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)
Authors: Cramer Paula , von Tresckow Julia , Bahlo Jasmin , Robrecht Sandra , Tausch Eugen , Fürstenau Moritz , Langerbeins Petra , Al-Sawaf Othman , Fink Anna-Maria , Fischer Kirsten , Wendtner Clemens-Martin , Eichhorst Barbara , Kneba Michael , Stilgenbauer Stephan , Hallek Michael 
Published: October 2019

Abstract
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:AbbVie: Consultancy, Other: Travel grants; Celgene: Consultancy, Other: Travel grants; Gilead: Consultancy, Other: Travel grants. 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:Abbvie: Honoraria; Gilead: Honoraria; Roche: Honoraria. Fink:Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Other: travel geants; Roche: Other: travel grants; Mundipharma: Other: travel grants. Fischer:Roche: Other: Travel support. Wendtner:Roche: Consultancy, Honoraria, Other: travel support, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: travel support, Research Funding; Genetech: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: travel support, Research Funding; MorphoSys: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: 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:Celgene: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding.