I would like to acknowledge Dr. Sameer Parikh for his review and edits as well as his thoughtful and expert CLL care.
Summary: Starting treatment for CLL / SLL requires a complex decision-making process. There are several well-established choices, but they differ in multiple ways. This essay describes a set of issues to consider in a deliberative process to transition from monitoring CLL / SLL to active treatment. Fortunately, whatever decision is made will likely achieve the goal of many years of feeling and suppression, possibly eradication, of CLL / SLL from the bloodstream.
Most people with CLL / SLL have had a journey similar to mine. The diagnosis was a complete surprise. After reassurance from my oncologist that I wouldn’t need treatment for many years (if ever), I began a journey of routine monitoring, with heightened anxiety, in the days before each follow-up appointment. What has changed since my diagnosis about eight years ago is that when I came to need treatment in 2022, I could be offered several excellent choices. This essay describes the deliberate process I used to make a complicated decision about how to start my treatment regimen.
I am a physician with expertise in internal medicine, geriatrics, and palliative care used to caring for others having a serious illness of my own. This dual role is both a blessing and a curse. It is easier for me than most people to imagine the worst-case scenarios. It has led me to search the medical literature for an association of every ache or pain I have to my CLL. My background also allows me to make my CLL treatment decisions with the wisdom gained from advising others with various medical dilemmas. I now seek to share my decision-making process to help others with CLL / SLL.
What were my options
When my oncologist recommended we plan for treatment, he ordered a new analysis of my CLL cells, called a FISH test, and a TP53 and 17p determination. These results were used to guide therapy recommendations. This is the basis for the CLL Society’s mantra, “Test before you treat.”
At the time I started treatment in late 2022, my best options were Obinutuzumab and Venetoclax (O+V) vs. a BTK-inhibitor, such as acalabrutinib (A) or zanubrutinib (Z). The likelihood of short-term response (improved blood counts and reduced symptoms) is very high for either approach. Similarly, both treatments have a very good (>70%) chance that there will be little or no evidence of CLL cells on standard blood tests over at least five years for most subgroups of people with CLL / SLL. One of the best sources I found to review recommended options is the National Comprehensive Cancer Network (www.nccn.org).
There are significant differences between these two approaches to treatment. First, the combination of O+V is a time-limited therapy (e.g., one-year). The research trial protocol to obtain its FDA approval was a series of 10 outpatient intravenous infusions of O spread over six months. It overlapped with 11 months of once-daily oral doses of V. The infusions take most of the day.
In contrast, treatment with a BTK inhibitor involves taking medication at least daily for the rest of one’s life (or until the treatment fails).
The number of people who can’t tolerate either of these protocols is low and relatively similar. For V + O, there is usually discomfort from fever or shaking chills during the first dose of O and the potential need for one night in the hospital after starting V. Both approaches increase the risk of infection, with O + V probably having a higher risk. However, the risk of a severe infection requiring hospitalization is less than 1 in 15 people, even for O+V therapy.
In summary, comparing the two options represent what is technically called a “Toss-Up .”Statistically, they have similar likelihoods of both good and adverse results but have different patient experiences and time commitments. There is no right or wrong choice. This makes this decision among the most difficult because it depends upon predicting the future and valuing intangible things like the number of hours receiving medical care or the effort to take medicine reliably.
Note: The most recent NCCN guidelines have added a protocol to provide O infusions at the beginning of continuous treatment with A. The combination may offer longer benefits than A alone for some people with CLL / SLL. Thus, the decision can be complicated by requiring a comparison of three choices. In addition, another approved and often effective option, chemoimmunotherapy (FCR), is rarely recommended due to its side effects. A different option of chemoimmunotherapy (BR) is also not frequently recommended due to toxicity; and major studies showing that newer agents are more effective and less toxic compared to chemoimmunotherapy.
Another good option for many people with CLL / SLL is enrollment in a research trial. Advantages include close oversight of care, reduced costs, and even stipends paid to enrollees. Disadvantages include extra appointments and tests, the potential need for travel to a study site, and loss of some control while enrolled. However, enrollment in a trial also provides the satisfaction of helping advance knowledge for others’ benefit. To find clinical trials for CLL worldwide, go to www.clinicaltrials.gov, a U.S. government Web site, or ask your oncologist or a medical librarian at your hospital to search for you. Many studies are now enrolling new patients examining novel combinations of approved drugs with many sites.
