Advertisement

Outcomes in Waldenström’s Macroglobulinemia Improved With Ibrutinib Plus Rituximab

Acalabrutinib Also Active in Phase II Study


Advertisement
Get Permission

In patients with Waldenström’s macroglobulinemia, the risk of disease progression was reduced by 80% with the combination of ibrutinib (Imbruvica) and rituximab (Rituxan) over rituximab alone, in the international phase III iNNOVATE trial, reported at the 2018 ASCO Annual Meeting1 and simultaneously published in TheNew England Journal of Medicine.2

In a separate phase II trial,3 another inhibitor of Bruton’s tyrosine kinase (BTK), acalabrutinib (Calquence), produced a 93% response rate in both treatment-naive and relapsed or refractory patients as a single agent, with the median progression-free survival not reached at 24 months. As a selective BTK inhibitor, acalabrutinib has fewer off-target effects than ibrutinib and therefore may be more tolerable, some specialists predicted.

Waldenström’s macroglobulinemia is characterized by the presence of serum monoclonal immunoglobulin M (IgM) and the infiltration of bone marrow and organs by IgM-producing lymphoplasmacytic cells. It was also recently discovered that MYD88 mutations are present in about 90% of patients with the disease, and they constitutively activate the NF-κB pathway via BTK, thus making BTK inhibitors an effective treatment. 

Ibrutinib Plus Rituximab

Ibrutinib is a first-in-class BTK inhibitor that is approved in Waldenström’s macroglobulinemia. Rituximab also remains a standard treatment in both newly diagnosed and relapsed patients and produces responses in about one-third of them. The drugs are often used as single agents.


We can still appreciate the significant activity of rituximab in these patients, with response rates up to 47%. However, the combination increases the response rate to 92%.
— Meletios A. Dimopoulos, MD

Tweet this quote

The iNNOVATE trial evaluated the combination of ibrutinib and rituximab in patients with Waldenström’s macroglobulinemia and found significant improvements in progression-free survival, regardless of prognostic or genotypic factors, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens in Greece. 

The study randomly assigned 150 patients with symptomatic disease (45% treatment-naive) to receive daily ibrutinib (420 mg) or placebo, both with rituximab (375 mg2/wk for infusion at weeks 1 to 4 and 17 to 20 [ie, in the “extended approach”]. The majority of patients were anemic, and about 20% had baseline serum IgM levels ≥ 50 g/L. Among 136 patients with available data, MYD88 L265P and CXCR4 WHIM point mutations were found in 85% and 36%, respectively. 

Primary Endpoint Met

By internal review at a median follow-up of 26.5 months, progression-free survival, the primary endpoint, was improved by the addition of ibrutinib to rituximab. Median progression-free survival was not reached with the combination and was 20.3 months in the placebo arm (hazard ratio [HR] = 0.20, P < .0001). Progression-free survival rates at 30 months were 82% with ibrutinib/rituximab and 28% with rituximab/placebo, Dr. Dimopoulos reported, adding that the results were consistent with the investigator assessment (HR = 0.22, P < .0001).

In the treatment-naive subgroup, 24-month progression-free rates were 84% and 59%, respectively. In relapsed patients, 80% were progression-free 30 months after ibrutinib/rituximab compared to 22% receiving rituximab alone.

Progression-free survival improved in all relevant subgroups, including treatment-naive patients (HR = 0.34), relapsed patients (HR = 0.17), and all categories of patients with MYD88 L265P and CXCR4 WHIM mutations (HR = 0.17–0.24). 

“We know ibrutinib has less activity in patients with mutations in MYD88 and CXCR4. This was not the case when ibrutinib was combined with rituximab,” he noted. In the three mutation genotypes, a risk reduction of about 80% was observed in each, similar to that seen in the overall population. 

“The combination was essentially able to abrogate the negative impact of mutations,” Dr. Dimopoulos said. “We see much the same progression-free survival, regardless of genetic variation.”

High Response Rates 

Overall responses were achieved by 92% in the combination arm vs 47% with rituximab, and they were major responses in 72% and 32% (P < .0001), respectively. Improvements in hemoglobin were seen in 73% vs 41% (P < .0001), respectively.

“We can still appreciate the significant activity of rituximab in these patients, with response rates up to 47%. However, the combination increases the response rate to 92%,” he commented. Progression-free survival rates were similar for patients achieving partial responses, very good partial responses, or complete responses, he noted. 

Among patients with IgM levels ≥ 50 g/L at baseline, the decline in IgM was rapid after ibrutinib/rituximab treatment. At week 9, the mean IgM level was reduced by 39% from baseline, and no plasmapheresis was required during the course of treatment. In addition, almost twice as many patients were able to achieve sustained improvement in hemoglobin levels, including 95% of those with baseline hemoglobin measurements ≤ 11 g/dL. “This is important because anemia is one of the most common reasons for initiating therapy,” he noted. 

Safety Shown in the iNNOVATE Trial

With a median time on treatment of 25.8 months for the combination, grade ≥ 3 treatment-emergent adverse events occurred in about 60% of patients on each arm, with serious adverse events in 43% of those receiving the two drugs, vs 33% of those receiving rituximab alone. 

