obinutuzumab.pdf

The n e w e ng l a n d j o u r na l of m e dic i n e original article Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions Valentin Goede, M.D., Kirsten Fischer, M.D., Raymonde Busch, M.S., Anja Engelke, M.D., Barbara Eichhorst, M.D., Clemens M. Wendtner, M.D., Tatiana...

The n e w e ng l a n d j o u r na l of m e dic i n e original article Obinutuzumab plus Chlorambucil in Patients with CLL and Coexisting Conditions Valentin Goede, M.D., Kirsten Fischer, M.D., Raymonde Busch, M.S., Anja Engelke, M.D., Barbara Eichhorst, M.D., Clemens M. Wendtner, M.D., Tatiana Chagorova, M.D., Javier de la Serna, M.D., Marie-Sarah Dilhuydy, M.D., Thomas Illmer, M.D., Stephen Opat, M.D., Carolyn J. Owen, M.D., Olga Samoylova, M.D., Karl-Anton Kreuzer, M.D., Stephan Stilgenbauer, M.D., Hartmut Döhner, M.D., Anton W. Langerak, Ph.D., Matthias Ritgen, M.D., Michael Kneba, M.D., Elina Asikanius, M.Sc., Kathryn Humphrey, B.Sc., Michael Wenger, M.D., and Michael Hallek, M.D. A BS T R AC T Background The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions. Methods We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival. Results The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab–chlorambucil or rituximab–chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab–chlorambucil vs. 11.1 months with chlor­ ambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab–chlorambucil vs. 11.1 months with chlor­ambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab–chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P = 0.002). Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab–chlorambucil than with rituximab–chlorambucil, but the risk of infection was not increased. Conclusions Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT01010061.) n engl j med 370;12 nejm.org From the German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne–Bonn, University Hospital Cologne, Cologne (V.G., K.F., A.E., B.E., C.M.W., K.-A.K., M.H.), the Department for Geriatric Medicine and Research, St. Marien Hospital and University of Cologne, Cologne (V.G.), Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich (R.B.), Klinikum Schwabing, Munich (C.M.W.), private oncology practice, Dresden (T.I.), Medical Department II, University of Schleswig-Holstein, City Hospital Kiel, Kiel (M.R., M.K.), the Department of Internal Medicine III, Ulm University, Ulm (S.S., H.D.), and Cluster of Excellence “Cellular Stress Responses in Aging-Associated Diseases” (CECAD), University of Cologne, Cologne (M.H.) — all in Germany; Penza Regional Oncology Dispensary, Penza (T.C.), and Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod (O.S.) — both in Russia; Servicio De Hematologia, Hospital Universitario 12 De Octubre, Madrid (J.S.); Hôpital Haut Lévêque, Bordeaux, Pessac, France (M.-S.D.); the Department of Hae­ ma­tology, Monash Medical Centre, Clayton, Australia (S.O.); University of Calgary, Calgary, AB, Canada (C.J.O.); the Department of Immunology, Erasmus Medical Center Rotterdam, ­Rotterdam, the Netherlands (A.W.L.); F. Hoffmann–La Roche, Basel, Switzerland (E.A.); F. Hoffmann– La Roche, Welwyn, United Kingdom (K.H.); and Genentech, South San Francisco, CA (M.W.). Address reprint requests to Dr. Hallek at the German CLL Study Group, University of C ­ ologne, 50924 Cologne, Germany, or at [email protected]. This article was published on January 8, 2014, at NEJM.org. N Engl J Med 2014;370:1101-10. DOI: 10.1056/NEJMoa1313984 Copyright © 2014 Massachusetts Medical Society. march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1101 The n e w e ng l a n d j o u r na l C hronic lymphocytic leukemia (CLL), which is characterized by a neoplastic accumulation of B lymphocytes,1 is the most common leukemia in Western countries. The majority of patients with CLL are older than 70 years of age, and many present with coexisting conditions.2,3 In the past, CLL was treated with chemotherapy without improving survival.4-8 The addition of the monoclonal anti-CD20 antibody rituximab to fludarabine and cyclophosphamide has been shown to