William G. Wierda, MD, discusses data from the following presentation:

TRANSCEND-CLL-004 phase 1 cohort of lisocabtagene maraleucel combined with ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia (R/R CLL/SLL). (Wierda EG, et al. iwCLL 2021; September 17-20, 2021)

Recent studies in patients with R/R CLL suggest that CD19-directed CAR (chimeric antigen receptor) T-cell therapy combined with ibrutinib improves response rates with CTL119 and JCAR014 (Gill SI, et al. 

. 2020;135:1650-60). This study reports initial safety and preliminary efficacy from the phase 1 lisocabtagene-maraleucel and ibrutinib combination cohort of the ongoing phase 1/2 TRANSCEND-CLL-004 study (NCT03331198) in patients with R/R CLL/SLL.

Eligible patients with CLL/SLL met ≥1 of the following: 1) received ibrutinib and progressed at time of study enrollment; 2) had high-risk features and received ibrutinib for ≥6 months with less than a complete response (CR); 3) had a Bruton tyrosine kinase (BTK) or PLCγ2 gene mutation, with or without progression on ibrutinib; 4) had received prior ibrutinib with no contraindication to reinitiating ibrutinib.

Primary end points were safety and to determine the recommended dose of lisocabtagene-maraleucel in combination with ibrutinib for R/R CLL/SLL; overall response rate (CR + CR with incomplete blood count recovery [CRi] + partial response (PR) and pharmacokinetics were exploratory end points.

At data cutoff, 23 patients received lisocabtagene-maraleucel (DL1, n = 4; DL2, n = 19) with ibrutinib. Median age was 61 (range, 50-77) years, and 22 patients (96%) had high-risk cytogenetics (del[17p], n = 9; 

 mutation, n = 8; complex karyotype, n = 10).

Patients had a median of 4 (range, 1-10) prior therapies. All patients were R/R to prior ibrutinib; 12 patients (53%) had prior BTK inhibitor and venetoclax therapy.

Patients received lisocabtagene-maraleucel infusion at 50 × 106 (dose level [DL]1) or 100 × 106 (DL2) CAR + T cells.

21 patients (95%) responded to therapy, including 13 (59%) who achieved CR/CRi and 8 (36%) who achieved PR

Deepening of response was observed in 4 patients who initially had a PR and improved to a CR at a later assessment.

No patients had PD during the first month after lisocabtagene-maraleucel

All responders (n = 21/22) achieved a response by Day 30 after lisocabtagene-maraleucel.

Among 18 patients with ≥6 months of follow-up, 83.3% (n = 15/18) maintained or improved response from Day 30.

Median progression-free survival was not reached (NR) (95% CI, 12.62—NR).

Median duration of response was NR (95% CI, NR—NR).

The combination of lisocabtagene-maraleucel and ibrutinib was well tolerated, with no reported dose-limiting toxicities.

No grade 5 adverse events or grade 4 or 5 cytokine release syndrome or neurological events were reported.

Grade 3/4 ibrutinib-related treatment-emergent adverse events included neutropenia/neutrophil count decrease (n = 6), anemia (n = 4), thrombocytopenia (n = 2), atrial fibrillation (n = 1), hypertension (n = 1), lung infection (n = 1), and staphylococcal infection (n = 1).

No clear difference in safety was observed between dose levels, and DL2 was selected as the recommended dose expansion of lisocabtagene-maraleucel and ibrutinib in patients with R/R CLL/SLL. Heavily pretreated, refractory patients with R/R CLL/SLL had rapid, high overall response rates and achieved undetectable minimal residual disease with lisocabtagene-maraleucel and ibrutinib treatment. Because of encouraging preliminary results, we continue to evaluate the impact of lisocabtagene-maraleucel combined with ibrutinib on efficacy and safety in this actively enrolling clinical trial.

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William G. Wierda, MD, discusses data from the phase 1 cohort of lisocabtagene maraleucel combined with ibrutinib for patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia that was presented at the 19th International Workshop on CLL (iwCLL) held in September 2021.

Rapid Readouts: Phase 1 Cohort of TRANSCEND-CLL-004 Study

 There was a prognostic model for ibrutinib-based therapy that was reported by the NCI [National Cancer Institute] group. I wonder if 1 of us can comment on that model and the 4 factors. It’s a 4-factor model looking at outcomes, both progression-free and overall survival, for patients treated with ibrutinib. Maybe someone can comment on that model, what the factors are, and whether we can extrapolate and apply it to other covalent irreversible inhibitors of BTK and expect similar correlations. Is anybody familiar with that model?