TREATMENT OF WALDENSTRÖM’S MACROGLOBULINEMIA

  • The international phase III iNNOVATE trial evaluated the combination of ibrutinib and rituximab, vs rituximab alone, in treatment-naive or relapsed patients with Waldenström’s macroglobulinemia.
  • The combination reduced the risk of disease progression by 80%; median progression-free survival was not reached with ibrutinib/rituximab but was 20.3 months with rituximab alone (HR = 0.20; P < .0001).
  • The international phase II ACE-WM-001 trial of acalabrutinib evaluated 106 patients with treatment-naive or relapsed/refractory Waldenström’s macroglobulinemia receiving monotherapy with the agent. 
  • The response rate was 93% in both patient subsets. Median duration of response, progression-free survival, and overall survival were not reached after a median follow-up of 24.7 months.

None of the toxicities were unexpected. There were fewer infusion-related reactions and less anemia, fatigue, and IgM flare with ibrutinib/rituximab but more hypertension, asthenia, and atrial fibrillation. While atrial fibrillation occurred in 15%, about half of these cases occurred in patients ≥ 75 years old, and it led to few treatment discontinuations, Dr. Dimopoulos pointed out. “Other significant side effects were scarce, with no particular signals seen,” he commented. 

The investigators recommended that the ibrutinib/rituximab combination become a standard treatment option for patients with Waldenström’s macroglobulinemia.

Acalabrutinib as a Single Agent

The international phase II ACE-WM-001 trial evaluated 106 patients with treatment-naive or relapsed/refractory Waldenström’s macroglobulinemia receiving monotherapy with acalabrutinib. Median duration of response, progression-free survival, and overall survival were not reached in either subgroup after a median follow-up of 24.7 months, reported Roger Owen, MD, of St. James’s University Hospital in Leeds, United Kingdom. 

Roger Owen, MD

Roger Owen, MD

Patients received acalabrutinib at 100 mg twice daily (or 200 mg once daily, before the protocol was modified) in 28-day cycles. The primary endpoint was investigator-assessed overall response rate. 

Overall response rates were 93% for both treatment-naive patients and relapsed/refractory patients. Progression-free survival rates at 24 months were 90% for treatment-naive patients and 81.9% for relapsed/refractory patients, and overall survival rates were 91.7% and 88.9%, respectively. Changes in serum IgM were accompanied by clinically meaningful improvements in hemoglobin in both treatment-naive and relapsed/refractory patients. 

Tolerability Profile

Serious adverse events occurred in 43% of the treatment-naive arm and 54% of the relapsed/refractory arm, the most common being neutropenia (16%). As for key events of clinical interest, atrial fibrillation occurred in 4 of 92 relapsed/refractory patients and in 1 of 14 treatment-naive patients, with 1 case being grade 3. 

Grade 3 hypertension occurred in 3 relapsed/refractory patients, and bleeding events occurred in 56% of all patients, most commonly contusion (29%) and epistaxis (11%). Three relapsed/refractory patients had a grade 3 bleeding event (epistaxis, dysfunctional uterine bleeding, and retinal hemorrhage). 

“Acalabrutinib was not held or discontinued in any patients because of atrial fibrillation. Also, all grade 3 bleeding events resolved, and no patient discontinued treatment because of this,” Dr. Owen said. 

“Acalabrutinib monotherapy is a highly effective treatment that yields durable responses in treatment-naive and relapsed or refractory patients with Waldenström’s macroglobulinemia,” he said. “Acalabrutinib’s pharmacokinetic and selectivity profiles allow twice-daily dosing. There are minimal off-target effects, while the drug achieves near-complete and continuous BTK inhibition over time. These results indicate that acalabrutinib has substantial activity and favorable tolerability in this disease.” ■

DISCLOSURE: Dr. Dimopoulos is an advisor for Amgen, Celgene, Janssen-Cilag, Takeda, and Bristol-Myers Squibb. Dr. Owen is a consultant and/or advisor for Celgene, Janssen, and Pharmacyclics and has received honoraria from Celgene and Janssen and reimbursement for travel/accommodation expenses from Janssen. 

REFERENCES

1. Dimopoulos M, Tedeschi A, Trotman J, et al: Randomized phase 3 trial of ibrutinib/rituximab vs placebo/rituximab in Waldenstrom’s macroglobulinemia. 2018 ASCO Annual Meeting. Abstract 8003. Presented June 1, 2018.

2. Dimopoulos MA, Tedeschi A, Trotman J, et al: Phase 3 trial of ibrutinib plus rituximab in Waldenström’s macroglobulinemia. N Engl J Med. June 1, 2018 (early release online).

3. Owen R, McCarthy H, Rule S, et al: Acalabrutinib in patients with Waldenström macroglobulinemia. 2018 ASCO Annual Meeting. Abstract 7501. Presented June 3, 2018.


Related Articles

Expert Point of View: Kenneth C. Anderson, MD, FASCO, Adam D. Cohen, MD, Craig Hofmeister, MD, MPH, and Bruce Cheson, MD

Kenneth C. Anderson, MD, FASCO

Kenneth C. Anderson, MD, FASCO

Adam D. Cohen, MD

Adam D. Cohen, MD

Craig Hofmeister, MD, MPH

Craig Hofmeister, MD, MPH

Bruce Cheson, MD

Bruce Cheson, MD

Kenneth C. Anderson, MD, FASCO, of Dana-Farber Cancer Institute, Boston, noted that the iNNOVATE trial is the first randomized comparison of ibrutinib (Imbruvica) plus...

Advertisement

Advertisement



;
Advertisement

By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.