ALPINE Trial Data Shows Effectiveness of Zanubrutinib in Relapsed CLL


In the first article of a 2-part series, Sameer A. Parikh, MBBS, discusses the makeup and design of the phase 3 ALPINE study that showed the promise for the next-generation Bruton tyrosine kinase inhibitor zanubrutinib.


History and Presentation:

A 70-year-old White man with asymptomatic lymphocytosis identified 4 years previously​

  • Initially monitored​
  • Two years later, developed anemia, night sweats, and splenomegaly​.
  • Treated with venetoclax (Venclexta) plus obinutuzumab​ (Gazyva)
  • Patient experienced undetectable minimal residual disease (MRD) at end of year 1 of treatment​.
  • Twenty-four months later, his disease progressed​.


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


  • Simvastatin​
  • Amlodipine​
  • Clopidogrel, aspirin ​

Current Status:

  • ECOG performance status: 1​

Six Months Later​:

  • On physical examination: palpable splenomegaly​
  • CT scan: largest node, 4.2 x 2.8 cm​
  • All others <3 cm​

Diagnostic Workup:

  • White blood cell count: 35.0 x 109 cells/μL​
  • absolute lymphocyte count: 22.0 x 109 cells/μL​
  • Hemoglobin: 9.5 g/dL​
  • Platelet Count: 80 x 103/μL​
  • Lactate dehydrogenase: 255 U/L​
  • Karyotype: complex, 4 abnormalities​
  • Fluorescence in situ hybridization: del(11q); without del(17p)​
  • IGHV: unmutated​
  • Mutations of interest: wild type TP53
  • Largest node on imaging: 4.2 x 2.8 cm​

Due to progression of disease after BCL2 inhibitor, the decision was made to initiate therapy with a Bruton tyrosine kinase (BTK) inhibitor.

Targeted Oncology: What was the design of the phase 3 ALPINE study (NCT03734016) looking at the use zanubrutinib (Brukinsa) in patients with relapsed chronic lymphocytic leukemia (CLL)?

SAMEER A. PARIKH, MBBS: This study took all comers with relapsed CLL and they randomly assigned patients to either zanubrutinib or ibrutinib [Imbruvica].1 This was also a large study with a number of stratification factors, [such as age, geographic region of the patient, refractory and del(17p) or TP53 mutation status], but the primary end point was the overall response rate [ORR].1 This, however, is 1 of the criticisms of this study, because we know that BTK inhibitors [don't always get] complete responses, and all we care about is progression-free survival [PFS] or how long the duration of response is for the patient, but according to the FDA, the ORR was allowed to be a primary end point.

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Division of Hematology

Mayo Clinic

Rochester, MN

Sameer A. Parikh, MBBS

Assistant Professor of Medicine and Oncology

Division of Hematology

Mayo Clinic

Rochester, MN

What were the makeup of patients on this study?

They enrolled more than 600 patients from all across the world, and the median age [for these patients] was about 68 years old with the majority being male, which is what we expect in CLL.1 Now, [patients with this disease] can have a TP53 mutation without a del(17p). In this trial, 9.2% of patients had a TP53 mutation in their disease without 17p(del) in the zanubrutinib arm, [compared with] 7.7% in the ibrutinib arm. Other baseline characteristics [of patients on this trial] were typical, like [73.1%] of the patients had an unmutated IGVH status, and [58.7% of patients in the zanubrutinib arm] had a median of 1 prior line of therapy. [For patients in both arms], chemotherapy was the most prescribed regimen in the first-line setting [at 83.8% in the zanubrutinib arm and 79.4% in the ibrutinib arm].1

What would you highlight from the efficacy data from this study?

I [don't talk much about] the ORR from the trial because we don't think about it as an important end point [in the BTK inhibitor drug class]. The best improvement with this therapy is surprisingly associated with a superior PFS with zanubrutinib [compared with ibrutinib at 24-months at 78.4% vs 65.9%, respectively (HR 0.65; 95% CI, 0.49-0.86, P = .002].1

One of the [other points] that has been a criticism for the study is how did ibrutinib underperform in this study? I don't know the answer to that question. I think there [will be more follow-up], so it'll be interesting to see how these curves split [over more time], but certainly one thing's for sure is that zanubrutinib is an effective BTK inhibitor. Similar data was seen in patients with del(17p), TP53, or both mutations. This high-risk group of patients in the relapsed setting at 24-months [of follow-up] had a PFS rate of 72.6% with zanubrutinib [compared with 54.6% in the ibrutinib arm (HR, 0.53; 95% CI, 0.31-0.88)].1


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

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