CLL2-BXX Phase II Trials: Sequential, Targeted Treatment for Eradication of Minimal Residual Disease in Chronic Lymphocytic Leukemia

Cramer, Paula; Tresckow, Julia von; Bahlo, Jasmin; Engelke, Anja; Langerbeins, Petra; Fink, Anna‐Maria; Fischer, Kirsten; Wendtner, Clemens‐Martin; Kreuzer, Karl‐Anton; Stilgenbauer, Stephan; Böttcher, Sebastian; Eichhorst, Barbara; Hallek, Michael

doi:10.2217/fon-2017-0442

Cited by 30 publications

(25 citation statements)

References 62 publications

(102 reference statements)

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“…In contrast, their combined application may induce deep and durable remissions with long‐treatment‐free intervals. One of these trial concepts uses sequential, targeted therapies to eradicate residual disease . 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.…”

Section: Current Challenges and Uncertaintiesmentioning

confidence: 99%

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: Current Challenges and Uncertaintiesmentioning

confidence: 99%

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

2019

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“…This combination is also undergoing study in the CLL2-BAG trial (NCT02401503), which is evaluating a sequential regimen of bendamustine debulking followed by induction with obinutuzumab and venetoclax and maintenance for up to 24 months, in both treatment-naïve and pre-treated CLL patients. 140 Other combinations currently under investigation in phase II trials include obinutuzumab and idelalisib in the CLL2-BCG trial (NCT02445131) and obinutuzumab and ibrutinib in the CLL2-BIG trial (NCT02345863). 140 Aggressive B-cell lymphomas…”

Section: Cllmentioning

confidence: 99%

“…140 Other combinations currently under investigation in phase II trials include obinutuzumab and idelalisib in the CLL2-BCG trial (NCT02445131) and obinutuzumab and ibrutinib in the CLL2-BIG trial (NCT02345863). 140 Aggressive B-cell lymphomas…”

Section: Cllmentioning

confidence: 99%

Anti-CD20 monoclonal antibodies: reviewing a revolution

Casan

Wong

Northcott

et al. 2018

Human Vaccines & Immunotherapeutics

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Since the inception of rituximab in the 1990s, anti-CD20 monoclonal antibodies have revolutionised the treatment of B cell hematological malignancies and have become a cornerstone of modern gold-standard practice. Additionally, the potent efficacy of these agents in depleting the B cell compartment has been used in the management of a broad array of autoimmune diseases. Multiple iterations of these agents have been investigated and are routinely used in clinical practice. In this review, we will discuss the physiology of CD20 and its attractiveness as a therapeutic target, as well as the pharmacology, pre-clinical and clinical data for the major anti-CD20 monoclonal antibodies: rituximab, obinutuzumab and ofatumumab.

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“…On the Right, the most recent clinical trials incorporating BCR/BCL2 inhibitors. FCR, fludarabine+cyclophosphamide+rituximab (CLL8) (14, 81); R-Benda, rituximab+bendamustine (CLL10) (82); Chl+G, chlorambucil+obinutuzumab (CLL11) (83, 84); Benda+G, bendamustine+obinutuzumab (GREEN) (85); Ibr+R, ibrutinib+rituximab (Alliance A041202) (86); Benda+Ibr+Ofa, bendamustine+ibrutinib+ofatumumab (CLL2-BIO) (87); Ibr+G, ibrutinib+obinutuzumab (Illuminate PCYC-1130) (88); Benda+Ibr+G, bendamustine+ibrutinib+obinutuzumab (CLL2-BIG) (89); Ibr+FC+G, ibrutinib+fludarabine+cyclophosphamide+obinutuzumab (90); Ven+R (EOCT, End Of Combination Therapy) (EOT, End Of Therapy), venetoclax+rituximab (Murano) (23, 91); Benda+Ven+G, bendamustine+venetoclax+obinutuzumab (CLL2-BAG) (92); Ven+G, venetoclax+obinutuzumab (CLL14) (93); Ven+Ibr (+12 m, months), venetoclax+ibrutinib (TAP Clarity) (94); Ven+Ibr (+18 m, months), venetoclax+ibrutinib (95).…”

Section: Clinical Impact Of Mrd: From Chemoimmunotherapy To Novel Drugsmentioning

confidence: 99%

Minimal Residual Disease in Chronic Lymphocytic Leukemia: A New Goal?

et al. 2019

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In chronic lymphocytic leukemia (CLL), there is a growing interest for minimal residual disease (MRD) monitoring, due to the availability of drug combinations capable of unprecedented complete clinical responses. The standardized and most commonly applied methods to assess MRD in CLL are based on flow cytometry (FCM) and, to a lesser extent, real-time quantitative PCR (RQ-PCR) with allele-specific oligonucleotide (ASO) primers of immunoglobulin heavy chain genes (IgH). Promising results are being obtained using droplet digital PCR (ddPCR) and next generation sequencing (NGS)-based approaches, with some advantages and a potential higher sensitivity compared to the standardized methodologies. Plasma cell-free DNA can also be explored as a more precise measure of residual disease from all different compartments, including the lymph nodes. From a clinical point of view, CLL MRD quantification has proven an independent prognostic marker of progression-free survival (PFS) and overall survival (OS) after chemoimmunotherapy as well as after allogeneic transplantation. In the era of mechanism-driven drugs, the paradigms of CLL treatment are being revolutionized, challenging the use of chemoimmunotherapy even in first-line. The continuous administration of ibrutinib single agent has led to prolonged PFS and OS in relapsed/refractory and treatment naïve CLL, including those with TP53 deletion/mutation or unmutated IGHV genes, though the clinical responses are rarely complete. More recently, chemo-free combinations of venetoclax+rituximab, venetoclax+obinutuzumab or ibrutinib+venetoclax have been shown capable of inducing undetectable MRD in the bone marrow, opening the way to protocols exploring a MRD-based duration of treatment, aiming at disease eradication. Thus, beside a durable disease control desirable particularly for older patients and/or for those with comorbidities, a MRD-negative complete remission is becoming a realistic prospect for CLL patients in an attempt to obtain a long-lasting eradication and possibly cure of the disease. Here we discuss the standardized and innovative technical approaches for MRD detection in CLL, the clinical impact of MRD monitoring in chemoimmunotherapy and chemo-free trials and the future clinical implications of MRD monitoring in CLL patients outside of clinical trials.

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CLL2-BXX Phase II Trials: Sequential, Targeted Treatment for Eradication of Minimal Residual Disease in Chronic Lymphocytic Leukemia

Abstract: This strategy represents a new era of chronic lymphocytic leukemia therapy where chemotherapy is increasingly replaced by targeted agents and treatment duration is tailored to the patient's individual tumor load and response.

Cited by 30 publications

References 62 publications

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

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

Anti-CD20 monoclonal antibodies: reviewing a revolution

Minimal Residual Disease in Chronic Lymphocytic Leukemia: A New Goal?

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