prolong overall survival in physically fit patients with previously untreated CLL.9-11 However, randomized trials have not shown that targeting the CD20 antigen in patients with CLL and coexisting conditions would result in a similar benefit. Previous phase 2 trials suggested that combining rituximab with the alkylating drug chlorambucil was a reasonable treatment approach for such patients.12,13 Rituximab is a chimeric type 1 antibody that kills CLL cells primarily by means of complement-dependent and antibody-dependent cellular cytotoxicity after binding to CD20.14 Obinutuz­ umab (also known as GA101) is a humanized, glycoengineered type 2 antibody also targeted against CD20.15 In preclinical studies, obinutuzu­ mab showed superior efficacy, as compared with rituximab, by inducing direct cell death and enhanced antibody-dependent cellular cytotoxicity (with less complement-dependent cytotoxicity).16-20 We wondered whether this difference in mechanism of action would translate into a clinical benefit for patients with CLL. We conducted a phase 3, randomized trial to determine whether anti-CD20 antibody–based chemoimmunotherapy (with chlorambucil as the chemotherapy backbone) would be beneficial in patients with CLL and coexisting conditions and whether targeting of the CD20 antigen by obinutuzumab could improve outcomes as compared with rituximab. Me thods PATIENTS In this open-label, three-group study, we enrolled patients with CD20-positive CLL that was diagnosed according to the criteria of the International Workshop on Chronic Lymphocytic Leukemia.21 Previously untreated patients requiring treatment (i.e., those with Binet stage C or symptomatic disease) were included. Central screen1102 n engl j med 370;12 of m e dic i n e ing before randomization was performed to exclude patients with an incorrect diagnosis or without a need for therapy. Enrolled patients were required to have a clinically meaningful burden of coexisting conditions, as reflected by a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or a creatinine clearance of 30 to 69 ml per minute as assessed with the use of the Cockcroft–Gault formula.22,23 Additional eligibility criteria are summarized in the Supplementary Appendix, available with the full text of this article at NEJM.org. All patients provided written informed consent. STUDY OVERSIGHT AND CONDUCT The study was approved by the institutional review board or independent ethics committee at each participating institution and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was designed by the German CLL Study Group and the sponsor (F. Hoffmann–La Roche). The sponsor gathered and, in conjunction with the German CLL Study Group, analyzed the data. The first author wrote all manuscript drafts. All the authors vouch for the completeness and accuracy of the data and the adherence of the study to the protocol (available at NEJM.org). A medicalcommunications agency paid by the sponsor provided initial versions of figures and editing support. (Details of the conduct of the study are provided in the Supplementary Appendix.) There were no agreements concerning confidentiality of the data among the sponsor, the German CLL Study Group, and the academic authors. RANDOMIZATION AND TREATMENT This multinational trial was conducted in 26 countries; 189 centers enrolled patients. Enrollment was preceded by a safety run-in phase.24 Between April 2010 and July 2012, patients were enrolled and randomly assigned to one of the following treatment groups on a 1:2:2 basis: chlorambucil alone, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. After 118 patients had been assigned to the chlorambucil-alone group, this group was closed on the basis of predefined criteria, and randomization to the two antibody groups was performed on a 1:1 basis. Randomization was stratified according to geographic region and Binet stage. Patients assigned to the nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Obinutuzumab plus Chlor ambucil in Patients with CLL chlorambucil-alone group in whom progressive disease