This month in The Lancet Haematology, Richard R. Furman from the Weill Cornell Medical College, New York, and colleagues reported the results of a multicenter, single-arm, phase II trial into the safety and efficacy of ofatumumab in untreated or relapsed Waldenström’s Macroglobulinemia (WM). The need for different therapies in the treatment of WM arises, the authors write, from high AE rates following ibrutinib treatment, and the 40–50% rate of IgM flare following rituximab treatment.
- Pts= 37, 76% underwent prior treatment (89% rituximab)
- Treatment: 16 week cycles, cycle 1 week 1 = 300mg ofatumumab:
- Group A (n=15) week 2–4 = 1,000mg ofatumumab
- Group B (n=22) week 2–5 = 2,000mg ofatumumab
- At week 16 of cycle 1, pts with SD or minor response eligible for re-dosing at 300mg ofatumumab week 1, 2,000mg ofatumumab week 2–5 (group A n=8, group B n=4)
- Disease progression after response within 36 months of treatment received cycle 2 (300mg ofatumumab week 1, 2,000mg ofatumumab week 2–5; group A n=5, group B n=8)
- ORR 51% after cycle 1, ORR = 59% after re-dosing, ORR = 77% after cycle 2 (n=13)
- OS = 100%
- Median PFS: group A = 18.3 months, group B = 17.6 months
- All pts reported at least one AE
- Grade 3–4 AE: 11% infusion reactions, 5% chest pain, 5% hemolysis, 5% neutropenia
- Serious AEs in 12 pts
- 2/22 responding pts had IgM flare
In conclusion, the authors state that ofatumumab monotherapy has clinical activity in untreated and relapsed WM and is well tolerated. Ofatumumab was shown to have a relatively low incidence of IgM flare (9%) and mild AEs, for the majority of patients did not trigger withdrawal. Finally, the authors conclude that trials with longer follow-up time would allow for the durability of response to be properly assessed, however they suggest that ofatumumab might be suitable as a non-chemotherapy based treatment for patients with WM.
- Furman R.R. et al. Once-weekly ofatumumab in untreated or relapsed Waldenström’s macroglobulinaemia: an open-label, single-arm, phase 2 study. The Lancet Haematology. 2017 Jan 17. DOI: http://dx.doi.org/10.1016/S2352-3026(16)30166-1 [Epub ahead of print 2016 Nov 30].
Background. The development of more effective and safer treatments, especially non-chemotherapeutics, is needed for patients with Waldenström’s macroglobulinaemia. The aim of the study was to assess the safety and clinical activity of intravenous ofatumumab monotherapy for untreated and relapsed Waldenström’s macroglobulinaemia.
Methods. We did a phase 2, open-label, single-arm study at six centres (hospitals and cancer clinics) in the USA. Patients aged at least 18 years who were diagnosed with untreated or relapsed Waldenström’s macroglobulinaemia and required treatment, received up to three cycles of weekly ofatumumab for 5 weeks. For cycle 1, patients received one of two treatment regimens. Group A received ofatumumab 300 mg during week 1 followed by 1000 mg during weeks 2–4. Because of the acceptable safety of the 1000 mg dose in treatment group A and clinical activity of the 2000 mg dose established in chronic lymphocytic leukaemia, the study was amended on Dec 9, 2009, to change cycle 1 for group B who received ofatumumab 300 mg during week 1 and 2000 mg during weeks 2–5. We followed up patients during weeks 5–16 for treatment group A and during weeks 6–16 for treatment group B (no treatment was given during this follow-up). Patients in both groups with stable disease or a minor response after 16 weeks were eligible to then receive a redosing cycle of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2–5. We followed up patients during weeks 6–16 after the redosing cycle (no treatment was given during this follow-up). Patients responding to cycle 1 or the redosing cycle who developed disease progression within 36 months could receive cycle 2 of ofatumumab 300 mg during week 1 and 2000 mg during weeks 2–5. The primary endpoint for this study was the proportion of patients who achieved an overall response (complete responses plus partial responses plus minor responses) after each treatment cycle in the intent-to-treat population every 4 weeks starting at week 8. This trial is registered at www.ClinicalTrials.gov, NCT00811733, and is now complete. Findings. Between March 17, 2009, and Feb 24, 2011, we enrolled and assigned 37 patients to treatment (15 in treatment group A and 22 in treatment group B). All 37 were included in the efficacy and safety analyses. 19 (51%, 95% CI 34·4–68·1) of 37 patients achieved an overall response after cycle 1 and 22 (59%, 42·1–75·2) of 37 achieved an overall response after the redosing cycle; 15 (41%) with partial responses, seven (19%) with minor responses. 13 patients received treatment cycle 2; ten (77%) of the 13 achieved a response. All 37 patients had at least one adverse event; 16 (43%) patients had events of grade 3 or more (30 grade 3, one grade 4). The most common grade 3 or 4 adverse events were infusion reactions (four [11%] of 37), chest pain (two [5%] of 37), haemolysis (two [5%] of 37), and neutropenia (two [5%] of 37). Two (9%) of 22 patients (both in treatment group B) had an IgM flare. 12 patients reported serious adverse events; haemolysis and pyrexia were the most common (each occurring in two [5%] of 37 patients). Interpretation. A high proportion of patients achieved an overall response with ofatumumab monotherapy and this treatment was well tolerated, with a low incidence of IgM flare. This therapy might be a non-chemotherapeutic treatment option for patients with Waldenström’s macroglobulinaemia, especially those with high IgM concentrations.