We have great new drugs approved and in development to treat CLL that inhibit the B cell receptor (BCRi), such as ibrutinib, idelalisib, acalabrutinib, idelalisib, umbralisib, duvelisib and others, but they don’t work for everyone, especially when they are not used as the frontline treatment.
Inhibiting BCR removes the cancer cell’s “raison d’etre’, to communicate with other cells, and they eventually die off. This is usually an extremely effective therapy, and that is why ibrutinib and idelalisib have changed the way that CLL is treated.
But what happens if we don’t respond (we are refractory) or if we lose the response (we relapse).
We know from prior trials that if we fail ibrutinib that idelalisib may work, and vice versa. We also know that the even better response rates are found with venetoclax after failing either of the approved BCR inhibitors.
But what if we fail two BCRi?
At ASH 2107 held in Atlanta, Georgia during a rare December snowstorm, Dr. Michael Choi out of the Moore Cancer Center at UCSD, discusses the first multi-center trial to look at venetoclax to treat relapsed chronic lymphocytic leukemia after failing two BCR inhibitors.
Key Take Aways:
- 28 relapsed and refractory (R/R) patients were studied who had received more than one prior BCRi (including ibrutinib, idelalisib, and investigational agents) averaging 6.5 prior treatments for their CLL.
- 36% (10/26) had 17p deletion.
- Overall response rate (ORR) was 39%.
- This number is lower that the ORR seen with venetoclax after failing a single BCRi, where it works over 60% of the time. See the research here.
- Surprisingly there was no difference in response to venetoclax for those who discontinued prior BCRi for intolerance or for progressive disease. This may be because venetoclax works in an entirely different way than a BCRi.
- The median progression-free survival was 16.4 months and median overall survival was 21.6 months.
- The median time to discontinuation for CLL progression was 7.8 months.
- 17 discontinued: 10 due to CLL progression, 2 had Richter’s transformation, 2 due to adverse events (AEs), 1 due to investigator request, 1 due to non-compliance, 1 proceeded to stem cell transplant in remission.
- The most common side effects were low neutrophil count or neutropenia (57%), diarrhea (54%) and anemia (50%).
Summary:
The early data suggested a grim prognosis for those who relapse after ibrutinib and others, but that circumstance is changing.
While the results of single agent venetoclax are not as strong as we might hope, it is clearly active, with manageable side effects. Combination therapies may improve the response rate in this difficult to treat group, but venetoclax is very likely to be the critical backbone of any such combination. This research is an important step in the direction of finding the best path forward in the long-term management of CLL.
Here is a link to the ASH abstract.
You can watch my interview with Dr. Choi below or read the transcript here.
Brian Koffman, MD 2/6/18
