Jennifer Woyach, MD, Discusses How to Best Sequence Regimens for Patients with R/R CLL

Jennifer A. Woyach, MD, Principal Investigator, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, recently shared updates on how to best sequence available regimens for the management of patients with recurrent chronic lymphocytic leukemia (CLL) during the virtual Great Debates & Updates in Hematologic Malignancies.

Dr Woyach said there are 3 initial considerations to take when approaching patients with relapsed CLL, including the nature of the relapse, prognostic factors, and initial treatment.

In terms of the nature of the relapse, Dr Woyach said relapse with CLL can take many different forms.

“I’ve broken them into categories, where some of them are ones where you certainly wouldn’t treat at this time. Some are ones where you wouldn’t treat right now, but might warrant very close follow up, and then some relapse in areas where treatment should be started immediately,” Dr Woyach said.

Indolent relapses are an area where treatment isn’t necessary right away, she said, using the example of a patient who had completed time-limited therapy, such as chemotherapy or venetoclax-based therapy, where after the therapy was complete, they started to have an increase in their white blood cell count as their only sign of disease. Or someone who either has new lymph nodes or an enlargement of lymph nodes that are not symptomatic.

“In these scenarios, I wouldn’t treat the patient, but would just consider continuing to monitor them,” she stated.

Next are, for example, patients where lymph nodes are detectable by exam or those who have an increase in their white blood cell count during treatment, she added.

“These criteria don’t necessarily mean that you need to start therapy right away, but certainly these are worrisome signs that you are going to have to start treatment pretty soon,” she said.

Lastly, she focused on patients who either had a return of autoimmune conditions, symptomatic increase of lymph nodes, or return of fatigue.

“Those are scenarios where you’d want to start treatment right away,” she said.

In general, Dr Woyach said, second line therapy follows the same guidelines as initial therapy in terms of when to start treatment, taking into account things like CLL-related symptoms (B symptoms like night sweats, weight loss, sever fatigue), tumor burden (progressive lymphadenopathy and splenomegaly), bone marrow failure (progressive anemia and thrombocytopenia), and immune dysfunction (autoimmune anemia and/or thrombocytopenia if not responsive to corticosteroids or other standard treatment).

The next thing to focus on, Dr Woyach said, are pre-therapy prognostic factors for patients with relapsed CLL, including IGHV mutation status, FISH testing, stimulated cytogenetics, and a re-check for the TP53 mutation, Dr Woyach said.

“These are all things that can evolve during the course of a disease both with or without therapy,” she said.

The last consideration, she said, is what was the initial treatment.

If the initial treatment was chemoimmunotherapy, “here is a time where you are really in luck because there’s as many options as you had when you were choosing your frontline treatment,” Dr Woyach said. Options include the continuous administration of a BTK inhibitor as monotherapy with ibrutinib or acalabrutinib as well as venetoclax plus rituximab, PI3K kinase inhibitors such as idelalisib plus rituximab or duvelisib, and repeating the initial chemotherapy regimen (only considered in cases of long remission).

Data shows that BTK inhibitors produce long remission durations for CLL patients in the relapsed setting, Dr Woyach said. Referring to a phase 1/2b study ibrutinib in relapsed CLL, many patients had multiple prior therapies before their ibrutinib therapy. In this case, the median number of prior lines of therapy was 3, but there were patients who had upward of 10-13.

“These aren’t reflective of what we’re seeing in clinical practice today, where most patients have had 1 or at most 2 prior therapies by the time they would get a BTK inhibitor for relapsed disease,” Dr Woyach said.

She also discussed data from the RESONATE phase 3 study, which compared ibrutinib to ofatumumab. In that trial, the median progression free survival (PFS) for ibrutinib was 44 months. Traditional prognostic factors, including cytogenetic abnormalities, are important when thinking of ibrutinib in the relapse setting, she said.

For example, patients who have good-risk markers, like Del13q (n=13), had the longest median PFS (NR), while those with high-risk markers, like Del17p (n=13), had the shortest (26 months). Interestingly, Del11q (n=28), which is typically associated with more aggressive CLL, did not have any prognostic importance with BTK inhibitors, and in some studies showed a longer PFS.

In terms of acalabrutinib in the relapsed setting, Dr Woyach cited data from a 4-year phase 1/2b trial showing a 45 months PFS rate of 62%. There, she said, patients with Del17p had a shorter remission duration.

With both ibrutinib and acalabrutinib, it’s been shown that complex karyotypes (3 or more cytogenetic abnormalities) are associated with a higher risk of relapse with BTK inhibitors. Recent data presented from the head-to-head comparison study showed acalabrutinib is noninferior to ibrutinib in terms of PFS.

“They have fairly equivalent PFS,” Dr Woyach said.

Also, acalabrutinib has less cardiovascular toxicity and less of the other toxicities that are commonly seen with ibrutinib.

“Both of these are options for patients with relapsed disease,” she said.

Focusing on the MURANO study of venetoclax plus rituximab in relapsed/refractory CLL, Dr Woyach said the combination demonstrated long remission durations. The median PFS was 53 months, which was “significantly better than bendamustine-rituximab in this setting,” she said.

Also, based on multiple data coming out of various venetoclax trials, the depth of remission at the end of treatment is “very important” for long-term outcomes, she said.

