Ibrutinib Plus Venetoclax Yields High Rates of Undetectable MRD in CLL
Constantine Tam, MBBS (Hons), MD, FRACP, FRCPA, discusses the results of the minimal residual disease (MRD) cohort of the CAPTIVATE trial, a multicenter phase 2 trial evaluating ibrutinib plus venetoclax in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). These results were presented at the virtual 2020 EHA Annual Congress.
My name is Professor Con Tam from the Peter MacCallum Cancer Centre and the University of Melbourne in Melbourne, Australia. Dr. Siddiqi and colleagues, including myself, presented the study of the first‑line CAPTIVATE MRD cohort at EHA 2020.
This is a study that examines the combination of ibrutinib and venetoclax as first‑line treatment of CLL patients. We previously reported the study results in ASH of last year, and in EHA this year, we further updated the results with longer follow‑up. In short, we treated 164 patients with either CLL or SLL as front‑line therapy.
These patients had to be aged under the age of 70, had to have good performance status, and they were treated with ibrutinib as the leading therapy for 3 months to debulk the CLL and to reduce the tumor lysis risk before they were introduced to the combination of both ibrutinib and venetoclax for a total of 12 months.
At the end of 12 months combination therapy, patients were then, depending on their MRD status, assigned to further therapy. Those who were MRD‑negative were randomized to either ongoing ibrutinib or placebo, and those who were MRD‑positive were randomized to continuing combination or receiving ibrutinib monotherapy.
Now, what we are reporting is the phase before the randomization. We're reporting the results we get from 3 months of ibrutinib followed by 12 months of combination ibrutinib and venetoclax.
In terms of patient characteristics, the median age is 58. Of course, this is a study that restricted itself to patients under the age of 70. These patients were younger. For front‑line study, there were actually quite a number of high‑risk patients, including 20% with p53 abnormality, 19% with a complex karyotype, and 59% with unmutated IgVH status.
We think the reason why this study has such a large number of poor prognostic risk patients despite being a front‑line study is because, in many countries, including mine, this was the only way that you can access novel therapy for patients who are unsuitable for chemotherapy on the basis of poor risk biology.
When you interpret these results, you have to remember that these patients are worse than usual in terms of front‑line CLL studies. 164 patients started the ibrutinib leading. All 164 completed ibrutinib, and 159 completed the 12 months of combination of ibrutinib plus venetoclax.
The total completion rate of the planned therapy, including the 3 months of ibrutinib and the 12 months of ibrutinib and venetoclax, is in fact very high at 90%. I think this demonstrates how well‑tolerated this oral regimen is.
What was really interesting was that the 3‑month ibrutinib really did make a very large difference in terms of tumor lysis risk. At baseline, 24% of patients were high tumor lysis risk. After 3 months of ibrutinib leading, this 24% rate has been reduced to 2%.
There was a 90% reduction in the number of patients who were at high tumor lysis risk. This is a very important practical consideration for using this combination in the future, because it means that very few patients would require hospital admission for observation due to tumor lysis risk when one applies 3 months of ibrutinib leading.
In terms of side effects, the combination really, the main side effect of the combination was additional risk of neutropenia associated with a lower risk of infection and also an increased risk of nausea and diarrhea when both drugs were combined, compared with only ibrutinib monotherapy.
As stated above, 90% of patients were able to complete the planned therapy, thus the regimen is in fact very well‑tolerated in the majority of patients. Now, the headline result is MRD clearance.
This is our measurement of CLL by high‑sensitive flow cytometry at the level of 1 in 10,000 cells. What we demonstrated is that, with the combination, that there is a 75% of patients, 75% achieved MRD clearance in the peripheral blood, and 72% achieved MRD clearance in the bone marrow.
Thus, this is a highly active regimen, capable of clearing MRD in the majority of patients. In fact, the patients who responded had very durable response. At 15 months of observation, 98% of the patients were progression‑free with no deaths.
When we examined the MRD clearance rate by risk category, remembering that this is a study that was disproportionately loaded with high‑risk patients, what we find was that even the worst biological categories, including those patients in 17p deletion, or bulky disease, IgVH unmutated status, or complex karyotype, all of these patients achieved high MRD clearance rate.
Showing that this all‑oral combination, at least at the level of response rate, is able to overcome the adverse factor of poor biology. In conclusion, we demonstrated in an international, multi‑center study that the ibrutinib and venetoclax regimen was a feasible regimen with good tolerance, and 90% of patients were able to complete this regimen.
There is a very high MRD clearance rate of 75% in the peripheral blood and 72% in the bone marrow. We showed that the way we did this, with 3 months ibrutinib followed by 12 months of combination, resulted in a very low risk of tumor lysis syndrome. It's a very good way to introduce this combination while minimizing the risk.
In conclusion, we think that this is a very promising regimen. We're hoping that this is one of many steps towards replacing chemotherapy as front‑line therapy in patients and providing patients with the ability to clear MRD and to stop the treatment as opposed to the current paradigm of either getting chemotherapy with for limited-duration treatment or getting novel agent therapy with an indefinite duration of therapy.
We thought that this is a new way to handle things by an all‑oral, chemotherapy‑free regimen capable of achieving MRD clearance and stopping drug. Thank you.