We know that the leading reason most patients stop taking ibrutinib and other kinase inhibitors (KI) is that they become intolerant to their side effects or in medical jargon, adverse events (AE).
Ibrutinib and idelalisib are the only two approved KIs for CLL. A KI is a targeted therapy that inhibits an enzyme, a kinase, important to the cancer’s growth and survival. In the case of ibrutinib, it’s BTK, for idelalisib it’s PI3K-δ. Both these drugs block the B-cell receptor (BCR) that when unchecked, keeps the chronic lymphocytic leukemia alive and active.
These medications are generally much better tolerated than old school chemotherapy drugs that kill any fast-growing cells, such as cancerous cells, but also affects the skin, hair and the gastrointestinal tract.
But AE are still common with KI for several reasons. Here’s a partial list of some broad categories of AE:
- Off target effects where the KI inhibits other enzymes, besides the main target enzyme.
- On target effects where blocking the targeted enzyme has effects on other cells and tissues beside the cancer.
- Allergic reactions to the medication.
It is important to understand the category of AE if we are going to be able to offer other drugs with a different AE profile.
If the AE is a result of an on-target activity of the drug, it is likely that any new medicine that is equally effective would share the same side effect profile.
Ibrutinib, the most widely used KI for chronic lymphocytic leukemia, is generally well tolerated. Still, intolerance is the main reason for discontinuation.
Here is a link to my earlier interview with Dr. Mato on the real-world experience with ibrutinib and intolerance.
And if we CLL patients need to stop our ibrutinib, it is important to have choices that are both effective and well tolerated.
The generally go-to medication has been another KI, from ibrutinib to idelalisib and vice versa, or more recently with a slightly higher response rate, venetoclax, a BCL-2 inhibitor that works in an entirely orthogonal way.
Dr. Anthony Mato, recently at U. Penn and now at Memorial Sloane Kettering in NYC, reported at ASH 2017 in Atlanta Georgia on an experimental KI, umbralisib, formerly known as TGR-1202. Umbralisib is a PI3K-δ inhibitor, like idelalisib, but with a different structure that may have fewer off-target side effects. To qualify for this trial, patients had to have stopped ibrutinib or idelalisib due to intolerance, not disease progression.
Take Away Points:
- 22 patients were enrolled in this prospective trial, 20 coming off ibrutinib and 2 off idelalisib.
- Median age was 66 years, with patients having an average of 2 prior therapies. 55% were female. 45% had bulky disease, 14% del(17p), 27% del(11q) and 59% were IGHV unmutated.
- The most common reasons for stopping the prior KI were arthralgia (joint pains), atrial fibrillation, bleeding, rash, and bruising. Only one of the top five reasons for stopping was grade 4 (very serious).
- On umbralisib treatment: serious AEs (≥ 10% patients) were limited to neutropenia or low neutrophil counts at 23% of the patients or a total of 5, and leukocytosis (high white blood cell counts, common with most KI therapies) at 14%, n=3. The high white counts were not related to CLL progression.
- Common Grade 3-4 (serious) AE associated with other PI3K-δ inhibitors were rare. No liver or lung inflammation was seen and Grade 3-4 diarrhea only occurred in 9% of patients.
- With a median follow-up of 6 months, no patient has discontinued umbralisib due to intolerance.
- At 9 months, median progression-free-survival (PFS) has not been reached.
The study is very small and very short, but there is reason to be hopeful that umbralisib may be another option for CLL patients who can’t tolerate other KIs. Dr. Mato makes the point that if intolerance and not progression is the issue, it may make sense to not give up on the class of medications that block the B-cell receptor (BCR) pathway before jumping to a different class of drugs, such as venetoclax.
The optimal sequencing of the novel medications is an active area of research.
On a personal note, I experienced significant joint pain and bruising and only mild gut issues, but I never considering stopping my ibrutinib. The AE were less of an issue for me than my CLL, but we are all different and have different tolerances.
Here is a link to ASH abstract titled: KI Intolerance Study: A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients with Chronic Lymphocytic Leukemia (CLL) Who Are Intolerant to Prior BTK or PI3K-δ Inhibitor Therapy
Here is my action packed three minute interview with Dr. Mato. You can also read the transcript here.
Here is a link with a slightly different emphasis on the same research with Dr. Brander from Duke.
As you can see, the pace of research is not slowing down.
And that is a good thing, because CLL is not yet a curable disease for the majority of patients.
Brian Koffman, MD 2/20/18