Dr Woyach said with venetoclax-based therapies, it’s traditional to measure minimal residual disease (MRD), either by flow cytometry (FC) or next generation sequencing. Pointing out data from a couple years ago, Dr Woyach said patients in therapy who have a high rate of MRD have shorter PFS in the absence of therapy when compared to patients who have undetectable MRD. Patients who have a low level of MRD fall somewhere in the middle.

“We’ve seen with venetoclax-based regimens that the MRD remaining in the blood and the bone marrow seems to be much more important for prognosis than the presence of lymph nodes at the end of therapy,” she said.

PI3 kinase (PI3K) inhibitors—including idelalisib, duvelisib, and umbralisib—were also tested on CLL patients who had not received other novel therapies. After chemoimmunotherapy in this setting, they all had a median PFS between 1 and 2 years.

“Definitely some efficacy, but probably a little less efficacy than we see with our other 2 primary classes of drugs,” Dr Woyach said.

In the initial treatment was venetoclax plus obinutuzumab in a fixed-duration setting, there are a lot of options for targeted therapies, including ibrutinib, acalabrutinib, idelalisib with rituximab, and duvelisib, she added.

“You could also consider repeating venetoclax-based regimens, especially depending on the remission duration. So, for somebody who has a longer remission duration, this may be an especially appealing option,” Dr Woyach said.

In the long-term follow up data from the MURANO study of patients treated with venetoclax who went on to receive a subsequent therapy, 10 out of 10 patients responded to BTK inhibitors post-venetoclax, 1 patient responded to PI3K post-venetoclax, and 6 out of 11 responded to venetoclax again.

“I think the big caveat here with the venetoclax/post-venetoclax cohort is that data right now are really biased toward patients who had an early relapse. We may see that when we are looking at patients who have 2- or 3-year remission durations off therapy, those patients might be much more likely to respond to venetoclax again. But, this does give us some great data in a prospective evaluation looking at BTK inhibitors and venetoclax in showing some efficacy in this setting,” she said.

Dr Woyach then mentioned a retrospective study of 326 patients with relapsed CLL that were treated with venetoclax. Forty-four of those patients were BTKi-naïve and then subsequently treated with a BTK inhibitor. The overall response rate (ORR) was 84% and the estimated PFS of 32 months. Also, 17 patients were PI3K-naïve and went on to be treated with a PI3K inhibitor as their next therapy. For that cohort, the ORR was 47% and PFS was 5 months.

“That data is fairly similar to what we’ve seen with the BTKi given on their own for relapsed CLL. … There’s some efficacy in this setting, but probably not a long-term solution for most patients,” Dr Woyach stated.

If the initial treatment was ibrutinib or acalabrutinib, there are also many options for targeted therapies, including venetoclax/rituximab, idelalisib/rituximab, and duvelisib.

Many patients in the frontline setting do not progress on a BTK inhibitor itself, she said. So, if you have a patient who started therapy with ibrutinib and discontinued for toxicity and they subsequently progress, treatment with acalabrutinib is effective.

If the progression occurs after acalabrutinib is discontinued for toxicity, Dr Woyach said other treatments, such as venetoclax or PI3K inhibitor, are likely effective.

In a more difficult scenario, she said, where progression occurs during treatment with ibrutinib/acalabrutinib, venetoclax has been shown to be effective compared to PI3K inhibitors.

Venetoclax, she said, is also effective after ibrutinib discontinuation, remarking on a phase 2 study of 91 patients where the majority progressed during ibrutinib therapy although some had intolerances discontinued and then progressed. In this setting, the ORR was 65% for venetoclax given by itself. The median PFS was 22 months. Notably, venetoclax was given continuously. Of 56 patients assessed, 41% were MRD negative in the peripheral blood while very few were MRD negative in the bone marrow.

This study shows that “patients who progressed on a BTKi are a pretty special population who have high risk disease, and while venetoclax is likely effective in these patients, at least in the short term, it’s probably not going to be a home run in the long-term setting for most patients,” she said.

If the initial therapy was BTKi with venetoclax, unfortunately, there’s almost no data in this area, she stated.

However, the GLOW study focused on BTKi (specifically ibrutinib) with venetoclax as a fixed-duration therapy given for 1 year. Most resistance to BTKi and venetoclax occurred after 2 years of therapy, she said, so it’s very likely that either type of therapy could be reinitiated at a later time, although subsequent remission duration could be shorter.

“I think this really emphasizes the need for studies of sequential versus combination approaches with these agents,” she said.

In terms of the next steps in clinical trials for relapse CLL, Dr Woyach said CAR-T cells look very promising, as well as other immune therapies (CAR-NK, TILs), non-covalent BTK inhibitors, novel targets currently under investigation, and novel antibodies and bispecific antibodies.

“Certainly a lot on the horizon to look out for for these patients with relapse CLL in addition to what’s currently available,” she stated.

In conclusion, Dr Woyach said current data suggests switching between novel agents is effective, regardless of initial therapy. Longer-term data and current studies will be helpful to expand knowledge in this area, as well as novel therapies and strategies that are currently in development.

“The future in CLL, including for patients with relapsed disease, remains very bright,” Dr Woyach concluded.—Emily Bader