A comprehensive analysis of the CLL treatment landscape, including available agents, risk stratification, and triggers to initiate therapy.
Brad S. Kahl, MD: The development of novel targeted agents in CLL [chronic lymphocytic leukemia] has revolutionized this field. Not surprisingly, these new agents have consistently performed better than traditional cytotoxic chemotherapy in phase 3 trials. Not surprisingly, when groups are starting to analyze population-based data for long term outcomes, they’re seeing improvement in those outcomes. We assume this is because of the availability of these new agents. Ibrutinib has been around for a few years in CLL now and had ample opportunity to make an impact. Then we had venetoclax added to the options and then acalabrutinib, and we’ve had the PI3 kinase inhibitors for a number of years—a whole host of new targeted therapy options in CLL.
There was an interesting analysis at ASCO [American Society of Clinical Oncology Annual Meeting] this year, where this group of investigators looked at a SEER [Surveillance, Epidemiology, and End Results] database analysis, and the time frame they used was 1985 to 2017. They were able to show that the 5-year overall survival from the earliest time interval—they chunked it into 5-year time intervals—improved in men from 72% to 88%, comparing the earliest time interval to the latest time interval, and for women from 76% to 90%, from the earliest time interval to the latest time interval. There it is in black and white, strong evidence that these new therapies are having a positive, beneficial effect on overall survival in CLL.
When we’re assessing risk in CLL, there are 2 main parameters to look at. There are some more esoteric ones, but those aren’t as key as these 2 main ones. It’s pretty simple. It’s the immunoglobulin heavy-chain gene mutational status, IGHV. This refers to that CLL cell in its maturation, when it turned into a malignant cell, or where that B cell can be thought of as like the cell origin: where the cell of origin was when it turned into a CLL cell. Cells that have had trafficking through the germinal center of a lymph node undergo what’s called somatic hypermutation. That can be measured, so for patients with CLL whose CLL cells are somatically hypermutated, or so-called IGHV mutated, that turns out to be favorable or good in CLL. If patients have the mutated version of IGHV, everything works better. Immunochemotherapy works better. Venetoclax works better. With BTK [Bruton tyrosine kinase] inhibitors, it’s not so clear that those work better. They work equally great in both mutated and nonmutated, but to have the mutated version of IGHV is a good thing for a patient.
The other thing to look at is the CLL FISH [fluorescence in situ hybridization] panel. If people have a 17p deletion, then that’s a strong adverse prognostic marker. Nowadays it’s probably worth sending the material for a TP53 mutation analysis. Sometimes 17p and TP53 mutation go hand in hand—travel together—but not always. That’s such an important adverse risk factor, that it’s worth knowing both 17p deletion status and TP53 mutational status. Those are the 3 things I recommend. A CLL FISH panel, TP53 mutational testing, and IGHV mutational testing. Then you can have your patient risk stratified adequately. The IGHV-mutational status shouldn’t change over time—you should have to do that test only once—but patients can acquire a 17p deletion or a TP53 mutation over time. Before each time you start a new line of treatment, it’s worth repeating the FISH panel and the TP53 mutational testing.
The criteria for initiating treatment doesn’t depend on those risk factors we just mentioned. In other words, if you have a patient who has biologically high-risk disease, because they’re IGHV unmutated, 17p deleted, or TP53 mutated, that by itself isn’t a reason to start treatment. The criteria for starting treatment are the traditional criteria that have been published many times. Does the patient have symptoms? If they have symptoms, then starting treatment is appropriate. Are they becoming significantly anemic? A hemoglobin level less than 11 g/dL is a good line in the sand. Are they becoming significantly thrombocytopenic? A platelet count of 100,000 per mm3 is a pretty good line in the sand. Those are the strongest criteria. A little softer are things like the lymphocyte doubling time. If the lymphocytes double in 2 months, some people say it’s time to consider starting treatment. I don’t start treatment based on the absolute lymphocyte count; that’s not an indication for treatment. Sometimes your patients are getting significantly bulky lymphadenopathy, and that would be a reason to start, or symptomatic splenomegaly. They’re uncomfortable from a big spleen. That’s a reason to start. Cytopenias, significantly lymphadenopathy, significant splenomegaly, or the development of symptoms. Those are the main reasons to initiate treatment in CLL.
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