The Glow study examined whether fixed duration venetoclax and ibrutinib was superior to chlorambucil and obinutuzumab, the standard chemo-immunotherapy regimen, for less fit elderly patients with CLL. The background and the rationale for the study is that we have two very powerful drugs in CLL – we have ibrutinib, which is very effective in chasing cells out of their lymph node microenvironment. Within this lymph node microenvironment they obtain signals from other cells which make them not only to a proliferative state but also make them into an apoptotic resistant state. And we have venetoclax, which is a very specific BCL2 inhibitor which very effectively kills cells in the blood but because of this protective microenvironment those cells are less vulnerable, less sensitive for venetoclax in the lymph node compartment. So if you combine these two drugs, in theory at least, then you actually have the best of two worlds – you chase cells out of the protective microenvironment, sensitising them for the killing effect of venetoclax. That was the rationale of the study.
The idea is that if you combine such very effective agents you might be able to stop treatment instead of continuous treatment after relapse. So that was tested in this trial. In this trial we gave a lead-in of ibrutinib for three months, which also effectively debullked patients also lowering the risk of tumorlysis problems because of venetoclax. Then for twelve cycles venetoclax was combined with ibrutinib and then treatment was stopped.
What was the methodology used in this study?
This is a phase III global head-to-head comparison of the ibrutinib venetoclax combination, three months of ibrutinib lead-in and then twelve cycles of combination with venetoclax where for the first cycle venetoclax was given as a ramp-up dose. This was compared with six cycles of chlorambucil obinutuzumab which is the labelled duration of treatment.
What were your findings?
What we reported at EHA already a few months ago was that the progression free survival was very significantly better in the study arm than in the standard arm with a hazard ratio of 0.2, very powerful. What we show at this ASH is we focus very much on MRD. Minimal residual disease is more and more used now as a surrogate endpoint for depth of remission in CLL and as a surrogate endpoint for progression free survival. The threshold is usually set at 10-4, meaning if you have less than one leukaemia cell in 10,000 normal cells you have an undetectable MRD and if you are above that you are positive MRD. We know from other trials with chemo-immunotherapy and with venetoclax plus an antibody that patients with a positive MRD usually do very poorly after stopping treatment.
So three key messages in this trial. The first key message is that there was a significantly higher proportion of patients who got into this undetectable MRD state with the ibrutinib venetoclax treatment, both measured in blood and in marrow. The second take-home message is that not only more patients came into an undetectable MRD stage but with next generation sequencing we could actually measure what happened below 10-4 and we found that significantly more patients had deeper undetectable MRD levels at 10-5, which is one log deeper. The third take-home message is that after stopping treatment the MRD levels, regardless of if it was negative or positive or intermediate, they were much more sustainable. What I mean by that is that in the standard treatment patients with a positive MRD almost always went up at least a log up or even go into a progressive state after stopping treatment. In this study we saw that MRD rates were much more sustainable. So even if you had an intermediate level of MRD most of those patients remained at that very same level 12 months after stopping treatment.
How can these results impact the future treatment of CLL?
Now it gets very interesting because now we have a few different options for patients with CLL. Of course we still have a big debate which patients it should be but you still have chemo-immunotherapy that you can give to patients. You have BTK inhibitor treatments as maintenance treatment so you continue until relapse. Now you also have two very effective combined targeted agents that you can give for a fixed duration – one is venetoclax ibrutinib, which is an all-oral once-daily regimen that we discussed in the Glow study, and the other is the venetoclax obinutuzumab set-up where you give twelve months of combination of venetoclax and the first six months combine it with obinutuzumab which is an antibody that has to, of course, be given intravenously. Which treatment you should give for which patients, that’s still an open question. Currently in Europe we are very fast actually enrolling the CLL17 trial led by Othman Al-Sawaf from Germany where we actually head-to-head compare ibrutinib venetoclax, one arm, venetoclax and obinutuzumab second arm and ibrutinib maintenance as a third arm. That kind of study will help to determine which patients will best do in what set-up.