Peter Hillmen1, Tadeusz Robak2, Ann Janssens3, K Govind Babu4, Janusz Kloczko5, Sebastian Grosicki6, Michael Doubek7, Panagiotis Panagiotidis8, Eva Kimby9, Anna Schuh10, Andrew R Pettitt11, Thomas Boyd12, Marco Montillo13, Ira V Gupta14, Oliver Wright15, Iestyn Dixon15, Jodi L Carey14, Chai-Ni Chang16, Steen Lisby17, Astrid McKeown15, Fritz Offner18. 1. Department of Haematology, St James's University Hospital, Leeds, UK. Electronic address: peter.hillmen@nhs.net. 2. Department of Haematology, Medical University of Lodz, Lodz, Poland. 3. Universitaire Ziekenhuizen Leuven, Leuven, Belgium. 4. Kidwai Memorial Institute of Oncology, Bangalore, India. 5. Medical University of Bialystok, Bialystok, Poland. 6. Medical University of Silesia, Katowice, Poland. 7. Department of Haematology and Oncology, University Hospital Brno, Brno, Czech Republic. 8. University of Athens, Laikon General Hospital, Athens, Greece. 9. Department of Hematology, Karolinska University Hospital, Stockholm, Sweden. 10. Churchill Hospital, Oxford, UK. 11. Royal Liverpool and Broadgreen Hospitals NHS Trust, University of Liverpool, Liverpool, UK. 12. Yakima Valley Memorial Hospital, Yakima, WA, USA. 13. Department of Haematology, Ospedale Niguarda Ca'Granda, Milan, Italy. 14. GlaxoSmithKline, Collegeville, PA, USA. 15. GlaxoSmithKline, Uxbridge, UK. 16. GlaxoSmithKline, Research Triangle Park, NC, USA. 17. Genmab, Copenhagen, Denmark. 18. Universitair Ziekenhuis Gent, Gent, Belgium.
Abstract
BACKGROUND: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging becausefludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. METHODS: We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. FINDINGS:We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumaband 226 patients tochlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. INTERPRETATION: Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. FUNDING: GlaxoSmithKline, Genmab A/S.
RCT Entities:
BACKGROUND: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. METHODS: We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. FINDINGS: We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group. INTERPRETATION: Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy. FUNDING: GlaxoSmithKline, Genmab A/S.
Authors: Benjamin L Lampson; Haesook T Kim; Matthew S Davids; Jeremy S Abramson; Arnold S Freedman; Caron A Jacobson; Philippe A Armand; Robin M Joyce; Jon E Arnason; Laura Z Rassenti; Thomas J Kipps; Joshua Fein; Stacey M Fernandes; John R Hanna; David C Fisher; Jennifer R Brown Journal: Blood Adv Date: 2019-04-09
Authors: Jan A Burger; Mariela Sivina; Nitin Jain; Ekaterina Kim; Tapan Kadia; Zeev Estrov; Graciela M Nogueras-Gonzalez; Xuelin Huang; Jeffrey Jorgensen; Jianling Li; Mei Cheng; Fong Clow; Maro Ohanian; Michael Andreeff; Thomas Mathew; Philip Thompson; Hagop Kantarjian; Susan O'Brien; William G Wierda; Alessandra Ferrajoli; Michael J Keating Journal: Blood Date: 2018-12-07 Impact factor: 22.113