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Expert Discusses "Sequential Triple-T" Trials in CLL

Allie Strickler @Alliejayes
Published: Tuesday, Jan 03, 2017

Julia von Tresckow, MD

Julia von Tresckow, MD

In the treatment paradigm of chronic lymphocytic leukemia (CLL), anti-CD20 antibodies such as obinutuzumab (GA101), and other targeted agents like ibrutinib (Imbruvica), have shown promising efficacy and tolerability when compared with standard chemoimmunotherapy.

The CLL2-BIG trial,1 designed by the German CLL Study Group (GCLLSG), investigated the safety and efficacy of a novel combination regimen of obinutuzumab and ibrutinib for induction and maintenance treatment of physically fit and unfit patients with CLL. To reduce the risk of severe infusion-related reactions (IRRs) during the first infusion of obinutuzumab, patients with high tumor burden were administered bendamustine (Treanda) as debulking. This resulted in the proposed "sequential triple-T" concept: a tailored and targeted treatment aiming at total eradication of minimal residual disease (MRD).

Thus far, the data suggest that debulking prior to treatment with obinutuzumab may reduce the occurrence of severe IRRs compared with patients who did not receive debulking. The rate of infections seen with bendamustine in this trial appears to be comparable to previous reports for bendamustine monotherapy in CLL.

In an interview with OncLive, Julia von Tresckow, MD, specialist in oncology, University of Cologne, Department of Internal Medicine, and Center of Integrated Oncology Cologne-Bonn, GCLLSG, discussed both the findings of the CLL2-BIG trial, as well as interim safety results from a similar study2 evaluating the “sequential triple-T” concept in CLL, all of which she presented at the 2016 ASH Annual Meeting.

OncLive: Could you begin by providing a background of the CLL2-BIG study you presented at ASH?

von Tresckow: We all know that improved anti-CD20 antibodies, such as GA101, or obinutuzumab, and targeted drugs such as ibrutinib, prolong overall survival for patients treated with CLL. Therefore, we designed this exploratory phase II trial based on the so-called “triple-T” concept of tailored and targeted treatment aiming at total eradication of MRD.

It’s an open-label, multicenter, phase II trial recruiting about 62 patients in an exploratory design just to approve the “triple-T” concept and have an idea about how the combination works in CLL.

What were the major findings of the study?

We found that the treatment was tolerated very well in general and that the efficacy is very promising, reaching the primary endpoint. But this is an early time point, and we have to see how the overall response rate will be confirmed by further evaluations.

What are the next steps following these results?

As this is an MRD-tailored regimen, there are many patients who are allowed to stop the therapy when they reach an MRD-negative complete remission. For now, we know that about one-third of the patients already completed the therapy, and we will see how the others are doing and show that the primary endpoint is being reached.

You’re also presenting interim safety results from another study. Could you discuss the background on that trial as well?

It’s almost exactly the same situation. It’s an exploratory, multicenter, phase II trial with the same exclusion criteria and the same number of patients. This study is also based on the sequential “triple-T” concept, so it’s almost the same study, but ibrutinib was exchanged with ABT-199, or venetoclax.

What were the major findings from that study?

The primary endpoint has not been reached so far. What we presented here were results on the safety of the patients, especially with regard to infusion-related reactions to obinutuzumab and tumor lysis syndrome with venetoclax.

The next step is to publish the efficacy findings as soon as the primary endpoint is reached.

What impact do you see these results having on the treatment landscape of CLL?

These were studies that were performed to get a feeling for the novel drugs and to get a feeling for MRD-tailored treatment with those drugs. We use the results of these trials to plan the next steps for CLL treatment, and this is especially the case for the phase III randomized trial, in which we test 3 combinations against the standard with FCR or bendamustine/rituximab for the first-line treatment of physically fit patients with CLL. That trial also has venetoclax- and ibrutinib-containing arms.


  1. von Tresckow J, Cramer P, Bahlo J, et al. CLL2-BIG – A novel treatment regimen of bendamustine followed by GA101 and ibrutinib followed by ibrutinib and GA101 maintenance in patients with chronic lymphocytic leukemia (CLL): Interim results of a phase II trial. Blood. 2015 126:4151.
  2. Cramer P, von Tresckow J, Bahlo J, et al. Low incidence of tumor lysis syndromes (TLS) and infusion related reactions (IRR) in the CLL2-Bag trial evaluating a sequential treatment of bendamustine (B), obinutuzumab (GA101, G), and venetoclax (ABT-199, A) in patients with chronic lymphocytic leukemia (CLL): Interim safety results a phase-II-trial of the German CLL Study Group (GCLLSG). Presented at: 58th Annual ASH Meeting and Exposition; December 3-6, 2016; San Diego, CA.

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