 I can speak to it a little. You may have to correct me on all the models. I know 

 disruption, deletion, or mutation was 1. I believe unmutated 

 is another. I want to say age was 1. The fourth could have been relapse disease. In that paper, they actually took that factor out because in frontline treatment, it doesn’t matter if you’ve been treated or not. Ultimately, whether or not you’re treated out of it, those 3 factors I previously spoke to were still prognostic and predictive for an outcome on a frontline therapy with ibrutinib.

These scoring systems are useful and helpful, but they’re somewhat intuitive, because they identify people that we already know are high-risk with 

 disruption. In the CLL-IPI [Chronic Lymphocytic Leukemia International Prognostic Index], you automatically become high risk and get 4 points just by having a 

 disruption. I don’t believe this is weighted, but many times 

 disruption is associated with an unmutated 

. Therefore, all of a sudden, these things stack together and help prognosticate. I find them useful in terms of time to first treatment, because while it predicts for some outcome after therapy, the CLL-IPI and the NCI scoring system can predict the time to first treatment as well, which is very important to calculate for your patient and then provide some discussion on what the future may hold in the next 2 or 3 years to prepare them for this eventual reality that will come to fruition.

That’s how I like to use these. We need to study them in these different approaches. Now that we’re talking about combinations and things, every scoring system that we do with a single type of treatment has to be almost reinvented, because the biology and outcomes may change. These scoring symptoms are nice and useful things we can calculate. But in my clinical practice, I’m not using them or putting them in my notes because, for the most part, they’re intuitive. They identify that patient with high-risk deletion 17p, and you’re treating them the same way just by having that 1 little piece of information. That’s how I’m using it. I don’t know if people are different, though.

 I do think that the NHLBI [National Heart, Lung, and Blood Institute] [model] is typically for people who are going on treatment. That 1 didn’t focus so much on time to treatment. It was 

, beta-2 microglobulin, LDH [lactate dehydrogenase], and whether they had been previously treated.

 I find them useful because it gives me a gauge, but they’re very intuitive, as you said. We know 17p and mutated 

An overview of prognostic models in chronic lymphocytic leukemia (CLL). 

CLL: Prognostic Markers 

 Let’s talk a little more about the prognostic factors. Nicole, who do you think of as high risk? I assume we all do somewhat similar prognostic factor work-up. I assume the information is similarly useful to you all. It gives me a good picture of the patient and what to anticipate knowing their prognostic factor profile. Given that, who are the patients you’re nervous about who are high risk and may not need treatment, but you’re going to watch them a bit closer and you have to start thinking about treatment planning eventually and what the long-term plan will be for them?

 Dr Atallah just mentioned some of them. Of course, the things we worry about are those patients with 17p deletions. We didn’t mention the IGHV molecular testing as well for those who are unmutated. These are baseline prognostic markers. In the academic world, we test for a lot more. We can talk about other molecular mutations. But it’s important for physicians who are embarking on initiating their patients on any CLL [chronic lymphocytic leukemia] therapy, whether it’s front line or in the relapse setting, to absolutely test their cytogenetics, FISH [fluorescence in situ hybridization], and their molecular IGHV status, because that may influence the type of treatments you’re going to be administering. We can talk about that—certainly for the mutation—as we go through some of the data that have come out. But for baseline, you’re going to watch your higher-risk patients who tend to be the 17p or the 

 mutations. You may watch them a little more closely.

As many of you know, there have been many international prognostic scoring indexes and scoring systems for patients with CLL that take into consideration the stage, their 

 status, IGHV, beta-2 microglobulin, and so on. We can use that to help categorize the patients by risk factors. It certainly shouldn’t change treatment indications. We obviously haven’t changed what we’re doing. But it gives you a higher level of suspicion based on their prognostic scoring system, where they might be, or when the time to their treatment might be based on their risk factors. It’s important to obtain these because those who still might use chemotherapy-immunotherapy might lean away from that if they’re a patient with 17p or 

 or if they’re unmutated. Now the novel agents have come into play, so there’s far less use of chemotherapy-immunotherapy. But for those who still may use some of it, these factors are very important to test prior to starting anybody on a new therapy.

 Triggers are still obviously development of cytopenias, bulky lymphadenopathy, symptomatology, weight loss, fatigue that usually is in conjunction with progressive disease. Symptoms can be a little tricky because some people will have fatigue and other symptoms that might be out of proportion to what their disease looks like. We have to weigh those as well. But typically, the development of progressive cytopenias, bulky adenopathy, and the concern for whether somebody got Richter syndrome. But as you pointed out, it’s not very common in frontline therapy.