developed during treatment or within 6 months after the end of treatment were allowed to cross over to the obinutuzumab–chlorambucil group. Patients received chlorambucil alone, obinutuz­ umab–chlorambucil, or rituximab–chlorambucil in six 28-day cycles. Chlorambucil was administered orally at a dose of 0.5 mg per kilogram of body weight on days 1 and 15 of each cycle (equivalent to the median dose in a previous trial showing noninferiority of chlorambucil to flu­dar­ abine in elderly patients with CLL).25 A rationale for the selection of the chlorambucil dose is provided in the Supplementary Appendix. Obinutuzumab was administered intravenously at a dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 through 6 (on the basis of previous pharmacokinetic studies and modeling).26 After amendment of the study protocol, the first infusion of obinutuzumab was administered over a period of 2 days. Rituximab was administered intravenously at a dose of 375 mg per square meter of body-surface area on day 1 of cycle 1 and 500 mg per square meter on day 1 of cycles 2 through 6. Prophylaxis for infusion-related reactions and the tumor lysis syndrome included fluid intake and premedication with allopurinol, paracetamol (acetaminophen), antihistamines, and glucocorticoids. ASSESSMENTS AND END POINTS Assessments at baseline included immunophenotyping of circulating lymphocytes, central analysis of genomic aberrations by means of fluorescence in situ hybridization, and mutational analysis of the immunoglobulin heavy-chain variable-region gene (IGHV) by means of DNA sequencing.27,28 The site investigators were provided with guidelines for CIRS assessment.29 Adverse events were reported according to the National Cancer Institute Common Toxicity Criteria (version 4.0).30 The response to therapy at 3 months after the end of treatment and the status with respect to remission during follow-up were assessed according to the guidelines of the International Workshop on Chronic Lymphocytic Leukemia.21 Complete and partial responses were confirmed by means of computed tomographic scanning, and complete responses were confirmed by means of bone marrow biopsy. Minimal residual disease was analyzed centrally according to international guidelines21,31 by means n engl j med 370;12 of an allele-specific oligonucleotide polymerasechain-reaction assay at baseline and 3 months after the end of treatment.32,33 The primary end point was progression-free survival, as assessed by the site investigators. Key secondary end points were progression-free survival as assessed by an independent review committee, response rates and the rate of negative testing for minimal residual disease after the end of treatment, event-free survival, the time to new treatment, overall survival, adverse events, and patient-reported outcomes. A data and safety monitoring board reviewed the data regularly once randomization was opened. STATISTICAL ANALYSIS The statistical design of the study is outlined in the Supplementary Appendix. Progression-free survival as the primary end point was used to calculate the sample for the study. Time points for the three pairwise comparisons were determined on the basis of the predefined numbers of progression-free survival events needed for each comparison. Assumptions for median progression-free survival were 12 months for the chlor­ ambucil-alone group, 20 months for the rituximab–chlorambucil group, and 27 months for the obinutuzumab–chlorambucil group. The number of required events was based on a two-sided logrank test at an alpha level of 5% with a power of at least 80%. The primary analyses for the comparisons of the obinutuzumab–chlorambucil group and the rituximab–chlorambucil group with the chlorambucil-alone group were conducted in July 2012 and August 2012, respectively, and were updated in May 2013, when the primary analysis of the comparison between the obinutuzumab–chlor­ ambucil group and the rituximab–chlorambucil group was performed. The efficacy boundary was crossed at a preplanned interim analysis. All results presented here