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Ofatumumab improves overall response in Waldenström macroglobulinemia
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Patients with Waldenström macroglobulinemia had a favorable overall response and tolerance to ofatumumab monotherapy, according to an open-label, single-arm, phase 2 study published in The Lancet Hematology.
This suggests ofatumumab (Arzerra, Novartis) may be a nonchemotherapeutic option for these patients, researchers wrote.
“Findings in this study might have major clinical significance for patients with Waldenström macroglobulinemia and warrant further assessment,” Richard R. Furman, MD, distinguished associate professor of medicine at Weill Cornell Medicine, and colleagues wrote. “Immunotherapy offers the potential of clinical efficacy without the marrow toxicity of cytotoxic chemotherapy. The large proportion of patients with a response and the low risk [for] initial immunoglobulin M (IgM) flare suggests that ofatumumab might be a nonchemotherapeutic treatment option for patients with Waldenström macroglobulinemia, particularly those with high IgM concentration.”
Before the FDA approved ibrutinib (Imbruvica; Janssen, Pharmacyclics) in January 2015 for patients with Waldenström macroglobulinemia, there were no treatments specifically approved for the disease. Ibrutinib, however, can have adverse events, such as diarrhea, bleeding risk, hypertension, joint pain and atrial fibrillation.
Furman and colleagues designed their study to assess the safety and clinical activity of IV ofatumumab monotherapy for untreated and relapsed Waldenström macroglobulinemia .
The researchers identified 37 adult patients — from six hospitals and cancer centers in the United States — who were untreated or had relapsed.
All patients received up to three cycles of weekly ofatumumab for 5 weeks. In cycle 1, group A (n = 15) received 300 mg ofatumumab during week 1, followed by 1,000 mg during weeks 2 through 4. After researchers assessed the safety of 1,000 mg in group A, the study was amended to increase the cycle 1 dose for Group B (n = 22) to 2,000 mg during weeks 2 through 5.
Patients in both groups with stable disease or minor response after 16 weeks were eligible to receive a redosing cycle of 300 mg ofatumumab during week 1 and 2,000 mg during weeks 2 through 5. Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of 300 mg ofatumumab during week 1 and 2,000 mg during weeks 2 through 5.
The proportion of patients who achieved an overall response — which included complete responses plus partial responses and minor responses — after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8 served as the primary endpoint.
The median time to response for cycle 1 plus redosing cycle was 78.5 days; the median time to IgM nadir, or best response, was 298 days; and the median time to normalization of hemoglobin was 20.9 weeks.
Nineteen patients (51%, 95% CI, 34.4-68.1) achieved an overall response after cycle 1; 22 (59%, 95% CI, 42.1-75.2) achieved an overall response after the redosing cycle; 15 (41%) achieved partial responses; and 7 (19%) had minor responses. Ten (77%) of the 13 patients who received cycle 2 achieved a response.
All patients reported at least one adverse event, with 16 (43%) reporting grade 3 or worse events (grade 3, n = 30; grade 4, n = 1). The most common grade 3 or grade 4 adverse events were infusion reactions (n = 4; 11%), as well as chest pain, hemolysis and neutropenia (n = 2; 5% for each).
Twelve patients reported serious adverse events, the most common of which were hemolysis and pyrexia (n = 2 for each; 5%). Two patients from group B experienced an IgM flare.
Furman and colleagues acknowledged they were unable to draw any conclusions regarding the efficacy of ofatumumab compared with rituximab (Rituxan; Genentech, Biogen), because they did not obtain information on the outcome and tolerability of previous rituximab treatments, and because of the difficulties comparing across two separate phase 2 studies. They noted their findings are further limited by the small sample size and the change in dosing regimen for all patients, which prevented a definitive conclusion.
“These findings indicate that response to ofatumumab in Waldenström macroglobulinemia is a prolonged process, supporting the hypothesis that the therapy kills a compartment of malignant lymphocytes that probably differentiate into the IgM–secreting cells, which die at a standard rate,” Furman and colleagues wrote.
In an accompanying editorial, Christian Buske, MD, director of the Institute of Experimental Cancer Research and professor of medicine at medical department for internal medicine III, Hematology/Oncology of University Hospital Ulm in Germany, noted that longer follow-up of the trial and additional studies regarding ofatumumab are necessary to define more precisely its role in the treatment of Waldenström macroglobulinemia.
“Because this study was a single-group phase 2 trial, it was not possible to judge whether ofatumumab was better tolerated or had greater efficacy than rituximab,” Buske wrote. “Furthermore, although 89% of the patients had received previous rituximab, the study was not designed to test the efficacy of ofatumumab in patients who were refractory to rituximab. But clearly, the findings from this study showed that ofatumumab had high activity as monotherapy in patients with Waldenström macroglobulinemia and in this situation, availability of ofatumumab will be important. – Chuck Gormley
Disclosure: Furman reports a consultant role with and is a member of a speaker bureau for GlaxoSmithKline. Please see the full study for a list of all other researchers’ relevant financial disclosures. Buske reports no relevant financial disclosures.
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