Ο Πρύτανης του ΕΚΠΑ Καθηγητής Μελέτιος Α. Δημόπουλος παρουσίασε τα αποτελέσματα της μελέτης INNOVATE που αφορά στην θεραπεία της Μακροσφαιριναιμίας του Waldenström στην συνεδρία των σημαντικότερων ανακοινώσεων στο ASCO

Hematologic Malignancies: Ibrutinib/Rituximab Improves PFS in Waldenström’s Macroglobulinemia

The combination of ibrutinib and rituximab significantly improved progression-free survival (PFS) and response rates compared to placebo plus rituximab in patients with Waldenström’s macroglobulinemia (WM), according to a prospective randomized trial (Abstract 8003) presented during an Oral Abstract Session on June 1.

“Waldenström’s macroglobulinemia is an unusual disease,” said Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens, Greece. It is characterized by serum monoclonal immunoglobulin M (IgM) levels and by infiltration of bone marrow and of organs by IgM-producing lymphoplasmacytic cells. Rituximab, which has shown activity in patients with treatment-naive and relapsed or refractory disease, is commonly used to treat WM. Dr. Dimopoulos presented results from a planned interim analysis of the iNNOVATE trial that added the Bruton’s tyrosine kinase inhibitor ibrutinib to rituximab.

The study included 150 patients with confirmed symptomatic WM. They were randomly assigned to receive either daily ibrutinib (420 mg; 75 patients) or placebo (75 patients), both in combination with rituximab infusions of 375 mg/m²/week at weeks 1 to 4 and 17 to 20. In both groups, 45% of patients were treatment naive. Patients who had received a prior rituximab-based therapy were required to have had a response to that treatment.

After a median follow-up of 26.5 months, the ibrutinib/rituximab combination resulted in a significantly prolonged PFS. In that group, the median PFS was not yet reached compared with 20.3 months with placebo (HR 0.20, 95% CI [0.11, 0.38]; p < 0.0001). At 30 months, the PFS rate was 82% with ibrutinib and 28% with placebo. Investigator-assessed PFS was similar to the IRC assessment.

This advantage was seen across all relevant subgroups. These included patients with treatment-naive disease (HR 0.34, 95% CI [0.12, 0.95]) as well as patients who relapsed. In patients who relapsed, the 30-month PFS rate was 80% with ibrutinib and 22% with placebo.

Data on MYD88^L265P and CXCR4^WHIM mutations were available in 136 patients. The PFS advantage with ibrutinib was seen in patients who had MYD88^L265P but wild-type CXCR4 (HR 0.165, 95% CI [0.06, 0.49]); those who had both MYD88^L265P and CXCR4^WHIM mutations (HR 0.237, 95% CI [0.09, 0.66]); and in those with both wild-type variants, although this did not reach statistical significance (HR 0.214, 95% CI [0.04, 1.1]).

The overall response rate was 92% with ibrutinib plus rituximab compared to 47% with placebo and rituximab (p < 0.0001); the major response rates for the two groups were 72% and 32%, respectively (p < 0.0001). There was a more rapid decline in IgM levels with ibrutinib, and 73% of all patients treated with ibrutinib saw an improvement in hemoglobin compared with 41% of patients receiving a placebo (p < 0.0001). Dr. Dimopoulos noted that this is an important outcome with regard to patient quality of life.

The median time to next treatment was not reached in the ibrutinib group compared with 18 months in the placebo plus rituximab group (HR 0.096; p < 0.0001). Overall survival data were not yet mature.

Grade 3 or higher treatment-emergent adverse events occurred in 60% of patients treated with ibrutinib/rituximab and in 61% of those treated with placebo/rituximab. Serious adverse events occurred in 43% and 33% of patients, respectively; there were three fatal adverse events with placebo/rituximab and none with ibrutinib/rituximab. IgM flare of any grade occurred in 8% of the ibrutinib group and in 47% of the placebo group.

“This is a combination with remarkable activity as far as PFS is concerned,” Dr. Dimopoulos said. “[It is] well-tolerated, becoming a new standard of care for this disease.”

Craig C. Hofmeister, MD, MPH, of The Ohio State University, was the discussant for the abstract. He said that the high response rate in patients with the MYD88^L265P mutation make it particularly appealing in that setting. He also pointed out that atrial fibrillation and infections should be closely monitored when using this combination.