are from the analyses of May 2013; earlier results are summarized in Table S1 in the Supplementary Appendix. The primary analysis was a two-sided logrank test stratified according to Binet stage. The type 1 error was controlled through the closedtesting procedure (the global test was a three-group log-rank test). The comparison between the obinu­ tuzumab–chlorambucil group and the rituximab– chlorambucil group included two interim looks at the data and an O’Brien–Fleming efficacy bound­ ary with a Lan–DeMets alpha-spending function nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1103 The n e w e ng l a n d j o u r na l of m e dic i n e to adjust for multiple comparisons. Secondary end points were analyzed with the use of a twosided test at a 5% alpha level without adjustment for multiple comparisons. bers of patients who were enrolled and assigned to each treatment group are shown in Figure S1 in the Supplementary Appendix. Pairwise comparisons of the three treatment groups were performed in different study cohorts. Age and clinical characteristics at baseline R e sult s were well balanced among the treatment groups PATIENTS (Table 1, and Tables S2 and S3 in the SuppleA total of 781 patients were enrolled and treated mentary Appendix). The patients had a median with chlorambucil alone, obinutuzumab–chlor­ age of 73 years, creatinine clearance of 62 ml ambucil, or rituximab–chlorambucil. The num- per minute, and CIRS score of 8 at baseline. Most Table 1. Baseline Characteristics, Intention-to-Treat Population.* Obinutuzumab–Chlorambucil vs. Chlorambucil Alone Obinutuzumab– Chlorambucil Chlorambucil Alone (N = 238) (N = 118) Characteristic Age — yr Median 74 Range 39–88 Cumulative Illness Rating Scale† Score — median (range) 8 (1–20) Affected organ system or disorder — no. (%) Cardiac 120 (50) Hypertension 168 (71) Vascular 91 (38) Respiratory 85 (36) Eye, ear, throat, or larynx 86 (36) Upper gastrointestinal 80 (34) Lower gastrointestinal 50 (21) Hepatic or biliary 39 (16) Renal 104 (44) Genitourinary 83 (35) Musculoskeletal 106 (45) Endocrine or metabolic 127 (53) Neurologic 46 (19) Psychiatric 39 (16) Median calculated creatinine 61.4 clearance — ml/min Binet stage — no. (%) A 55 (23) B 98 (41) C 85 (36) Unmutated IGHV — no./total no. (%) 129/210 (61) del(17p) on FISH — no./total no. (%) 16/203 (8) Rituximab–Chlorambucil Obinutuzumab–Chlorambucil vs. Chlorambucil Alone vs. Rituximab–Chlorambucil Rituximab– Chlorambucil Obinutuzumab– Rituximab– Chlorambucil Alone Chlorambucil Chlorambucil (N = 233) (N = 118) (N = 333) (N = 330) 72 43–87 73 40–90 72 43–87 74 39–89 73 40–90 8 (0–18) 8 (0–18) 8 (0–18) 8 (0–22) 8 (0–18) 62 (53) 88 (75) 34 (29) 43 (36) 53 (45) 39 (33) 25 (21) 21 (18) 45 (38) 44 (37) 45 (38) 64 (54) 33 (28) 11 (9) 63.8 111 (48) 155 (67) 68 (29) 85 (36) 102 (44) 70 (30) 38 (16) 40 (17) 111 (48) 76 (33) 96 (41) 117 (50) 48 (21) 36 (15) 61.8 62 (53) 88 (75) 34 (29) 43 (36) 53 (45) 39 (33) 25 (21) 21 (18) 45 (38) 44 (37) 45 (38) 64 (54) 33 (28) 11 (9) 63.8 171 (51) 228 (68) 114 (34) 121 (36) 131 (39) 104 (31) 68 (20) 56 (17) 137 (41) 114 (34) 148 (44) 183 (55) 72 (22) 59 (18) 62.5 165 (50) 225 (68) 95 (29) 127 (38) 141 (43) 102 (31) 55 (17) 66 (20) 145 (44) 114 (35) 135 (41) 161 (49) 72 (22) 49 (15) 62.6 24 (20) 50 (42) 44 (37) 58/99 (59) 49 (21) 100 (43) 84 (36) 126/204 (62) 24 (20) 50 (42) 44 (37) 58/100 (58) 74 (22) 142 (43) 117 (35) 188/305 (62) 74 (22) 135 (41) 121 (37) 182/298 (61) 10/96 (10) 9/196 (5) 10/97 (10) 22/295 (7) 20/287 (7) * The intention-to-treat population included all patients randomly assigned to a treatment group. There were no significant differences in the listed baseline characteristics between groups in the three pairwise comparisons. Pairwise comparisons of the three treatment groups were performed in different study cohorts and therefore are always displayed side by side. FISH denotes fluorescence in situ hybridization, and IGHV the immunoglobulin heavy-chain variable-region gene. † Scores on the Cumulative Illness Rating Scale range from 0 to 56, with higher scores indicating worse health status. 