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.