Case Study: Treatment Options and Sequencing for an Older Patient

Christina Russomanno

Hi, Leigh Ann. Today I thought we’d focus on a case study about John, a 72-year-old male with CLL, deletion 13q, mutated IGHV. His medical history includes hypertension and hypothyroid. He works full-time and exercises 5 days a week. He has been monitored for 5 years, but now he’s presenting with cytopenias so it’s determined he should start treatment. So, Leigh Ann, what upfront options do you feel are available to John? And would you prefer a certain treatment plan over another? And if so, why?

Leigh Ann Childress

Considering his cytogenetics, John is a standard risk patient. It looks like he has good performance status, as  he works full-time and exercises regularly. He does have a comorbidity of hypertension to consider. Considering all of those things, I think his options include venetoclax-obinutuzumab,  or a triplet of venetoclax, acalabrutinib, plus or minus obinutuzumab. We could also consider a single-agent BTK inhibitor for him. But first, we should have an upfront goals discussion with John. He’s 72 with a good performance status, so I’d like to know what his goals are to determine time-limited therapy vs. continuous therapy.

For example, is time off work a concern since there will be multiple appointments with the venetoclax-obinutuzumab regimen? Logistics for this regimen can be daunting, especially during ramp-up because of laboratory monitoring for tumor lysis syndrome and other issues. Would that be a concern for him? Perhaps he’s just started a new job, and if that’s the case this could produce some financial toxicity for him. Or maybe he wants to get everything done in a year to allow time off the therapy so he can enjoy retirement or time with grandkids and family. Perhaps he’s caring for someone, maybe a spouse, children, or parents, so multiple appointments would interfere with his ability to do that. An upfront goals discussion is essential in determining what the next step in choosing a therapy for this patient would be.

Christina Russomanno

I totally agree with you. There's nothing in his case that points us to one specific therapy over another. Even the hypertension doesn’t impact the choice of whether or not a BTK inhibitor is used. A patient can develop hypertension and/or worsening hypertension on BTK inhibitors, so we educate them on this ahead of time. Antihypertensives can be added or adjusted if needed. It’s a controllable situation. Considering exactly what John feels strongly about and what he values the most is very important, and that would lead us toward either time-limited or continuous therapy.

Leigh Ann Childress

All things considered, even with the hypertension, venetoclax-obinutuzumab would be a great choice for this patient if he’s interested in time-limited therapy. Considering that he’s only 72, if we treat him upfront with venetoclax-obinutuzumab, then it’s hopeful that we’ll get disease control for 3–5 years. When we potentially retreat this patient, he's going to be 77 or 78 years old. With his comorbidity of hypertension, I can see a single-agent BTK inhibitor fitting perfectly in that particular phase of his life and meeting his needs very well as a second-line therapy.

Christina Russomanno

Yes, that’s a smart way to think about it. It makes sense because we also know that the option of upfront time-limited therapy can be more daunting at initiation. The patient is younger now and in great shape, so he may be in a better position to handle that, whereas, when he's in his late 70s or early 80s and needs retreatment, the continuous therapy might be a little gentler, a little easier on him. And we also don't know what other therapies will be approved or how sequencing will be at that time.

Leigh Ann Childress

So, John did opt for time-limited therapy with venetoclax-obinutuzumab, and he responded very well. However, his disease progressed 6 years later and it was determined that he needed second-line treatment. Retesting of cytogenetics by FISH showed that he now has a 17p deletion. It's essential that APPs who are learning how to manage the patients with CLL who require subsequent lines of therapy know that retesting is very important at this point to redetermine what the risk and prognostic factors for these patients can be with therapy. A great little clinical pearl here is that while repeating the cytogenetic testing is always a good idea, the APP doesn’t have to repeat that IGHV because that doesn’t change with time or therapy, whereas cytogenetics can. A standard-risk patient can eventually become a high-risk patient, which makes retesting at progression important in informing the next therapy.

Christina Russomanno

I completely agree. Yes, the IGHV doesn’t change. What we know is that John went from having what are considered the best prognostic features in the beginning to now having a high-risk marker. Knowing this high-risk marker can point us toward certain therapies that we know might work better for him. So, it's really important that FISH is rechecked before retreatment, no matter what.

Leigh Ann Childress

Given the fact that he is now high risk with a 17p deletion, a comorbidity of hypertension, and it’s about 6 years later so he’s now 77 or 78 years old, what would be your preferred second-line therapy for John?