1104 n engl j med 370;12 nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Obinutuzumab plus Chlor ambucil in Patients with CLL patients (82%) had more than three coexisting conditions, and nearly one third (27%) had at least one coexisting condition that was not well controlled at baseline according to CIRS grading. The median number of treatment cycles and the total dose of chlorambucil administered per patient were similar among the treatment groups. As a consequence of different dosing schedules, the median total dose of obinutuzumab was higher than that of rituximab (Table S4 in the Supplementary Appendix). SAFETY Adverse events occurred more frequently in the antibody groups than in the chlorambucil-alone group and were most frequent with obinu­ tuzumab–chlorambucil treatment (Table 2, and Tables S5 and S6 in the Supplementary Appendix). The incidence of grade 3 or 4 neutropenia was highest with the combination of obinutuzu­ mab and chlorambucil and was lowest with chlor­ ambucil alone. Rates of grade 3 to 5 infection ranged from 11 to 14% and did not differ significantly among the treatment groups. Most reported infections were of bacterial origin. Infusion-related reactions were more frequent with obinutuzumab–chlorambucil treatment than with rituximab–chlorambucil treatment. In the obinutuzumab–chlorambucil group, grade 3 or 4 infu- sion-related reactions occurred in 20% of patients during the first infusion of obinutuzumab, but there were no grade 3 or 4 reactions during subsequent obinutuzumab infusions. No deaths were associated with infusion-related reactions. Neither the lymphocyte counts nor the tumor burden at baseline was a strong predictor of obinutuzumab-related infusion reactions. Prophylactic measures had only a moderate effect on the frequency of infusion-related reactions (Fig. S2 and Tables S7 and S8 in the Supplementary Appendix). The tumor lysis syndrome was reported in 15 patients in the study and resolved in all cases. Frequencies of newly diagnosed neoplasms were similar among the treatment groups (Table S9 in the Supplementary Appendix). As compared with both patients receiving obinutuzumab–chlorambucil and those receiving chlorambucil alone, patients receiving rituximab–chlorambucil were less likely to discontinue therapy early owing to adverse events. This imbalance between the obinutuzumab–chlorambucil group and the rituximab–chlorambucil group was primarily due to infusion-related reactions in the obinutuzumab–chlorambucil group (Tables S10 and S11 in the Supplementary Appendix). The most frequent serious adverse events were infections, infusion-related reactions, and neoplasms (Table S6 in the Supplementary Table 2. Adverse Events of Grade 3 or Higher, Safety Population.* Obinutuzumab–Chlorambucil vs. Chlorambucil Alone Event Obinutuzumab– Chlorambucil Chlorambucil Alone (N = 241) (N = 116) Rituximab–Chlorambucil vs. Chlorambucil Alone Rituximab– Chlorambucil (N = 225) Obinutuzumab–Chlorambucil vs. Rituximab–Chlorambucil Chlorambucil Obinutuzumab– Rituximab– Alone Chlorambucil Chlorambucil (N = 116) (N = 336) (N = 321) number of patients (percent) 175 (73) 58 (50) 125 (56) 58 (50) 235 (70) 177 (55) Infusion-related reactions Any event 51 (21) — 9 (4) — 67 (20) 12 (4) Neutropenia 84 (35) 18 (16) 60 (27) 18 (16) 111 (33) 91 (28) Anemia 11 (5) 5 (4) 10 (4) 5 (4) 14 (4) 12 (4) Thrombocytopenia 27 (11) 5 (4) 8 (4) 5 (4) 35 (10) 10 (3) Leukopenia 13 (5) Infections 27 (11) 0 3 (1) 16 (14) 30 (13) 15 (4) 3 (1) 16 (14) 0 40 (12) 44 (14) Pneumonia 8 (3) 4 (3) 11 (5) 4 (3) 13 (4) 17 (5) Febrile neutropenia 4 (2) 5 (4) 4 (2) 5 (4) 8 (2) 4 (1) * The safety population included all patients who received at least one dose of study medication. Shown are adverse events of grade 3, 4, or 5 with an incidence of 3% or higher in any treatment group, irrespective of whether the event was considered related or unrelated to treatment by the investigators. n engl j med 370;12 nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1105 The n e w e ng l a n d j o u r na l Patients with a Response (%) 100 90 80 70 60 50 40 30 20 10 0 P<0.001 G-Clb Complete response Partial response 22.3 7.3 58.4 55.0 Clb Complete response Partial response R-Clb 31.4 G-Clb (N=238) Complete response Partial response Clb (N=118) R-Clb (N=233) Probability of Progression-free Survival B 1.0 Stratified hazard ratio for progression or death with G-Clb, 0.18 (95% CI, 0.13–0.24) P<0.001 0.9 0.8 0.7 0.6 most common grade 5 adverse events were newly diagnosed neoplasms and cardiac events in the antibody groups and infections in the chlorambucil-alone group (Table S12 in the Supplementary Appendix). 