Othman Al-Sawaf, MD, discusses findings from the CLL14 trial, the rationale for exploring this proposed combination, and shares his thoughts on the emerging treatment paradigms in chronic lymphocytic leukemia.
Othman Al-Sawaf, MD
The treatment landscape of chronic lymphocytic leukemia (CLL) has evolved rapidly over the past several years, with the availability of targeted therapies that offer the potential for improved patient outcomes.
Drugs that inhibit CD20—such as obinutuzumab (Gazyva)—have entered the space, as has the BCL-2 inhibitor venetoclax (Venclexta). Interest in the feasibility of using combination regimens is high, but therapeutic selection for these approaches remains challenging.
The FDA approved this combination for the frontline treatment of patients with CLL or small lymphocytic lymphoma in May 2019. The approval is based on data from the phase III CLL14 trial, in which venetoclax/obinutuzumab reduced the risk of disease progression or death by 67% versus obinutuzumab plus chlorambucil in patients with treatment-naïve CLL and co-existing medical conditions (HR, 0.33; 95% CI, 0.22-0.51; P <.0001).1
Complex karyotype (CKT), which is defined as the presence of ≥3 chromosomal aberrations, is frequently observed in older, treatment-naïve patients with CLL, and is associated with a particularly poor prognosis. Results of a prospective analysis of the CLL14 trial, which were presented at the 2019 European Hematology Association (EHA) Congress, showed that the combination of venetoclax and obinutuzumab was able to overcome adverse risks associated with CLL who have CKT.2
The findings suggest the significance of chromosomal analysis prior to physicians choosing frontline therapy for their patients with CLL, should they harbor CKT.
In an interview with OncLive during the 2019 EHA Congress, lead study author Othman Al-Sawaf, MD, University Hospital, Cologne, Germany, discussed these findings from the CLL14 trial, the rationale for exploring this proposed combination, and shared his thoughts on the emerging treatment paradigms in CLL.
OncLive: Could you discuss the rationale for exploring the combination of venetoclax and obinutuzumab in patients with CLL who have CKT?
Al-Sawaf: Venetoclax with obinutuzumab is a chemotherapy-free regimen that has been developed now for several years, originally in phase Ib and in phase II trials, and now, for the first time, in a randomized phase III trial. The idea behind that is to target BCL-2 in CLL, and to combine BCL-2 inhibition with a CD20-directed antibody as another target in CLL.
We showed in the CLL14 trial that the combination of both of these compounds is superior to standard chemoimmunotherapy in patients with previously untreated CLL. That was the rational to have a deeper look now at patients with the CKT.
Please provide an overview of the phase III CLL14 study.
CLL14 is a randomized, phase III trial. It was performed globally and in a broad range of countries—Europe, the United States, and South America. In this study, 432 patients were randomized to either receive 12 cycles of venetoclax and obinutuzumab or 12 cycles of chlorambucil and obinutuzumab. Each regimen was separated into 6 cycles of combination and 6 cycles of monotherapy with either venetoclax or chlorambucil.
The ultimate aim was to check whether there was a difference in progression-free survival (PFS) in these patients. This was the primary endpoint. The primary endpoint was met [in 2018], and venetoclax and obinutuzumab was superior to chlorambucil and obinutuzumab.
What is the likelihood of relapse for patients with CKT, and what is a typical prognosis for them?
[CKT] is a phenomenon that we see in lots of hematological malignancies. Many hematologists know it from acute myeloid leukemia or myelodysplastic syndrome. We also make treatment decisions based on its presence.
In CLL, similarly, we’ve seen several trials—mostly of a retrospective nature—that CKT is associated with a very poor prognosis, similar to TP53. And, in some analyses, it is even worse than TP53 aberrations.
The issue with CKT is that, in the past, it wasn’t as easy to detect during the diagnostic workup of CLL, because you need stimulated karyotyping for that. This is, in some cases, more challenging, but nowadays, the procedure has been widely standardized, and it’s relatively easy to do that in routine diagnostics.
We’ve seen that the prognosis of patients with CKT is poor when treated with chemoimmunotherapy, but interestingly, it is also very poor when treated with targeted agents. This has been shown in retrospective analyses of patients treated with ibrutinib (Imbruvica), where CKT was even worse than TP53 mutations or aberrations. In small datasets, it was also observed that venetoclax monotherapy was not efficient in patients with CKT.
