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694 Durable Remissions after Discontinuation of Combined Targeted Treatment in Patients with Chronic Lymphocytic Leukemia (CLL) Harbouring a High-Risk Genetic Lesion (del(17p)/TP53 Mutation)

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation: Advances in CLL Using Novel Combination Therapy
Hematology Disease Topics & Pathways:
antibodies, Biological, Leukemia, Diseases, Non-Biological, Therapies, CLL, chemotherapy, Biological Processes, enzyme inhibitors, Technology and Procedures, Study Population, Lymphoid Malignancies, Clinically relevant
Monday, December 3, 2018: 11:15 AM
Ballroom 20A (San Diego Convention Center)

Paula Cramer1*, Julia von Tresckow, MD2*, Jasmin Bahlo, PhD2*, Sandra Robrecht, PhD3*, Eugen Tausch, MD4*, Moritz Fürstenau, MD5, Petra Langerbeins, MD2*, Othman Al-Sawaf, MD3*, Anna-Maria Fink, MD2,3*, Kirsten Fischer, MD2*, Clemens-Martin Wendtner, MD6, Barbara Eichhorst2*, Michael Kneba7, Stephan Stilgenbauer, MD, PhD8 and Michael Hallek, MD3*

1Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital Cologne, Foster City, CA
2Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital Cologne, Cologne, Germany
3Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany
4Department III of Internal Medicine, Ulm University, Ulm, Germany
5Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, German CLL Study Group, University Hospital Cologne, Koeln, Germany
6Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany
7University Hospital Schleswig-Holstein, Kiel, Germany
8Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany

Background:

Based on the “sequential triple-T” concept of a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD) [Hallek M., ASH 2013], the German CLL study group (GCLLSG) performed three similar prospective, open-label, multicenter, phase-II-trials evaluating different combinations of targeted drugs in an all-comer population of treatment-naïve or relapsed/refractory CLL patients, irrespective of fitness and high-risk genetics [Cramer P., et al. Future Oncol 2018].

Methods:

A debulking with two cycles bendamustine was recommended for patients with relevant tumor burden (defined as absolute lymphocyte count > 25.000/µl and/or lymph nodes > 5cm). In the induction and maintenance phase, the CD20-antibodies obinutuzumab (G, for GA-101) or ofatumumab (O) were combined with the targeted agents ibrutinib (I) or venetoclax (A, for ABT-199) until achievement of a MRD negative complete remission or up to 24 months. I was combined with O in the CLL2-BIO trial and with G in CLL2-BIG, while A plus G was evaluated in CLL2-BAG. Central diagnostics included FISH cytogenetics/molecular genetics at baseline and MRD evaluations by 4-color flow cytometry.

Results:

Between 27th January 2015 and 4th October 2016 189 patients with CLL were enrolled in the 3 trials, among them 51 patients with a del(17p) or a TP53 mutation (Table 1). Median observation time of these 51 patients with high risk genetic features was 29 months (range 15-39 months). Twenty-one patients were treated with ibrutinib and ofatumumab (IO), 13 with ibrutinib and obinutuzumab (IG) and 17 with venetoclax and obinutuzumab (AG). Twenty-seven patients received a debulking with bendamustine prior to induction and maintenance treatment with the above mentioned combinations of targeted agents. After 8 months of induction treatment, the overall response rates were 81%, 100% and 94% with IO, IG and AG, respectively and the corresponding rates of MRD negativity (<10-4 by flow cytometry) in peripheral blood were 0%, 23% and 82%. Forty-eight patients continued treatment in a maintenance phase and until data-cutoff, 34 patients stopped all treatment. Reasons for discontinuation were completion of the full eight cycles (24 months) in 8 patients, progressive CLL in 7 patients, death and adverse events in 1 patient each. Seventeen patients discontinued treatment as per protocol due to MRD negativity (Figure 1); of these, 13 (77%) are still in remission after a median observation time of 16 (range 6-23) months after discontinuation.

Conclusions:

In patients with del(17p)/TP53 mutations, the rate of MRD negative remissions achieved with venetoclax and obinutuzumab is higher than with ibrutinib combined with either obinutuzumab or ofatumumab. Disease control seems durable in patients achieving a MRD negative remission by one of these combinations, as 13 of 17 patients show ongoing remissions after a median observation time of more than one year after termination of therapy.

Disclosures: Cramer: AstraZeneca: Consultancy; Acerta: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel grants, Research Funding; GlaxoSmithKline: Research Funding; Roche: Honoraria, Other: Travel grants, Research Funding; Gilead: Other: Travel grants, Research Funding; Mundipharma: Other: Travel grants; Janssen: Consultancy, Honoraria, Other: Travel grants, Research Funding. von Tresckow: Janssen-Cliag: Consultancy, Honoraria, Other: Travel grants, Research Funding; Roche: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Other: Travel grants; AbbVie: Consultancy, Honoraria. Bahlo: Roche: Honoraria, Other: Travel Grants. Tausch: Roche AG: Other: Advisory board, lectures; Gilead: Consultancy, Other: Travel grants; Celgene: Consultancy, Other: Travel grants; AbbVie: Consultancy, Other: Travel support, expert testimony. Langerbeins: Sunesis: Consultancy; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding; Mundipharma: Consultancy, Other: Travel grants; Roche: Consultancy, Other: Travel grants, Research Funding. Al-Sawaf: Roche: Honoraria; Gilead: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Fink: F. Hoffman La-Roche: Other: travel grants; Mundipharma: Other: travel grants; Janssen: Honoraria; Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants. Fischer: Roche: Other: Travel grants. Wendtner: Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding. Eichhorst: AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Kneba: Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stilgenbauer: Roche: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding. Hallek: Gilead: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding.

*signifies non-member of ASH