Leslie Reviews Relevant Data for Treatment of Relapsed/Refractory CLL

Lori A. Leslie, MD

Director

Indolent Lymphoma and Chronic Lymphocytic Leukemia Research Programs

John Theurer Cancer Center

Assistant Professor

Hackensack Meridian School of Medicine

Hackensack, NJ

CASE SUMMARY

History and presentation:​

• A 70-year-old White man with asymptomatic lymphocytosis, identified 4 years ago​.
• Initially monitored​
• Two years later, he developed anemia, night sweats, and splenomegaly​.
• PET scan: no evidence of transformation
• Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
• Twenty-four months later, he had ECOG performance status 1​, palpable splenomegaly​, and a CT of chest, abdomen, pelvis showed the largest node at 4.2 x 2.8 cm; all others <3 cm.​

Comorbidities:​

• Coronary artery disease
• High cardiovascular risk due to history of non–ST-elevation myocardial infarction, status post 2 stents​

Medications:​

• Simvastatin​
• Amlodipine​
• Clopidogrel, aspirin ​

Diagnostic workup:​

• White blood cell count: 35.0 x 10³ cells/μL​
• Absolute lymphocyte count: 22.0 x 10³ cells/μL​
• Hemoglobin level: 9.5 g/dL​
• Platelet count: 80 x 10³/μL​
• Lactate dehydrogenase level: 255 U/L​
• Karyotype: complex, 4 abnormalities​
• Fluorescence in situ hybridization (FISH): 11 q deletion (del[11q]), without 17 p deletion (del[17p]) ​
• IGHV: unmutated​
• Mutations of interest: unmutated TP53​
• Largest node on imaging: 4.2 x 2.8 cm​
• Due to progression of disease after a BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.

Targeted Oncology: What are some of the data behind approved treatment options for a patient such as this with relapsed/refractory chronic lymphocytic leukemia (CLL)?

LORI A. LESLIE, MD: ELEVATE RR [NCT02477696] looked at acalabrutinib [Calquence] in relapsed/refractory disease and included over 500 patients.¹ They had to be previously treated and required therapy at the current time. They were high risk, so everyone either had del(17p) or del(11q) by FISH, and they had to have a relatively preserved performance status, but [those patients with an] ECOG performance status of 2 were allowed.

They were stratified based on their high-risk features, whether they were 17p abnormal, and then randomly assigned 1:1 to get acalabrutinib or ibrutinib [Imbruvica] at the standard CLL doses. This is a non-inferiority study, so the primary end point was non-inferiority of progression-free survival [PFS]. Then there were some key secondary end points, mostly looking at toxicity. Patients with underlying cardiovascular disease were permitted as long as it was well controlled and people who needed to be on blood thinners were permitted as long as it wasn't Coumadin, so it was a relatively real-world population.

Patients receiving acalabrutinib had either del(17p) in about 45% of patients, del(11q) at 62%, or complex karyotype in about 46% of patients, [with similar rates in the ibrutinib arm]. TP53 was mutated in about 37% and 42% of patients [receiving acalabrutinib and ibrutinib, respectively].¹ I think it was selected as a high-risk group hoping that would help the data mature more quickly. I felt like I was waiting forever to hear these data mature and it took longer than expected. Most of the prior therapies included things like chemoimmunotherapy because of the era in which this was done, even some patients like alemtuzumab [Lemtrada].

What were the main takeaways from the ELEVATE RR trial?

PFS non-inferiority was met....and [the trial] met its primary end point for ibrutinib vs acalabrutinib.1 In terms of the toxicity profile, I think many [physicians have] shifted away from ibrutinib due to cardiac toxicity [seen with it]. Atrial fibrillation and hypertension were significantly and favorably lower with acalabrutinib compared with ibrutinib. These were some of the data [that showed] why acalabrutinib is favored over ibrutinib and ibrutinib has been demoted mostly due to that cardiovascular toxicity profile.¹

Which other therapies have shown efficacy in this setting?

There's the relapsed/refractory head-to-head of ibrutinib and zanubrutinib [Brukinsa] in the ALPINE study [NCT03734016].² This was a superiority study, looking at zanubrutinib vs ibrutinib, so it's not non-inferiority. The primary end point was also different [from ELEVATE RR]; it was the overall response rate [ORR]. The secondary end point was PFS, including incidence of afibrillation, aflutter, and other kinds of toxicity. These were relapsed/refractory patients who had to need treatment, [and those with] prior BTK inhibition were excluded on these studies, because everyone got a BTK. They could have cardiac comorbidities as long as they weren't on Coumadin or vitamin K antagonists. This was not only high-risk patients; this was all comers.

Patients got zanubrutinib at the twice-daily dosing, and ibrutinib at the standard daily dosing. del(17p) and TP53 mutations [were seen in] about 23% of patients from both arms. About 45% to 50% of patients did have some high-risk feature in terms of del(17p) in either arm. This is a more varied population than what we saw when everyone was high risk on the ELEVATE RR trial.1 This study was done slightly later, but still most people had like chemoimmunotherapy; there were some patients that had a PI3K or BCL2 inhibitors.²

What were the initial and long-term results with zanubrutinib?

The ORR was favorable with zanubrutinib over ibrutinib, so it met its primary end point for superiority based on ORR. But these data first presented the PFS, which was a secondary end point at ASCO, and it surprised me when I saw it because we had heard a lot already about this comparative covalent BTK inhibitor story. It's all about toxicity. So, I was surprised to see a PFS difference that emerged. The follow-up that was presented by Dr Brown at the 2023 American Society of Hematology Annual Meeting with 3-year follow-up, that PFS difference remained...with zanubrutinib over ibrutinib.³

REFERENCES:

1. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

2. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319-332. doi:10.1056/NEJMoa2211582

3. Brown JR, Eichhorst BF, Lamanna N, et al. Extended follow-up of ALPINE randomized phase 3 study confirms sustained superior progression-free survival of zanubrutinib versus ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL). Blood. 2023;142(1):202. doi:10.1182/blood-2023-174289.