There is a spectrum of ways to make a healthcare decision. At one extreme, a patient can delegate a decision to the clinicians or a family member. In other words, I could have asked my oncologist what to do and simply followed his instructions. Prior generations of doctors were very comfortable making decisions on patients’ behalf under the paternalism principle. In some cultures, the delegation of health care decisions to a family member or community leader is common. This is ethically acceptable, but only if a patient wants to take that approach. On the other extreme, a patient can bring their decision to the doctor and ignore any contrary advice from the oncology team. This, too, is ethically acceptable if the patient can provide a reasoned justification. Finally, the most common decision-making model is somewhere in-between, as a collaboration between the patient and health care team, typically including at least the oncologist, nurses, and pharmacist. In this model, the team presents options. It helps the patient decide, or the patient makes a request but explores other options with clinicians. My approach was a variation of this, which like during the Cold War, could be called “Trust but Verify.” First, my oncologist recommended a well-established and proven treatment protocol. I then did extensive research about this, which included reading the original published studies, professional society guidelines, recent research presentation slide decks, and even FDA package inserts. I also got a second opinion from another oncologist and spoke with others who opted for this treatment.
Goals or “What Matters”
Before choosing therapy for CLL, consider the trade-offs in doing everything possible to eradicate the CLL (achieving remission) versus enjoying every day as much as possible. For people near death from other causes or who cannot make decisions due to brain disease, it could be appropriate to forgo treatment directed at the CLL cells. Instead, there are approaches to manage and reduce symptoms, accepting the progression of the disease and death. In more typical circumstances, consider risks of death or serious illness due to the treatment compared to the likelihood of success of treatment. For example, the O + V protocol may have greater risk offset by some evidence of more frequent or longer benefits. Similarly, O + V is more time intensive in the first six months than a BTK inhibitor but requires no daily effort after the first year.
There are other aspects to “what matters” that need to be considered in choosing a CLL / SLL treatment. These include how you would feel about the cost of care (to you or society) and about taking medicines several times per day long-term, possibly life-long. In addition, simultaneous management of other illnesses and/or responsibilities, such as work or caregiving, may influence CLL-related decisions. I didn’t assume my oncology team would have the time or expertise to assist me in exploring my views on such issues during appointments, so I spent time thinking and talking to family and CLL support group members about these topics.
What might come next?
All treatment options for CLL / SLL have a risk that they won’t be tolerated or that the CLL / SLL will become resistant to that treatment. Therefore, deciding what to use for initial treatment should consider what will be done next. The NCCN guidelines describe the current recommendations after each initial treatment. For example, suppose O + V fails. In that case, the next step might be retreatment or switching to a BTK inhibitor, depending upon the circumstances. If a BTK inhibitor fails, the next step would typically be O + V. Thus, if the O + V protocol is substantially easier or harder now versus in the future, this should be considered when choosing an initial therapy.
Also, consider the rapid development of newer treatments. Integrating treatments still under investigation into current decision-making is challenging, but knowing that there will be more options in the future may be reassuring.
Consider when to start
Long-standing guidelines in CLL / SLL care specify criteria to begin treatment. These standards allow some people with CLL / SLL to complete their life without ever needing treatment and delay treatment for years after diagnosis for most everyone else. Unlike most cancers, there is no evidence that early treatment adds enough benefit to recommend it. However, studies of this for people most likely to need treatment within a few years of diagnosis are ongoing. The criteria to start treatment are based upon CLL affecting the production of red blood cells or platelets, causing spleen or lymph node discomfort, or having significant general symptoms such as weight loss, persistent and consistent night sweats, or fatigue. A long list of additional common symptoms may or may not be due to CLL for a patient, such as heartburn, leg cramps, shortness of breath, or infections, which may also justify starting treatment. A rapid rise in the number of lymphocytes, even without symptoms, may also be a reason to start treatment.
Early treatment before such signs or symptoms are present hasn’t been shown to be beneficial. Once criteria are met, planning for treatment should begin; only rarely is treatment suddenly urgent. A typical process may be a recommendation for treatment at one oncologist visit, with a timeline to decide which treatment and make necessary arrangements at the next visit some months later. Sometimes, symptoms diminish between visits, and treatment is postponed.
Once a firm decision to start treatment is made, scheduling becomes essential. Treatment may require an increased frequency of medical appointments or cause side effects, so other obligations or vacation plans should be considered before picking a start date. Addressing general health and preventive care, including dentistry, may be better before starting treatment, especially if the therapy could delay healing or recovery from procedures. Health insurance issues may affect timing, such as expected changes in coverage (e.g., starting Medicare or switching plans). If medical appointments require travel, seasonal weather may factor in choosing a start date. Because they are so expensive, CLL treatments often require prior authorization/approval from the health insurer, which may delay start dates if not sought as soon as a decision is made. For protocols that require infusions, scheduling those appointments may require some lead time. Finally, some oncologists may only be in your preferred office on certain days of the week and have busy schedules, so that a start date may depend on the oncologist’s availability. Time is required from the decision about treatment to the start date, so I would discourage waiting until symptoms of CLL / SLL are making life miserable.