Christina Russomanno

The first thing I think of is a BTK inhibitor. We know that BTK inhibitors work quite well on 17p-deletion CLL and that patients can have durable responses. They don’t obtain undetectable MRD usually; that would be quite rare. But we know these patients do quite well on these drugs and can be on them for some time, on average 4-6 years, though this average may be a bit lower in the relapsed setting. Whether 17p is noted prior to initial therapy, or found later when rechecked at disease progression, we prefer BTKis for these patients. Also, there are usually clinical trials available for relapsed/refractory patients, and trials should be considered in any patient who needs retreatment. Whether the trial is testing a new drug or a new combination of drugs together, these can be a great option for patients.

Leigh Ann Childress

I would agree with that. In my opinion, offering clinical trials is often overlooked in the community setting. We think more about it in much younger patients where we know they’re going to have lots of therapy down the road, but we don't necessarily think about including our more standard risk older patients in trials because we think we already have the right regimens for them. But discussing clinical trials at all lines of therapy is really important so that we get the best patient samples and the best data for the population we're truly treating.

Speaking of trials and new regimens, newer on the stage of BTK inhibitors is pirtobrutinib, which is something we could consider for him for the next line of therapy. Where do you see that positioning potentially in John's sequence of therapy? And would you see CAR-T as part of his sequence of therapy eventually if he progresses on a second-line BTK inhibitor?

Christina Russomanno

Yes, absolutely. Right now, considering the FDA approval for pirtobrutinib, I think it would be positioned beyond second line. Patients at that stage should have already received a BCL-2 inhibitor like venetoclax and a BTK inhibitor, and possibly even participated in a clinical trial. That said, I know pirtobrutinib is being used sooner than third line in some situations, and that is why medicine is an art. For example, we have seen some use in accelerated-phase CLL with suspicion of Richter transformation that cannot be proven. It is also often used as a bridge to CAR-T, which we know is approved for CLL after at least two prior therapies. Regarding CAR-T as an option, the patient is in his late 70s, so it depends on the center and the provider and how comfortable they are with CAR-T at that age. But if John is in great shape, doing well, and progresses after a BTK and BCL2 inhibitor, referral for CAR-T evaluation would be reasonable. In summary, my thought for John would be a clinical trial or pirtobrutinib at this stage, with referral for CAR-T evaluation.

Leigh Ann Childress

This is exactly how I picture sequencing him, with venetoclax-obinutuzumab upfront providing hopefully 5 or 6 years of quality survival followed by a single-agent BTK inhibitor in the second line, given the high-risk disease and hypertension. I’d want to reserve pirtobrutinib for third-line therapy, and dependent on performance status, possibly as a bridge to CAR-T.

Speaking of CAR-T, I have a question for you from a community oncology standpoint. What factors would you consider for John that would lead you to conclude that he is or isn’t a good candidate for CAR-T evaluation?

Christina Russomanno

I think performance status is a huge part of it, as in the physical shape the patient is in. It’s not an easy process and is in fact very challenging for these patients. We know that these patients can develop CRS, and/or neurotoxicity; the process can be quite daunting and patients can become quite ill. A patient should be in good physical shape, good emotional shape, and fully educated on the process, expectations, and risk. Age is obviously a factor. Once a patient is getting up into their late 70s or early 80s, it becomes debatable whether a provider feels comfortable giving this therapy safely. We also consider whether the patient has support at home and/or in the community. These patients need to have direct support in the form of family or a friend, someone they can rely on to take care of them, who can bring them in for appointments, and make sure they have all their needs met.

Leigh Ann Childress

We also assess the patient and caregiver's health literacy. Patients and/or caregivers must have the capacity to know what to report, when to report, and potentially how to do some remote patient monitoring tasks. It’s also important when we’re referring for more complicated and intensive therapies that require a lot of care coordination.

Christina Russomanno

Oh, I completely agree. It’s not always easy deciding on the right treatments, especially when there’s not always a “right” answer. But again, if the patient is progressing after second-line therapy but in great shape, CAR-T is definitely something you can consider, even if it’s just a consultation for information on the option.

Leigh Ann Childress

Christina, I think that’s about it for CLL, at least for now. Thanks again for such a great discussion.

Christina Russomanno

Thanks to you too! We were able to touch on so much in these three conversations and as always, I appreciate your insights!