Ofatumumab plus reduced-dose CHOP (miniCHOP) after pre-phase vincristine and prednisone improves OS in older patients
This month, Frédéric Peyrade from the Centre Antoine Lacassagne, Nice, France, and colleagues published in The Lancet Haematology the result of the LYSA group multi-center, phase II study into the combination of ofatumumab and reduced-dose CHOP in patients over 80 with DLBCL. This work was based on attempting to improve on a previous study from 2011 and improve the reported OS, by switching from rituximab to ofatumumab and reduce toxicity through the use of pre-cycle vincristine and prednisone.
- Pre-phase treatment:
- Vincristine 1 mg (oral) total 7 days before cycle 1
- Prednisone 60 mg/m2 (oral) total for 4 days (7, 6, 5, and 4 days before cycle 1)
- Treatment (6 three week cycles):
- 1,000 mg ofatumumab (co-administered with 1,000 mg paracetamol and 50 mg diphenhydramine), 25 mg/m2 doxorubicin, 400 mg/m2 cyclophosphamide, 1 mg vincristine on day 1 of each cycle, 40 mg/m2 for first 5 days of each cycle
- Pts recruited = 120, 115 were considered in ITT analysis
- Performance status was measured at Day 0 of cycle 1, with performance status of 3–4 excluded
- OR = 68%, CR = 56%, PR = 12%
- Full analysis set:
- Median OS not reached (95% CI 30·2–not reached); 2-year OS = 64.7% (95% CI 55·3–72·7); 2-year PFS = 56.6% (95% CI 47·7–65·6)
- Forty-five pts died, 28 from lymphoma progression
- AEs reported were: 21% grade 3–4 neutropenia, 15% of ITT had red blood cell transfusions
- Pts who experienced ≥1 AE = 71%, 53% had at least one grade 3 or higher AE
The authors concluded by stating that this study showed an improved death rate versus the previous study with rituximab, which had a death rate of 18% (27 of 150 pts) during treatment (12 due to immunochemotherapy). Whereas in this study, only 7 patients died during treatment, 2 due to lymphoma, 5 due to other causes (pulmonary edema n = 1, stroke n = 1, and psychiatric syndromes n = 3). Furthermore, the authors stated that this treatment regimen is both safe and effective, and can serve as a new treatment template for patients over 80 with DLBCL for further study.
- Peyrade F. et al. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. The Lancet Haematology. Jan 2017. DOI: 10.1016/S2352-3026(16)30171-5.
- Peyrade F. et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. The Lancet Oncology. Apr 2011. DOI: 10.1016/S1470-2045(11)70069-9.
Abstract: Background: In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49–67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment.
Methods: For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day −7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day −7 to day −4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of oral prednisone on days 1–5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714.
Findings: Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2–3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5–30·1). The 2-year overall survival was 64·7% (95% CI 55·3–72·7) and median overall survival was not reached (95% CI 30·2–not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was hematological toxicity. Among the 120 patients, grade 3–4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3–4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions.
Interpretation: Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years.