Incorporating MRD into Monitoring After Fixed-Duration CLL Treatment

John N. Allan, MD (Moderator)

Associate Professor of Clinical Medicine

Division of Hematology and Medical Oncology

Weill Cornell Medicine

New York, NY

[Continued from part 1]

CASE SUMMARY

History and presentation:​

• A 66-year-old woman presented with fatigue and unintentional weight loss​.
• ECOG performance status: 1​

Comorbidities:​

• Hyperlipidemia​
• Chronic kidney disease (stage III)​

Medications:​

• Atorvastatin​
• Omeprazole​

Imaging studies​

• CT scan: largest lymph node: 3.2 x 1.9 cm​
• PET scan: standardized uptake value (SUV): 3
• Splenomegaly: 17 cm along the long axis​

Laboratory profile results ​

1. White blood cells (WBCs): 66.8 × 10⁹ cells/μL​
2. Absolute lymphocyte count (ANC): 55.1 × 10⁹ cells/μL​
3. Hemoglobin: 9.7 g/dL​
4. Platelet count: 175 × 10³/μL​
5. Lactate dehydrogenase: 240 U/L​

Molecular testing results​

1. Karyotype: not complex​
2. FISH (fluorescence in situ hybridization): deletion 17p (del[17p])​
3. IGHV: unmutated (VH1-69)​
4. Mutations of interest: mutated TP53​

The patient is in the unfavorable risk category.​

DISCUSSION QUESTIONS

• What is the balance between efficacy and safety that leads you to choose between available treatment options for chronic lymphocytic leukemia?​
• What are your final thoughts on fixed-duration therapy?

John Allan, MD: There were some people who chose acalabrutinib [Calquence] plus obinutuzumab [Gazyva]. Can you let us know why and who do you use it for?

Kavita B. Kalra, MD: I chose it. Part of it had to do with insurance, because that's how it's approved [compared with] ibrutinib [Imbruvica] in the first line. The second part of this was many of the patients with CLL present with hemolytic anemia. At times, I ended up using rituximab [Rituxan] as opposed to obinutuzumab, but [the poll] didn't have that option.

Allan: So, you add it in those patients with hemolytic anemia. When you use acalabrutinib, do you use it with obinutuzumab?

Kalra: I am more familiar with rituximab. I know how to deal with those toxicities. Obinutuzumab is a little tougher for me.

Allan: We've shown that rituximab doesn't seem to add anything to ibrutinib.¹ We've never seen a head-to-head study of ibrutinib plus obinutuzumab vs ibrutinib monotherapy, but we do have acalabrutinib plus obinutuzumab over acalabrutinib. We extrapolate that obinutuzumab might be a better antibody. But to your point, it does have a lot more toxicities. We see tumor lysis, there are a lot more infusion reactions, and there are a lot of cytopenias. It's not so simple to get started, particularly in people with a lot of disease.

In our practice, we will use rituximab too, particularly in patients with a lot of disease and high WBC counts, because you sometimes find yourself in trouble when you try obinutuzumab. That is not to say that you can't. It's just you have to trust your infusion nurse or your team to monitor those laboratory results and be [watching] patients. But rituximab is sometimes easier; I hear that a lot, and I do use the antibody as well. For patients who are hemolyzing, it's very good at getting control pretty quickly, even though BTK [Bruton tyrosine kinase] inhibitors are also very good at hemolysis too. It just takes a lot longer, a month plus, to start to cool things off and you need some help.

I think most people view these BTK inhibitors similarly. It seems like most are choosing more selective drugs. There is no rhyme or reason other than getting experience and [deciding] that's the one you’re using, because there's no compelling reason to go otherwise. Patient factors and choices and insurance seems like driving the choice of the inhibitor.

Nelson Kalil, MD: Many patients decide to go for fixed-duration therapy. For those patients going to fixed duration with venetoclax [Venclexta] plus obinutuzumab, do you have any thoughts about after finishing the first year? How often you do minimal residual disease [MRD] testing and monitoring?

Allan: I check MRD. I use it frequently. I will usually check it at cycle 7, day 1 after the obinutuzumab. Most people are MRD [negative at sensitivity of] 10^-6. I frequently use the clonoSEQ assay. In New York State, it gets approved. I check it at the end of treatment. One thing that has come from the FLAIR study [ISRCTN01844152] is that we know if you can achieve MRD 10^-5, the likelihood of being at least MRD 10^-4 in the bone marrow is highly correlated.² So I use that to spare people bone marrow [biopsies], and I use clonoSEQ to be able to get below that 10^-5 level. So, if they're MRD 10^-5 or below or MRD 10^-6 in the peripheral blood at that cycle 13, I don't [biopsy the] marrow. I know they're negative in their bone marrow for the most part, and I spare them the toxicity of the marrow [biopsy].

Then I check it on a yearly basis, going forward—not that it's prognostic or predictive, but when you start to see it emerge, and it can be several years later, you set some expectations for when you might need to do something. I don't like to fly blind. If I don't have to, I don't send it a lot. You don't need to do it more than once a year or once every year and a half. Honestly, it doesn't come back quickly, but that's how I incorporate it. If they’re negative at the end, you could feel very comfortable to stop treatment.

The problem is if their [MRD is] positive. Fortunately, almost nobody is MRD positive at the end of venetoclax plus obinutuzumab, particularly in younger patients. In the CLL14 trial [NCT02242942], 86% of patients were MRD [negative at] 10^-4, and 60% were MRD 10^-6.³So, almost everybody's getting there. These truly resistant patients are pretty rare, and it makes me wonder if they have CLL, if it's not some atypical thing, maybe [something] marginal. It's hard to glean from these small numbers of people who are remaining positive, but there's still a problem on what to do [after] a fixed-duration therapy. There are some data that you could continue therapy and maybe deepen it. Sometimes I offer them 6 more months, but that's how I use it. You don't need to check it more than on a yearly basis after they're negative and stopped.

_{DISCLOSURE: Allan previously disclosed roles as consultant for AbbVie Inc.; AstraZeneca Pharmaceuticals LP; Genetech, Inc; Janssen Pharmaceutical Company; KLJ Associates, Inc.; Lilly USA, LLC; professional services for Merck and Projects in Knowledge, Inc, and advisory/scientific board membership for NeoGenomics Laboratories, Inc.}

_References:

_{1. Burger JA, Sivina M, Jain N, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011-1019. doi:10.1182/blood-2018-10-879429}

_{2. Munir T, Cairns DA, Bloor A, et al. Chronic lymphocytic leukemia therapy guided by measurable residual disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063}

_{3. Al-Sawaf O, Robrecht S, Zhang C, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study. Blood. 2024;144(18):1924-1935. doi:10.1182/blood.2024024631}