What were the findings of this analysis, and what are your next steps for research into this combination in CLL for patients with CKT?
In our analysis, we showed that, in this prospective setting of CLL14, we had a look at all patients randomized, and in 93% of patients, we had a CKT analysis done before we started treatment. [This way], we were able to evaluate how patients with and without CKT performed throughout the study and during follow-up.
What we’ve now observed is that, on the one hand, patients with CKT have a shorter PFS as well overall survival (OS) when treated with chemoimmunotherapy. In contrast to that, patients treated with venetoclax/obinutuzumab, irrespective of the presence of CKT, had a similarly high efficacy. This is the first time that a treatment regimen has shown, in a prospective manner, that it is similarly efficacious in patients with CKT.
For us, this means that, on the one hand, we should definitely check for CKT prior to initiating first-line therapy, because now we know that it even has a survival impact depending on the treatment regimen we choose, and to guide our treatment. Therefore, for a patient with CKT, the combination of venetoclax/obinutuzumab seems to be a good option.
When should a chromosome analysis be done in patients with CLL?
Patients should be checked for CKT before initiating therapy. From my perspective, we don’t have any data that indicates—at the moment at least—that we should start treatment when patients are asymptomatic. For patients with CLL, with a first diagnosis of CLL who don’t have any symptoms or complaints, they don’t need therapy—particularly if they have a normal blood count. This is also defined in CLL guidelines: no treatment [is needed] for these patients—just a watch-and-wait strategy. No treatment has shown any survival benefit for those patients when they are treated, irrespective of their symptoms.
We would suggest that patients, when they require treatment, should be checked for CKT, because then there are direct therapeutic implications. One should do that with the whole diagnostic workup: IGHV status, TP53 status, and CKT. This should be done before we start treatment, and it can guide us to choose the treatment.
Another timepoint as well, although we don’t have sufficient data for it at this stage, is to check once the patient relapses. If they’ve completed treatment and the patient relapses, and they require treatment for their relapse because they have symptoms and the blood count has moved, we should again check for it in case the patients didn’t have it before.
How is the treatment paradigm for CLL taking shape?
What is important now is that we have, due to this broad battery of trials we have seen in the last 2 or 3 years on CLL, we surprisingly have 2 treatment paradigms that have appeared: we’ve seen that the treatment with ibrutinib as continuous monotherapy is highly effective in patients. Although only a very small fraction of these patients achieve minimal residual disease (MRD) activity, we still see that these patients continue to be in remission in a very relevant proportion of these patients.
In contrast, we have also now seen that chemotherapy-free regimens like venetoclax and obinutuzumab can be given over a fixed duration—for example, 12 cycles over a year—and patients can stop treatment and still continue to be in MRD.
These are basically 2 new treatment paradigms: continuous therapy without MRD negativity, but still highly effective, and short-duration therapy with MRD negativity, where we can stop treatment and—at the moment, with short follow-up—see that patients continue to be in remission.
Each of those had advantages and disadvantages. For ibrutinib or continuous BTK inhibition, we see that, in most patients, it seems to be tolerable, but we also see that there are adverse events that may come up as you treat for a long period of time. The patient has to stay on medication, so there is a question of compliance; sometimes patients do not want to take any further medication. We know that once you stop ibrutinib, CLL usually pops up quite quickly, so this is a disadvantage. Also, of course, [there is] the question of costs. When patients take it for 5, 6, or 7, years, it is also, of course, a financial burden.
This would be an advantage of fixed-duration therapy: to give it just for 12 cycles, the patient knows that, like in conventional chemotherapy, they have 12 cycles and then they are finished and should remain in remission. On the other hand, it can, for some patients, be a disadvantage because they need to get infusions, or they have to be in treatment for 12 cycles—that might be a challenge for them.
We need to see, in the future, in randomized trials, whether we can compare these 2 treatment paradigms and see whether we see differences in efficacy. If we don’t see differences in efficacy, this would also be an interesting result. Then we can see, what the patient’s preference is. What has more complications? Are there any survival implications? All of that has to be seen in a randomized trial, so this will be the next step to do.