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Dr. Anthony Mato of the University of Pennsylvania asked questions about what happened when patient stopped their oral kinase inhibitors (KI) ibrutinib (BTK inhibitor) and idelalisib (PI3Kɣ inhibitor) due to toxicity or disease progression.
Take Away Points
- Most patients tolerate KIs well and stopping them is still rare.
- Adverse effects are the most common cause of coming off these meds.
- The overall prognosis in this trial was better for those who failed ibrutinib and idelalisib than reported in prior studies.
- Switching KIs or venetoclax may be effective options for many of these patients.
Before we get to the results, Dr. Mato first explains exactly what a kinase inhibitor is.
The research group that he led looked at the discontinuation of the two approved KIs, ibrutinib and idelalisib. Many others are coming in the pipeline including duvelisib (PI3Kɣ&∆), acalabrutinib (BTK), TGR-1202 (PI3Kɣ), ONO-4059 (BTK), BGB-3111 (BTK), SNS-062 (a non-covalently binding BTK inhibitor) and even more, so it is important to be investigating these questions now.
As the use of KIs expands, knowing what happens when we stop these meds becomes an increasingly relevant issue for more and more patients.
This was remarkable study in that it was completely unfunded and was a collaborative effort between ten different institutions.
It is also important to have the perspective that these medications work very well for most patients with few side effects. Therefore not many CLL patients discontinue these drugs. That explains why Dr. Mato and his team had to aggregate the data from a total of ten sites to identify enough patients who discontinued their KIs in order to get any significant results.
The researchers were surprised that more than half stopped due to toxicity and not CLL progression or Richter’s Transformation (RT).
Only 8% of those who discontinued did so due to RT, considerably lower than in other studies.
A significant number of patients who came off the meds did not need any immediate treatment, as their disease continued to be well-controlled after therapy was discontinued.
As one might expected, those patients that came off the meds due to toxicity did well when switched to a different kinase inhibitor.
Those who developed Richter’s had the worst prognosis.
However, contrary to earlier reports of poor outcomes after coming off a KI, in this multi-center study even those whose CLL progressed while on a KI often responded when switched to a different KI.
From the ASH abstract, we learn that the overall response rate (ORR) to idelalisib-based therapy following ibrutinib discontinuation was 50% and the ORR ibrutinib-based therapy following idelalisib discontinuation was 77%.
In a different paper by Dr. Jeff Jones out of Ohio State University (OSU), along with Dr. Mato and others, they studied rescue for a similar group of patients with venetoclax, an oral BCL-2 inhibitor and not a KI. (see 715 Preliminary Results of a Phase 2, Open-Label Study of Venetoclax (ABT-199 / GDC-0199) Monotherapy in Patients with Chronic Lymphocytic Leukemia Relapsed after or Refractory to Ibrutinib or Idelalisib Therapy)
When the data was collected to present at ASH 2015, there was only a very short follow-up. However, they did find was that 23 of the 28 patients that had progressed on either KI were still on venetoclax at the cut-off date for the data collection because they were continuing to respond. Patients who had RT were not included.
Here is the interview with Dr. Mato from ASH 2015
What this study and the smaller trial looking at venetoclax after failure of ibrutinib or idelalisib suggest is that there are potentially helpful options for this tough group of patients, but more research must be done to improve the odds and especially to help those with Richter’s Transformation.
Brian Koffman, MD 5-31-16