I agree about the CT scan imaging. I do a baseline CT scan prior to starting somebody on therapy depending upon, for instance, if you’re going to use venetoclax and you want to know if anybody might be at high risk for tumor lysis syndrome. If they have bulky adenopathy internally that you might not appreciate on the outside, some of the patients, like those with 11q or 6q deletions, can hide stuff in the abdomen that don’t seem to necessarily be on the periphery. You might want a baseline CT scan prior to starting therapy. Those traditional treatment indications are still the same until we define that it might be better to start some subgroups earlier based on their genetics and that we’re changing their outcome by starting therapy earlier.

 Speaking of that, we need data to justify doing that. That would require a clinical trial. I believe there are some ongoing earlier intervention clinical trials that enroll potentially high-risk patients. Does anybody want to comment on any of those ongoing trials? I see Jennifer nodding her head. Are you involved in any early intervention clinical trials?

 I’m not, but I’d be happy to put in a plug for this SWOG cooperative group study. That study is looking at early vs delayed venetoclax plus obinutuzumab. As you know, there haven’t been early intervention trials that have shown a survival advantage before. A lot of the thought behind that is, now that we know the best patients to choose, we need a therapy that’s going to eliminate disease and be relatively free of toxicity. This study is going to take patients within 1 year of their CLL diagnosis, and they have to be either high or very high risk with the CLL-IPI [CLL International Prognostic Index] criteria. This emphasizes the need for doing those prognostic studies when people are first diagnosed if they’re interested in participating in a study like this. People who have complex karyotype regardless of their IPI score would also be eligible for this study.

A discussion about prognostic factors in patients with newly diagnosed chronic lymphocytic leukemia (CLL).

Prognostic Factors in Chronic Lymphocytic Leukemia 

 We’re going to talk about prognostic factors in detail in a minute. But Dr Atallah, can you give us some idea of what your standard work-up is for a patient with CLL [chronic lymphocytic leukemia]? Are you doing a prognostic factor work-up at initial presentation? Realizing that the indications for treatment haven’t really changed and aren’t dependent on the prognostic factors we test for.

 Yes, the indications to treat have pretty much stayed the same. I still get prognostic factors—some patients want to know—although we can discuss later how much it makes a difference with the newer therapies we have. I make it clear, though, that if there’s no indication to treat and we do these prognostic factors, if they turn out good, then that’s great. If they turn out like having a higher-risk category, then it will just quadruple their anxiety for no good reason.

I spend some time discussing what we’re going to do with these tests when I order them. We still need to get a 17p deletions, cytogenetics, and FISH [fluorescence in situ hybridization]. It’s important to also get clonoSEQ testing for future follow-up, especially definition of MRD [minimal residual disease] on the blood initially for patients. Getting a 

 mutation is also really important, because that might help guide us in choosing which treatment I’d start with, whether it’s a BTK inhibitor or a BCL2 inhibitor. That’s usually what I start with after having a conversation with the patient.

 I don’t do a bone marrow. I used to do a bone marrow in the days of chemotherapy-immunotherapy to establish a baseline and make sure there’s no dysplasia or anything when I was planning on giving chemotherapy. With the current therapies, I don’t do a bone marrow. I consider a PET [positron emission tomography] scan if I have any suspicion for transformation. I would do a PET scan if there’s anything that looks different, but I don’t do a bone marrow.

 I’d like to remark that transformation is exceedingly rare in previously untreated patients, so I wouldn’t imagine you do that very often. Maybe can you comment on CT scanning, because I do see a lot of referrals of patients who don’t have any palpable adenopathy but get a CT scan. I also see patients who are in watch-and-wait who have serial CT scans. Can you comment on initial CT scan and serial CT scans for monitoring?

 I don’t do either unless there are symptoms that guide me toward doing that. If I’m suspicious of any internal organ involvement, that’s when I would do a CT scan. I don’t do serial CT scans for monitoring unless there are symptoms. Lots of radiation isn’t good, anyway.

Ehab Attallah, MD, provides an overview of molecular testing for patients with newly diagnosed chronic lymphocytic leukemia (CLL).

William G Wierda, MD, University of Texas MD Anderson Cancer Center

Articles

Rapid Readouts: Phase 1 Cohort of TRANSCEND-CLL-004 Study

CLL: Prognostic Markers

Prognostic Factors in Chronic Lymphocytic Leukemia

Molecular Testing for Newly Diagnosed CLL