What every doctor should know about CLL in today’s treatment landscape

Medicom talked to Dr Jennifer Brown, who is Chair of the 2023 International Workshop on CLL (iwCLL), director of the Chronic Lymphocytic Leukemia (CLL) Center and institute physician at Dana-Farber Cancer Institute, as well as a Worthington and Margaret Collett professor of medicine at Harvard University, to learn about the latest trends with respect to managing patients with CLL. Dr Brown focusses on a variety of aspects of CLL, which is a mature B-cell malignancy that patients can often live with for a long time without getting treated. Over the last 10 to 15 years, there has been a remarkable advance in the targeted therapy landscape and a lot of Dr Brown’s research has involved the development of those targeted therapies. “At this moment, my team and I are very interested in resistance to targeted therapies,” said Dr Brown. “I particularly focus on genomics of resistance. Next to that, we're interested in the heritability of CLL. It turns out that CLL is a rather heritable cancer, but we don't understand the basis of that nearly as well as we do for other cancers, like breast cancer and colon cancer.”

Medicom: Could you use data on genomics to determine which patients might be at risk for resistance?

“At the moment, we're still using clinical progression for our decision-making,” replied Dr Brown. “However, we do understand quite a bit about mechanisms of resistance to BTK inhibitors. The first-generation and second-generation drugs in that class bind to a particular cysteine residue, cysteine 481, covalently. As you might expect, the primary mechanism of resistance so far identified is the mutation of that cysteine to another residue that can't bind the drugs covalently. On average, these mutations can be detected 8 to 10 months prior to clinical progression. However, there are patients who can stay on the drugs for several years after a low-level mutation develops. Therefore, we do not discontinue the drug solely based on the detection of this mutation. It does appear however that about 50 to 70% of patients who clinically progress carry a BTK mutation.”

“One of the hottest new drugs is a non-covalent BTK inhibitor called pirtobrutinib. This agent works independently of that particular cysteine residue, which means that it can bind in patients whose disease has already progressed on the first- and second-generation BTK inhibitors. It received a first approval for mantle cell lymphoma in January of this year, and we expect it to be approved for CLL, adding another line of BTK inhibition therapy to the treatment landscape.”

Medicom: You mentioned that the treatment landscape has changed significantly in the last few years. Can you discuss about where we are now and where are we heading towards beyond the novel BTK inhibitor that you discussed?

“Currently, first-line therapy for patients with CLL is a choice between continuous therapy with BTK inhibitors and time-limited therapy,” commented Dr Brown. “For the first option, most specialists would recommend a second-generation covalent inhibitor, being either zanubrutinib or acalabrutinib. Both these agents have proven to be better tolerated than ibrutinib in head-to-head trials. Moreover, zanubrutinib showed improved efficacy compared to ibrutinib. The other option is time-limited therapy. This approach uses the BCL2 inhibitor venetoclax in combination with the anti-CD20 antibody obinutuzumab for a period of 1 year. The 4-year progression free survival rates of these two approaches are similar.”

Dr Brown added that, in coming years, it is likely that we will see a combination therapy in the frontline; potentially a BTK inhibitor plus venetoclax or obinutuzumab. “Many single-arm trials or phase 2 trials testing combination therapies for the first-line treatment of CLL have been conducted. However, we don't have head-to-head data comparing continuous BTK inhibitor therapy or time-limited therapy with a BCL2 inhibitor plus an anti-CD20 antibody to time-limited therapy with a BTK inhibitor and a BCL2 inhibitor. There is a trial that has completed accrual, but it has not yet reported results. In addition, other clinical trials comparing the different time-limited therapy options to one another and studies comparing continuous therapy with BTK inhibition to various time-limited therapies are underway. The hope with time-limited therapy is that you might be able to repeat it, without losing efficacy. if you choose continuous therapy with BTK inhibitors first, the patients can stay on it for a very long time. The downside is that once progression occurs on long-term BTK inhibition, patients are no longer sensitive to that class of drugs.”

Medicom: What do general physicians, say family doctors, need to know about CLL?

“An important thing to keep in mind is not to panic if someone has a mildly elevated lymphocyte count,” answered Dr Brown. “People are being diagnosed earlier than in the past and many of them end up being very fearful. That is unnecessary. The most important thing for general doctors seeing patients with CLL, however, is to make sure they get an aggressive vaccination schedule. Live virus vaccines are not allowed, but patients need their flu vaccine every year. Next to that, they need the recommended COVID vaccines for immunocompromised people. Even if they're not treated, these patients are still considered immunocompromised,” added Dr Brown. “Once diagnosed, we give them the pneumococcal vaccine ‘Prevnar 20’. At least 2 months after they received Prevnar 20 we give them ‘Pneumovax’ as well. We tend to repeat these pneumococcal vaccines every 5 years. Considering the fact that patients with CLL have inhibited responses to vaccines, the more you dose people, the better their response will be,” explained Dr Brown.

“Another important matter is second-cancer screening. Patients with CLL have an increased risk of second cancers, skin cancer and melanoma in particular. Therefore, patients need to visit a dermatologist regularly and do their age-appropriate cancer screening. Finally, pap smears are important, because we see HPV reactivation in women who may have had it 30 years before. The type of T-cell immunity that controls HPV is impaired by CLL. The same mechanism explains why patients with CLL have a higher risk of shingles as well.”

Medicom: Could you tell me about the conference that you're organising, the International Workshop on CLL (iwCLL), and what you're trying to achieve with that?

“This year it’s the 20th anniversary of the iwCLL meeting. The conference is organised by a core group of the iwCLL Executive Board, and it represents about 1,000 people who are very interested in CLL getting together to talk about CLL. One of the unique things about our community is that many of us both do research, including laboratory research, and see patients in the clinic. The conference spans the whole spectrum of CLL, from clinical activities to basic science. There are sessions on genomics and proteomics, novel therapies, and discussions on how to define success in CLL in the future.”

“For example, we’ll be talking about questions, such as: ‘Is it okay if a patient has to stay on a drug indefinitely, or does a patient need to get off the drug to be counted as having the best outcome?’ Furthermore, we will be discussing what our research agenda should look like now that we have all these effective drugs. What are the top questions that we need to address? A prominent issue is that our patients are still immunodeficient and some of them need to get immunoglobulins every month. This is an ongoing problem that affects the quality-of-life of patients. Next, the second malignancy risk is not reduced in the setting of treatment. It could even be increased. So, even though today’s treatments are highly effective, there is still a lot of work to be done.”

Medicom: What kind of obstacles do you think that patients experience with this disease?

“Being immunocompromised in the setting of the pandemic was very challenging for our patients,” said Dr Brown. “Patients were afraid to go out, even with a mask. I think many patients are only starting to come out of their shells now. The risks that come with being immunocompromised hang over their heads like the sword of Damocles.”

“Next, there is the adjustment of learning to live with CLL as a chronic disease, which is very challenging for people. Patients don't know what is going to happen and they tend to think that every symptom they experience is from CLL. In newly-diagnosed people with CLL, my first rule is that whatever you think is due to CLL, is not due to CLL.”

“Finally, when it comes to treatment, the oral drugs are extremely expensive. Depending on where people live in the country and their quality of insurance, the costs can be prohibitive. Although most of the companies have assistance programs, this is a concern for many patients.”

 

Copyright ©2023 Medicom Medical Publishers



Posted on 21 August, 202312 September, 2023