Updated NCCN Guidelines Now Include Zanubrutinib for WM

Pam Harrison

November 04, 2021

The updated guidelines for management of Waldenstrom's macroglobulinemia (WM)  from the National Comprehensive Cancer Network (NCCN) now include the second-generation product zanubrutinib (Brukinsa), which was approved for the treatment of this disease just a month ago.

This new drug is now the preferred agent for the treatment of symptomatic Waldenstrom's macroglobulinemia, noted a leading researcher in the field, Steven Treon, MD, PhD, professor of medicine at Harvard Medical School, Boston, Massachusetts.

He was speaking at the recent International Waldenstrom's Macroglobulinemia Foundation Educational Forum.

The preferred regimens as recommended by the NCCN are based on the highest level of evidence from large randomized clinical trials involving the drug in question tested against a proven comparator or placebo, he explained.

In the case of zanubrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, the pivotal trial upon which the NCCN recommendation was based was the ASPEN trial, led by Constantine Tam, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

In ASPEN, all 201 patients carried the MYD88 mutation and were randomly assigned to either ibrutinib (Imbruvica), at a dose of 420 mg a day, or zanubrutinib, at a dose of 160 mg, twice a day, until disease progression or unacceptable toxicity. Importantly, over 80% of patients had relapsed or refractory disease.

No patient achieved a complete response, but 28% of patients receiving zanubrutinib and 19% of patients receiving ibrutinib achieved a very good partial response. The secondary endpoint of major response rates was virtually identical at 77% and 78%, respectively.

However, more patients on zanubrutinib were event-free at 12 months (96% vs 72% of those treated with ibrutinib). Rates of atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were also less common among zanubrutinib recipients.

On the other hand, the incidence of neutropenia was higher with zanubrutinib, although grade 3 and higher infections rates were not more frequent, the researchers noted.

Both the US Food and Drug Administration and Health Canada recently approved zanubrutinib for the treatment of WM based on the findings from ASPEN. "BTK inhibitors are rapidly becoming a cornerstone of treatment for Waldenstrom macroglobulinemia," Tam told Medscape Medical News in an email.

"And the next-generation BTK inhibitor zanubrutinib has been proven to have fewer side effects compared with ibrutinib in randomized studies, which makes available a better-tolerated treatment option for patients with WM," he added.

"It's up to clinicians to decide which regimen might be the most appropriate treatment," Treon commented.  

However, the NCCN guidelines are important because they do give clinicians an understanding of what the current and recommended therapies are for WM, from which they can choose individual treatment for each of their WM patients, he said. Importantly, from an insurers' perspective, it allows insurers to know that if a particular drug choice is being made, "that the treatment has passed muster and this is an important factor in their reimbursement for a particular therapy as well," as Treon also pointed out.

Other preferred therapies for the primary treatment of WM include bendamustine (Treanda) plus rituximab (Rituxan); bortezomib (Velcade) dexamethasone and rituximab; ibrutinib plus or minus rituximab, and rituximab/cyclophosphamide and dexamethasone.

In the INNOVATE trial, for example, the use of ibrutinib–rituximab resulted in significantly higher rates of PFS at 82% than the use of rituximab alone at 28% (P < .001), both among those who had received no previous treatment and among those with disease recurrence. Rates of atrial fibrillation and hypertension were, however, more common with ibrutinib–rituximab, as the investigators noted.

Interestingly, the combination of bendamustine plus rituximab was initially presented at the 5th International Workshop on Waldenstrom's Macroglobulinemia in 2008 when it was first compared with the then often-used CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) plus rituximab, a fairly toxic regimen, as Treon noted. 

This trial was conducted as a non-inferiority study and involved a total of 549 patients with various types of lymphoma, including about 40 patients with WM. They were randomly assigned to one of the two treatment groups. Patients treated with bendamustine plus rituximab did significantly better from a PFS perspective than those who were treated with CHOP-R. "There was also more toxicity associated with CHOP-R which is why this study helps support the inclusion of bendamustine plus rituximab in the NCCN guidelines," Treon noted.

Treon cautioned, however, that although it may still be appropriate for patients who achieve at least a major response to the combination of bendamustine plus rituximab to be assigned to a "watch and wait" approach, the progression-free survival appears to be significantly poorer for patients over the age of 65 who are assigned to the watch and wait strategy compared to those who continue with maintenance rituximab.

"As we go ahead, there is some rethink that needs to be done on the current NCCN guidelines and perhaps fine-tuning the recommendations around maintenance rituximab for those individuals who are over the age of 65," Treon said.

Treon has disclosed financial relationships with Janssen, Pfizer, PCYC Inc, and BioGene. Tam reports receiving research funding from Janssen and AbbVie and honoraria from Janssen, AbbVie, BeiGene, Novartis, and Roche.

IWMF Educational Forum. Presented October 29, 2021.

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