Othman Al-Sawaf, MD, Discusses Results From the Phase 3 CLL14 Trial


My name is Othman Al‑Sawaf. I am a physician at the University Hospital of Cologne and the study physician at the German CLL Study Group. I have been working on the CLL14 study and presenting some new data from this phase III study at this year's ASH meeting.

In CLL14, we have been randomizing patients who had previously untreated CLL to receive either chemoimmunotherapy with chlorambucil‑obinutuzumab or venetoclax‑obinutuzumab, so a BCL2 inhibitor as an oral compound with the CD20 antibody, obinutuzumab.

The primary readout of the study was performed in 2019. The data were subsequently published in the "New England Journal of Medicine." In this report, it was shown that there is a significant PFS, so progression‑free survival, benefit of the fixed duration, 12‑cycle venetoclax‑obinutuzumab compared to chlorambucil‑obinutuzumab.

The follow‑up analysis earlier this year, in 2020, showed that patients continue to benefit from those 12 cycles. The PFS benefit was sustained, although all patients have been off treatment for at least two years. The study confirmed that a fixed‑duration treatment in the front‑line setting is feasible for patients. In this particular case, the patients all had coexisting conditions.

It was confirmed that an elderly, unfit patient population can benefit from this kind of treatment. One of the key secondary endpoints was also minimal residual disease in this study. It was previously shown that there is a high rate of undetectable MRD after 12 cycles of treatment.

Approximately 75 percent of all patients had undetectable MRD after they completed treatment in the venetoclax arm compared to approximately 35 percent or so in the chlorambucil‑obinutuzumab arm. The remissions were overall significantly deeper after those 12 cycles.

In order to better understand these MRD kinetics when patients come off treatment, we wanted to focus a little bit on the various measurements that we are continuing to do in this study until today and therefore provide a new analysis of the MRD values in this abstract.

What we were able to show, first of all, was how do the MRD values develop while the patients are on treatment. If the patients that receive those 12 cycles of treatment, in the first half, they receive six cycles of venetoclax and the CD20 antibody, obinutuzumab. Then, this is followed by six cycles where the patients only take the venetoclax tablets.

We were able to show that patients who were between cycle 6 and cycle 12 of treatment, we saw that there are significant changes in the MRD values of the patients. We saw that approximately a third of the patients actually experienced a deepening of their remissions while they were on the venetoclax monotherapy.

We were also able to see that of those few patients who had detectable MRD at the end of treatment, these were, overall, approximately 20 patients. Nevertheless, we saw that half of those patients who remained MRD‑positive at the end of treatment, half of those, again, was actually getting to deeper MRD levels while they were on those six cycles of venetoclax monotherapy.

They had higher values at cycle six. These MRD values were dropping steadily but still remained MRD‑positive when the patients completed treatment.

This would be the subgroup of patients that could potentially benefit from treatment extension, something that is often discussed by practitioners given that particularly high‑risk patients might still remain MRD‑positive at the end of treatment. This subgroup of patients might actually benefit from it in order to at some stage achieve MRD negativity.

On the other hand, we saw that the other half of those MRD‑positive actually had increasing MRD values while they were on venetoclax monotherapy, meaning that these patients would potentially not benefit from continuing simply on venetoclax, given that they had already lost their MRD response, so to speak, while they were on the same compound.

These patients would potentially benefit from treatment intensification by adding further compounds in order to deepen the remission rather than just continuing treatment with the same compound. This clearly shows that it is not that straightforward, in the context of MRD, to just look at one MRD value, given how dynamic this MRD status is in each patient.

This brought us to the next step of our analysis, which was to understand how do these MRD values actually develop throughout time. In order to combine all of the different measurements that we are continuing to do every three to six months in our patients.

In order to combine all of the MRD values that we have into one specific figure, we established a mathematical growth model that allowed us to extract patient‑specific clone growth rates based on the highly sensitive NGS measurements that we are making of the minimal residual disease.

Thereby, identify and really break down the whole growth kinetics that we observe in the observation period into one patient‑specific growth rate.

