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Call to Action: R/R CLL and MCL

CE / CME

Call to Action: Addressing Barriers to Optimal Management of Patients With Relapsed/Refractory CLL and MCL Using Innovative Therapies

Physician Assistants/Physician Associates: 0.25 AAPA Category 1 CME credit

Pharmacists: 0.25 contact hour (0.025 CEUs)

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Nurse Practitioners/Nurses: 0.25 Nursing contact hour

Released: September 13, 2023

Expiration: September 12, 2024

Farrukh T. Awan
Farrukh T. Awan, MD, MS, MBA
CME/CE Information

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Key Takeaways
  • All patients with R/R CLL and MCL should receive appropriate testing for high-risk features.
  • For R/R MCL, pirtobrutinib and brexucabtagene autoleucel are recently approved options that may be considered for specific patients.
  • Ensuring that patients have access to novel treatments and clinical trials including accurate information about these treatments is essential.

Treatment for patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) has evolved significantly over the past few years. Several novel treatment options associated with good tolerability and phenomenal outcomes are now available. Our patients must have access to these treatments and participate in ongoing clinical trials. In this commentary, I discuss common barriers to optimal treatment and best practices in overcoming these barriers.

Testing for High-Risk Features
When managing patients with CLL and MCL, especially in the relapsed/refractory (R/R) setting, it is very important that patients have the appropriate testing for risk stratification, which can make a large difference in terms of therapy selection. For both CLL and MCL, fluorescence in situ hybridization testing for deletion 17p and polymerase chain reaction– or next-generation sequencing–based TP53 mutation testing can be done easily in any setting; the presence of these alterations allows us to identify the high‑risk patient subsets who are not good candidates for conventional chemotherapy. All of our patients should receive this testing prior to starting treatment to allow for optimal therapy selection.

Additional tests can help us stratify our patients depending on the specific disease biology. For CLL, assessment of IGHV mutations and β-2 microglobulin levels can allow us to stratify patients into their appropriate risk group. For MCL, blastoid variants and Ki‑67 can be assessed for risk stratification.

CLL Treatment Considerations
Looking specifically at CLL, the field generally has moved away from chemotherapy, which is not indicated in the United States for most patients with CLL. BTK inhibitors and BCL2 antagonists are highly effective therapies that now form the standard of care for CLL and are recommended for patients in the first-line and R/R settings. These treatment classes typically provide a long disease‑free interval, but after a certain time, many patients will eventually relapse, and this is why it is essential to make sure there is access to new treatments for patients who are truly refractory to covalent BTK inhibitors and BCL2 inhibitors. Novel treatments include investigational BTK inhibitors such as pirtobrutinib or nemtabrutinib, which bind to BTK noncovalently, as well as investigational CAR T-cell therapies, bispecific antibody therapies, and combinations of BTK and BCL2 inhibitors. Patients must be informed and educated about the availability of these options, especially in the R/R setting.

MCL Treatment Considerations
Several novel therapies now are approved by the FDA for R/R MCL. Pirtobrutinib is approved for patients with R/R MCL after at least 2 lines of systemic therapy, including a BTK inhibitor; this approval was based on results from the single-arm phase I/II BRUIN trial. Of note, the binding sites for covalent BTK inhibitors (eg, ibrutinib, acalabrutinib, zanubrutinib) and noncovalent BTK inhibitors (eg, pirtobrutinib) are different. Pirtobrutinib has been assessed following intolerance or resistance to a covalent BTK inhibitor and should be used in that setting until more data become available.

Brexucabtagene autoleucel, a CAR T-cell therapy, also is approved for R/R MCL. We should consider early consultation for CAR T-cell therapy, especially in patients who progress after BTK inhibitors. This strategy can allow us to perform a basic workup, address insurance issues, and determine if a patient should be considered for CAR T‑cell therapy now or in the future.

There is a misconception that CAR T‑cell therapy is very toxic and may not be feasible for many patients. Our understanding and management of patients undergoing CAR T‑cell therapy have improved substantially in the past few years. Most of our patients can tolerate this therapy without significant long‑lasting toxicities, and mortality rates from treatment are low. It is true that many patients experience the characteristic acute adverse events associated with CAR T‑cell therapy, but these can be easily and effectively managed, and patients can resume reasonable everyday life shortly after treatment. Age used to be a consideration in determining eligibility for this treatment, but as our expertise and comfort level have improved, we have started performing these procedures for older patients well into their 80s and patients who may not have the best organ function. As such, it is critical to assess CAR T‑cell therapy eligibility in consultation with an expert in this treatment modality at a specialized CAR T-cell center that performs a fair number of these procedures regularly.

I also wanted to touch on the evolving role of stem cell transplantation, especially with MCL. Historically, some centers have performed autologous stem cell transplantation in the first complete remission after chemoimmunotherapy, but this practice has become questionable because our patients have access to many alternative therapies that are very effective. It is crucial to consider a second opinion or a consultation with a stem cell transplant center, especially for addressing whether a patient might be a candidate for a consolidative autologous stem cell transplantation—and especially for MCL. Autologous stem cell transplantation has no role in the management of patients with CLL.

Clinical Trials
It is essential to inform patients early in their treatment course that many treatments in oncology are done as part of a clinical trial. We should talk to patients about having access to the most recent exciting new treatments, which potentially can result in excellent outcomes. The biggest misconception for many of our patients is that “I will end up getting treated with a placebo in a clinical trial, and I don’t want to participate for that reason.” The vast majority of clinical trials in oncology are no longer placebo controlled. It is important to let our patients know that with a randomized clinical trial, one half of patients or a subset will get one type of treatment, and the other half usually get the standard treatment. The rationale behind many of these studies is that you compare the new treatments with the best available option. Many of these trials have what we call crossover arms in which all patients end up receiving the same treatment eventually. 

Treatments in randomized trials have gone through extensive testing to ensure that they are safe and effective, and the idea is to treat more patients in these trials before the treatment receives FDA approval. Many trials do not have a randomized arm, so all patients get the same treatment. There are many options for clinical trials that might be available or accessible for our patients at any given time. This is why it is important to have discussions with patients on an ongoing basis to evaluate them as candidates for participation in a clinical trial. This is the only way to make them more aware and less reluctant to participate and keep moving the field forward.

Access to Treatment
It is essential to ensure that patients are not considered candidates for a particular therapeutic option based on geography, travel time, or socioeconomic status alone. For example, many centers that perform CAR T-cell therapy or stem cell transplantation have social support mechanisms, including allowing patients to stay in local housing or providing subsidized housing so patients do not have to worry about commuting. Caregiver support also can be arranged in some cases. Insurance also may provide coverage for some of these options. 

Patients often work full time and have significant obligations toward their jobs and families. This can make starting a clinical trial or novel treatment difficult, but in the right supportive environment, many resources can be provided to patients so that they can get time off work, short‑term disability, and housing and meal support, which potentially can allow them to receive very effective novel therapy. It is essential to have these discussions up front, especially in the R/R setting, because the field is moving so fast that there is always access to novel therapies and clinical trials that may not be available in the practice where the patients currently are receiving treatment. 

Your Thoughts
What are some of the barriers you have experienced in providing optimal care for patients with R/R CLL and MCL? How did you overcome these? Please answer the polling question and join the conversation by posting a comment in the discussion section.

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Which of the following do you find to be the biggest barrier in getting your patients with R/R CLL and MCL access to novel therapies?

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