0.5 0.4 G-Clb 0.3 0.2 0.1 0.0 11.1 0 3 6 9 12 15 26.7 18 21 24 27 30 Clb 33 36 39 EFFICACY Months No. at Risk G-Clb Clb 238 220 218 207 188 156 122 93 118 101 89 68 36 18 11 6 60 4 34 3 12 1 4 0 1 0 0 0 Probability of Progression-free Survival C 1.0 Stratified hazard ratio for progression or death with R-Clb, 0.44 (95% CI, 0.34–0.57) P<0.001 0.9 0.8 0.7 0.6 0.5 0.4 0.3 R-Clb 0.2 0.1 0.0 11.1 0 3 6 9 12 15 Clb 16.3 18 21 24 27 30 33 36 39 31 4 14 3 5 1 2 0 0 0 0 0 Months No. at Risk R-Clb Clb 233 225 219 190 146 114 72 118 101 89 68 36 18 11 49 6 Appendix). The percentage of patients who died because of an adverse event was lower in the obinutuzumab–chlorambucil group (4%) than in the rituximab–chlorambucil and chlorambucilalone groups (6% and 9%, respectively). The 1106 m e dic i n e Figure 1. Response Rates and Progression-free Survival with Obinutuzumab–Chlorambucil or Rituximab–Chlor­ ambucil versus Chlorambucil Alone. Panel A shows response rates at 3 months after the end of treatment. Complete response included complete response with incomplete bone marrow recovery; partial response included nodular partial response. The response assessment was not available for one patient in the rituximab–chlorambucil group because the analysis occurred before the patient had a 3-month follow-up visit. Panel B shows progression-free survival with obinutuzumab–chlorambucil versus chlorambucil alone, and Panel C shows progression-free survival with rituximab–chlorambucil versus chlorambucil alone. Progression-free survival was assessed by the site investigators. P values were calculated with the use of a stratified log-rank test. CI denotes confidence interval, Clb chlorambucil alone, G-Clb obinutuzumab– chlorambucil, and R-Clb rituximab–chlorambucil. A P<0.001 of n engl j med 370;12 Overall response rates at 3 months after the end of treatment were increased in the obinutuzumab– chlorambucil and rituximab–chlorambucil groups as compared with the chlorambucil-alone group; complete responses were seen exclusively after antibody treatment (Fig. 1A). Therapy with obinutuzumab–chlorambucil or rituximab–chlor­ ambucil, as compared with chlorambucil alone, was associated with significant improvement in the median progression-free survival (26.7 months with obinutuzumab–chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab– chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001) (Fig. 1B and 1C). This benefit was seen in all analyzed subgroups, except in patients with del(17p) (Fig. S3 in the Supplementary Appendix). Quality of life did not deteriorate during or after antibody therapy as compared with treatment with chlorambucil alone (Fig. S4 in the Sup­ plementary Appendix). Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in higher rates of overall, complete, and molecular responses (Fig. 2A and 2B, and Table S13 nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Obinutuzumab plus Chlor ambucil in Patients with CLL Discussion This phase 3 study compared treatment with chlorambucil alone, obinutuzumab–chlorambucil, and rituximab–chlorambucil in patients with n engl j med 370;12 Patients with a Response (%) A P<0.001 100 90 80 70 60 50 40 30 20 10 0 G-Clb Complete response Partial response 20.7 R-Clb 7.0 57.7 58.1 G-Clb (N=333) R-Clb (N=329) Complete response Partial response Patients with a Negative MRD Test (%) B 100 90 80 70 60 50 40 30 20 10 0 G-Clb R-Clb P<0.001 P<0.001 37.7 19.5 2.6 3.3 Bone Marrow No. of Patients 26/133 