Blood cancers

BTKi shows potential in untreated CLL with del(17p): SEQUOIA


The next-generation BTK inhibitor zanubrutinib could be a potential treatment option for treatment naïve chronic lymphocytic leukemia and 17p deletion, results from the Australian-led SEQUOIA trial show.

Lead investigator Professor Con Tam from the Peter MacCallum Cancer Centre, Melbourne, notes that patients with CLL or small lymphocytic lymphoma with deletion of chromosome 17p13.1 [del(17p)] respond poorly to standard chemoimmunotherapy and generally have reduced rates of overall survival (OS) and worse clinical outcomes.

“Novel targeted therapies are therefore the preferred treatment modality for previously untreated patients whose disease bears the del(17p) mutation… [yet] only limited data are available for novel targeted therapies for previously untreated patients with del(17p) CLL/SLL, and no large multicentre studies have systematically examined this specific population,” he writes with colleagues in a paper published in Haematologica.

As part of a non-randomised arm of the phase 3 SEQUOIA trial (Arm C) 109 treatment-naive patients with centrally confirmed del(17p) were treated with zanubrutinib 160mg twice a day.

After a median of 18.2 months (range, 5.0 – 26.3), seven patients had discontinued treatment due to progressive disease, four due to an adverse event, and one due to withdrawal of consent.

The overall response rate was 94.5% with 3.7% of patients achieving complete response with or without incomplete haematologic recovery.

“The ORR with zanubrutinib observed in the present study appears at least comparable with the reported ibrutinib experience,” the study authors wrote.

While median PFS and OS were not reached, the estimated 18-month PFS was 88.6% (95% CI, 79.0 – 94.0) and the estimated 18-month OS was 95.1% (95% CI, 88.4 – 98.0).

Grade ≥ 3 adverse events were reported in 53 patients (48.6%), most commonly neutropenia (12.9%) and pneumonia (3.7%).  An adverse event of atrial fibrillation was reported in three patients (2.8%).

An exploratory post hoc analysis revealed that compared to patients with a low percentage of del(17p) (positive nuclei of > 7% vs  ≥ 20%) had a higher rate of unmutated IGHV (75% vs 56.4% of patients with a resulted test; P = 0.0478) and complex karyotype status (56.8% vs 22.4% of patients with sufficient metaphases for analysis; P = 0.0011).

Best ORR and estimated 18-month PFS were 98% and 89%, respectively, in the del(17p) high category and 92% and 88%, respectively, in the del(17p) low category.

The research team acknowledged that the trial was limited by its short duration of follow-up and its single arm design.

However they noted that a retrospective analysis for baseline TP53 mutations was currently being performed for the current study arm and the larger randomised arms.

The SEQUOIA trial was also enrolling patients into Arm D which will evaluate the safety and activity of a combination of zanubrutinib with venetoclax in TN CLL/SLL patients with del(17p).

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