The retail price of the treatments for CLL / SLL is typically over $10,000 per month or infusion session. For patients on Medicare plans, the out-of-pocket costs can be over $10,000 per year for either a BTK inhibitor or venetoclax in 2023. Medicare will have an overall cap on medications of $3,250 in 2024 and $2,000 in 2025. The cost may have an impact on a choice of therapy. For example, being on a BTK inhibitor for years will likely have higher out-of-pocket costs (as well as societal costs) than a 1-year protocol with O +V.
Several programs assist patients with CLL / SLL with their drug costs. For people with commercial (not on Medicare-related) insurance, the Genetech Oncology Copay Assistance Program can help with almost the entire cost of O + V. There are other programs that have income limitations but can be used by those on Medicare, such as Patient Assistance Network (PAN) and the Leukemia and Lymphoma Society Financial Assistance Programs.
For some people, it may have favorable or negative financial implications to start therapy before or after January 1, as many insurance programs reset copay caps annually. Before beginning treatment, check with your insurance company about copays and out-of-pocket costs. Then, at annual open enrollment, consider options to see if savings are possible in different plans. For Medicare plans, this can be done at: www.medicare.gov.
Consider where to receive care
Suppose a person with CLL / SLL is confident in their oncology clinic, and it is convenient. In that case, it is obvious where treatment will be provided/overseen. Some people have a local oncologist used for routine visits but use a distant CLL expert for complex issues such as treatment decisions. Some have only a distant oncologist who has monitored everything until treatment is needed. Some have an oncologist with too few appointment slots to see regularly while on a complex regimen such as O + V. In these last three scenarios, deciding which clinic to use for the treatment is necessary. There is research evidence that the use of an oncology team with expertise specifically in CLL / SLL has better outcomes, but not everyone can access such a clinic. The ease of access to a team with availability and experience with O + V may influence whether to pursue that option. The clinic’s ability to offer video visits may be a consideration. The experience level of the oncologist with your preferred BTK inhibitor (A or Z vs. the older ibrutinib) or with the O + V protocol may also influence where to receive treatment.
Another part of care when on treatment is lab monitoring. That does not have to occur at the oncologist’s office, but timely (e.g., within hours) reporting of results to the oncologist may be necessary. Primary care medical offices probably can’t deliver that speed. A hospital-based lab can serve this purpose. For example, it may be appropriate to have labs done at a local hospital the day before an infusion appointment if there is a several-hour trip to the oncology center’s infusion clinic. Similarly, the protocol for escalating venetoclax doses may include labs in the morning after a dose adjustment to monitor for side effects. Again, a local hospital lab may be the best location for that test rather than returning to a distant oncologist’s office.
Consider who will help
The prior sections highlight the complexity of the treatment process for CLL / SLL. Almost every patient will need some help. This assistance may include offering to drive to appointments, providing companionship during infusions, accepting delivery of medications, helping manage medications (e.g., set-up or reminders), managing a calendar of appointments, or managing bills and insurance. The infusion therapy protocols will require more help; a lack of reliable family members or friends may suggest taking a BTK inhibitor alone is the best option.
Oral medications for CLL / SLL are delivered by one of a handful of specialty pharmacies that dispense such expensive drugs through package delivery services. They have pharmacists and nurses who provide education about the medications and follow-up calls to monitor for side effects. Unlike community pharmacies, they will call the patient to schedule refills. Check with your prescription drug insurer to get the list of options and enroll with a specialty pharmacy as early as possible.
Accept your choice
Once a treatment choice is made between a BTK inhibitor (with or without O) vs. O + V, it is best to fully accept that decision rather than worrying about whether it was the right choice. As stated above, there is no right or wrong choice. Problems may arise, but it cannot be known what would have happened if the other option had been made. The goal is to get through the year of O + V or to take the BTK inhibitor until it stops working. A therapy change can occur if side effects can’t be addressed with a dose adjustment or other medications. Typically that would be crossing over to the other treatment protocol.
There are many points in the course of therapy that justify celebration. That includes: completing the six cycles of O, completing the first year of treatment, a good measurement of residual disease, and every anniversary (on a BTK inhibitor or in remission) after that. Plan to share the news with friends and family and to celebrate with those who have helped along the journey.
What I chose
Every individual’s circumstances are different, so my choice, after careful deliberation, may not be the best for you. I have favorable CLL markers (e.g., mutated IGHV, 13q deleted, and no TP53 genetic alteration) and have good kidney function. I live 90 miles from my CLL team located at Mayo Clinic. I have commercial insurance. With my oncologist’s advice and concurrence from a University of Minnesota CLL specialist, I chose to start my treatment with O + V, driving to Rochester for my care. When I complete my year of treatment, I plan to share my experience through the CLL Society.
Edward Ratner, MD
GRECC, Minneapolis Veterans Administration Health System and University of Minnesota
Disclaimer: The content is solely the responsibility of the author and does not necessarily represent the official views of the VA or the United States Government.