We saw that the mean growth rate after venetoclax‑obinutuzumab is significantly lower than the one that we observed in chlorambucil‑obinutuzumab, which suggests that the patients do not only have deeper remissions after venetoclax‑obinutuzumab but also a different quality of the minimal residual disease negativity.

It seems that different clones are eradicated by targeting the BCL2‑related pathways and thereby modulating the clonal growth that the patients ultimately might experience when they come off treatment. We were able to translate this also to the follow‑up PFS analysis that we did.

At this meeting, we, for the first time now, showed the data of the four‑year PFS analysis with a median observation time of approximately 50 months. What we see now is that the patients at four years, still in 74 percent of the patients, there is no PFS event so far, meaning that the responses and the remissions are maintained in the vast majority of patients.

All patients now being off treatment for more than three years, this suggests that these 12 cycles of treatment are highly effective and leads to sustained benefits in the patients who received this treatment. This also translates into a significantly better time to next treatment, with only 13 disease progressions until today.

Only 17 patients actually required a next line of therapy within those 216 patients who received venetoclax‑obinutuzumab. This shows that even those patients who do relapse, only half of those actually develop symptoms. Therefore, the other half of patients can be just managed with watch and wait, and thereby still benefit from a long treatment‑free period.

Overall, the analysis confirmed that the treatment strategy with venetoclax‑obinutuzumab is highly effective and feasible in this previously untreated and unfit patient group, and that the remissions continue to be durable and sustained, even now that the patients have been off treatment for over three years.

We will continue to follow up on the patients. We have extended the study for up to nine years in order to really understand what happens in the long term of these patients.

Given that this is a very novel treatment and a new treatment paradigm that has been introduced with CLL14 in the front‑line setting, as well as in the relapsed refractory setting with the MURANO data that do some sort of similar approach, a fixed duration venetoclax‑based treatment.

There will be continued follow‑ups, maybe not next year, but maybe the year afterwards, where we will try to report more mature data and particularly focus, again, on minimal residual disease but also on all the time‑related events. This is something to look forward to in the near future.

We will continue to work on that and better understand particularly the high‑risk patients and which patients do eventually relapse. Why are there patients in CLL14 that have high‑risk features but still are in deep MRD‑negative remissions, below 10^‑6. We have a few of those in the study as well.

It is worthwhile to really understand whether there are other risk factors that we need to be aware of to better understand the patient characteristics. This is something that will be very interesting. On the other hand, hopefully, in a few weeks, we will open or have our first patient in the CLL17 study, which is a little bit the successor trial of CLL14.

In this study, patients will be randomized to receive either this venetoclax‑obinutuzumab for a year or venetoclax plus ibrutinib, also for approximately a year. This will be compared to continuous ibrutinib as one of the standard‑of‑cares for patients with previously untreated CLL.

Ultimately, showing whether fixed‑duration treatment really can be equally used and reach similar efficacy as continuous BTK inhibition or whether there are certain differences in some subgroups.

Therefore, the study will, once it opens in Europe, allow us to really better understand how to individualize our treatment strategies for each patient depending on the individual risk profile and the individual circumstances, in order to ultimately improve treatment and our standard of care for our patients.

Maybe finally, next year, we will also eagerly look forward to the data from the CLL13 study, which compares, again, this venetoclax‑obinutuzumab treatment, among other treatments arms, to chemo monotherapy with FCR and BR in younger and fitter patients. Venetoclax‑obinutuzumab is approved for both groups, so for fit as well as unfit patients in a previously untreated setting.

Nevertheless, we do not have any data so far where venetoclax‑obinutuzumab is compared to these more intensive chemo monotherapies. This study will be, certainly, very informative in order to allow us to understand whether we can even improve on FCR. It is very likely given the high rates of undetectable MRD that we have seen and observed in CLL14.

Nevertheless, it is good that we will have data from a solid randomized study in order to ultimately address this question and generate more data to have a robust guidelines to use in our daily practice.   

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