint

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Targeted inhibition of Bruton's Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström´s Macroglobulinemia, Mantle cell lymphoma and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2 -/experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage mediated immune responses.

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CLL2-BIG: sequential treatment with bendamustine, ibrutinib and obinutuzumab (GA101) in chronic lymphocytic leukemia

Cited by 43 publications

References 20 publications

Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment

Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment

How to approach CLL in clinical practice

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

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