My name is Arnon Kater, I’m a haematologist here in Amsterdam and I’m the Chairman of the HOVON CLL Study Group. I updated at the last EHA our Vision 141 study on behalf of the HOVON and the Nordic study groups.
So far we have seen a transition from continuous treatment with targeted agents to fixed duration therapies in relapsed/refractory patients which significantly shortens treatment duration, thereby lowering exposure to long-term toxicities, reducing costs and preventing the development of resistant clones. We think that the next step is to go from fixed duration treatment to time-limited treatment based on the biology of the disease and treatment response. We have known and learned from in vitro studies but also from clinical studies that there is a strong synergy between venetoclax and ibrutinib. Inspired by MRD-guided treatment options in chronic myeloid leukaemia, we developed the HOVON 141 Vision trial to see whether or not we can, indeed, adapt the AML-like study where we can stop and restart patients’ need for treatment based on MRD numbers using ibrutinib and venetoclax as a backbone.
The study was performed in a way that we started with 15 months of combination treatment. If patients on the combination treatment had at least a partial response and had an undetectable MRD in the blood and in the marrow they were randomised in a 1:2 ratio between ibrutinib continuation, as you would normally do, or stopping the treatment until MRD positivity, so not until iwCLL progression but really until we saw an increase in MRD. At that time patients could be re-treated, and re-treatment because their MRD was not considered an event, it was considered as part of the protocol.
Earlier we reported already on the 27-month update where we showed that, indeed, the primary endpoint was reached with a progression free survival at 12 months post stopping the treatment of 98%. This was published in Lancet Oncology in 2022. What we presented at the last EHA was a long-term clinical outcome and MRD kinetics with now a median follow-up time of 51 months.
What we found here is that you have three patient groups. You have a patient group that was not randomised, just continued ibrutinib because they were not MRD undetectable in blood and marrow at month 15. Arm A patients are the patients that were randomised for continuation of ibrutinib although they had MRD negative disease and arm B were the patients that were allowed to stop and re-start. If you look to the total progression free survival what we can see is, although we’re not officially comparing the groups because it’s a phase II design, that the non-randomised patients had the lowest progression free survival and the lowest time to next treatment, of 75% and 88% respectively. Patients that were randomised in arm A for continuation of treatment had a PFS and time to next treatment of approximately 92% and patients that had stopped and partly re-started, I’ll come back to that later, had a PFS of 81% and time to next treatment of 88% respectively.
Looking at the overall survival, the overall survival of the total study was 88% but if you split it by group you see that the lowest overall survival was seen in the non-randomised patients and in the patients that were randomised for either continuation or stopping they were both above the 90% overall survival. If you look to patients that have stopped in arm B we can see that 19 patients had a conversion of their MRD response, so they came from MRD negative to positive above the threshold of 10-2 and re-initiated treatment according to the protocol for another twelve cycles of venetoclax and ibrutinib. This is 40% of the patients. Four of them went off protocol, one due to toxicity, two due to progression and the median time to MRD positivity was 24 months after start of observation.
What we have seen is that if you look to those patients that actually had, at the timeframe that we are now, a conversion to MRD positivity, this group was enriched for patients with complex genomic aberrations and for TP53 abnormalities. Of the 19 patients that were re-treated following twelve cycles, nine, so 47%, had again an undetectable MRD response, whereas 4 (21%) and 2 (19%) had low and high MRD responses respectively. At the last clinical evaluation of the 19 re-treated patients, 15 were still progression free, two had progressive disease and two went off protocol for other reasons.
If you look to the toxicity, that’s what we actually would have expected in that stopping the treatment really helps to alleviate toxicity. Lower bleeding, lower cardiac problems and lower other problems if you allow patients to stop after an undetectable MRD response.
In conclusion, what we now think and found is that at almost 4½ years of follow-up, 40% of undetectable MRD patients that stopped ibrutinib following the treatment with venetoclax and ibrutinib had an MRD conversion. Of these, almost half gained a second deep remission following re-treatment. The overall toxicity was lowest in the group randomised for stopping treatment and we therefore overall conclude that, very similar to chronic myeloid leukaemia, treatment cessation with MRD guided re-initiation is a very feasible approach in patients that become undetectable MRD after ibrutinib and venetoclax combinations.
How could this treatment impact CLL patients and what’s next for the study?
We of course need to do a longer-term follow-up to see how we can use this treatment. Unfortunately, ibrutinib and venetoclax, this specific combination, currently does not have a label, both not in America and not by the EMA. But it’s a proof of concept that, indeed, instead of continuous treatment or a fixed duration and stop for everybody, this seems to be a new paradigm that you can actually treat patients until you have a biologically meaningful response, in our case MRD, stop treatment, give the patients at least some time of treatment holiday which prevents side effects but also prevents the development of resistance and you can re-treat those patients. We need more clinical studies to confirm that this is a feasible approach but it’s a very attractive approach for future studies and finding future real-world treatment for CLL.
