Ibrutinib Induces Rapid, Durable Responses in Waldenström's Macroglobulinemia

Steven Treon, MD, PhD

The BTK inhibitor ibrutinib rapidly reduced serum immunoglobulin M (IgM) levels and improved hematocrit levels in patients with relapsed or refractory Waldenström’s macroglobulinemia (WM), and the responses to ibrutinib were durable, reported Steven Treon, MD, PhD, at the 55th annual meeting of the American Society of Hematology.

A major response to ibrutinib was less likely in patients who harbored a WHIM-like mutation of CXCR4, present in about 30% of patients with WM, according to Treon, director, Bing Center for Waldenström’s Research and attending physician for medical oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital.

Treon and colleagues initiated the prospective multicenter study after several discoveries in the laboratory. Whole genome sequencing had revealed MYD88 to be a highly prevalent somatic mutation in WM, and allele-specific polymerase chain reaction detected the presence of a MYD88 L265P mutation in persons with IgM monoclonal gammopathy, which suggested that this mutation was an early oncogenic event in WM pathogenesis.

“Later, through deactivation of BTK, ibrutinib was found to abolish binding of MYD88 to BTK in L256P-expressing WM cells,” Treon said. Preclinical studies also demonstrated ibrutinib’s ability to selectively kill tumor cells of L265P-mutant cell lines relative to wild-type controls.

As part of the study, 63 patients with relapsed/refractory WM received ibrutinib, 420 mg/day, orally for up to 2 years until progressive disease or unacceptable toxicity. Patients were treated with a median of two therapies prior to enrollment. At baseline, their mean hemoglobin level was 10.5 mg/dL and their mean serum IgM level was 3610. Bone marrow involvement was 70%, and 60.3% of patients had adenopathy. Anemia was overwhelmingly the most common reason for treatment initiation (87.3% of patients).

“Serum IgM levels were reduced rapidly,” said Treon, “You see profound drops in IgM, with a median of nine cycles, range 1 to 18 cycles,” he said. Median serum IgM levels declined to 1260 mg/dL (P = 1.46033^-17) at best response.

“Even as impressive is how fast the hemoglobin recovery occurs in these patients,” he said. With a median of none cycles of therapy, the best hemoglobin response was 13.4 mg/dL (P = 9.0366^-19). Bone marrow disease burden at cycle 6 declined to 36.75% (P = .00053).

“In some of these patients, very little if any tumor reduction occurred. Despite that, they still had impressive gains in their hemoglobin as well as reductions in IgM, so it’s important to keep in mind that maybe alternative mechanisms aside from tumor-cell killing could also exist that benefit these patients,” he said.

Among patients who had baseline and cycle six CT scans, adenopathy improved in 67.7%.

With a median follow-up of nine cycles, the best overall response rate, defined as a minor response or better using consensus criteria adapted from the 3rd International Workshop on WM, was 83%, with a major response rate (partial response or better) of 64.0%.

“By far, this was a very well-tolerated therapy,” Treon said. The most common grade ≥2 treatment-related toxicities were thrombocytopenia (n = 10) and neutropenia (n = 12), which predominantly occurred in heavily pretreated patients, reported Treon. Most bleeding events occurred in patients taking concomitant fish oil supplements.

At a median of nine cycles, 87.3% continued on treatment. Eight discontinued treatment, four for nonresponse or progressive disease.

The impact of MYD88 L265P and WHIM-like CXCR4 mutations on ibrutinib response was examined. Forty-eight of 53 and 10 of 40 patients had MYD88 L265P and WHIM-like CXCR4 mutations, respectively, as determined by Sanger sequencing.

Attainment of major responses was affected by mutations in CXCR4 but not MYD88 L265P.

The major response rate was 80% for patients with wild-type CXCR4 compared with 30% in those with WHIM-like CXCR4 mutations (P = .0065).

“The IgM reductions are far more impressive in those individuals that have wild-type CXCR4 status. The degree of gain in hemoglobin is also more impressive in individuals with wild-type CXCR4,” Treon said. Better responses to ibrutinib were associated with lymphocytosis.

Treon SP, Tripsas CK, Yang G, et al. A prospective multicenter study of the Bruton’s tyrosine kinase inhibitor ibrutinib in patients with relapsed or refractory Waldenström’s macroglobulinemia. Presented at: 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 251.

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