Blood 3/114 87/231 8/243 C Probability of Progression-free Survival in the Supplementary Appendix). Among all patients for whom a result for minimal residual disease was available plus those who had progressive disease or who died, the rate of negative testing for minimal residual disease in bone marrow and peripheral blood was significantly higher after obinutuzumab–chlorambucil treatment than after rituximab–chlorambucil treatment (bone marrow, 19.5% vs. 2.6%; blood, 37.7% vs. 3.3%, respectively) (Fig. 2B). Negative testing for minimal residual disease in blood after obinutuzumab–chlorambucil treatment was associated with a favorable disease course during follow-up (Fig. S5 and S6 in the Supplementary Appendix). A significant prolongation in progression-free survival was observed with obinutuzumab–chlorambucil treatment as compared with rituximab–chlorambucil treatment (median progression-free survival, 26.7 vs. 15.2 months; hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) (Fig. 2C). The progression-free survival benefit with obinutuzumab–chlorambucil as compared with rituximab–chlorambucil was supported in all preplanned subgroup analyses, although the hazard ratios for patients with del(17p) or other karyotypes had 95% confidence intervals that included 1. The robustness of the results for progression-free survival was confirmed by various prespecified analyses (Fig. S3 and S7 in the Supplementary Appendix). As of the most recent assessment of overall survival, treatment with obinutuzumab–chlor­ ambucil provided a significant benefit as compared with chlorambucil monotherapy (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P = 0.002) (Fig. 3A); the rates of death were 9% and 20%, respectively. No significant benefit was noted for rituximab–chlorambucil over chlorambucil alone (hazard ratio, 0.66; 95% CI, 0.39 to 1.11; P = 0.11) (Fig. 3B); the rates of death were 15% and 20%, respectively. A significant benefit also was not noted for obinutuzumab–chlorambucil over rituximab–chlor­­ambucil (hazard ratio, 0.66; 95% CI, 0.41 to 1.06; P = 0.08) (Fig. 3C); the rates of death were 8% and 12%, respectively. Overall survival medians were not reached. 1.0 Stratified hazard ratio for progression or death with G-Clb, 0.39 (95% CI, 0.31–0.49) P<0.001 0.9 0.8 0.7 0.6 0.5 0.4 G-Clb 0.3 0.2 R-Clb 0.1 0.0 15.2 0 3 6 9 12 15 18 26.7 21 24 27 30 33 36 39 60 31 34 14 12 5 4 2 1 0 0 0 Months No. at Risk G-Clb R-Clb 333 307 302 278 213 156 122 93 330 317 309 259 163 114 72 49 Figure 2. Response Rates and Progression-free Survival with Obinutuzumab– Chlorambucil versus Rituximab–Chlorambucil. Panel A shows response rates at 3 months after the end of treatment. Complete response included complete response with incomplete bone marrow recovery; partial response included nodular partial response. Panel B shows molecular response rates; MRD denotes minimal residual disease. Panel C shows progression-free survival, as assessed by the site investigators. P values were calculated with the use of a stratified log-rank test. G-Clb denotes obinutuzumab–chlorambucil, and R-Clb rituximab–chlorambucil. nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1107 The n e w e ng l a n d j o u r na l Probability of Overall Survival 1.0 0.9 G-Clb 0.7 0.6 Clb 0.5 0.4 Stratified hazard ratio for death with G-Clb, 0.41 (95% CI, 0.23–0.74) P=0.002 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 34 14 15 5 2 0 0 0 Months No. at Risk G-Clb Clb 238 226 223 221 215 211 170 144 115 71 118 109 105 103 102 94 70 56 44 29 B Probability of Overall Survival 1.0 0.9 R-Clb 0.8 0.7 Clb 0.6 0.5 0.4 Stratified hazard ratio for death with R-Clb, 0.66 (95% CI, 0.39–1.11) P=0.11 0.3 0.2 0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 233 227 223 218 214 202 169 138 105 61 118 109 105 103 102 94 70 56 44 29 27 15 8 5 0 0 0 0 Months No. at Risk R-Clb Clb C Probability of Overall Survival 1.0 G-Clb 0.9 0.8 R-Clb 0.7 0.6 0.5 0.4 Stratified hazard ratio for death with G-Clb, 0.66 (95% CI, 0.41–1.06) P=0.08 0.3 0.2 0.1 0.0 27 30 33 36 39 333 316 310 303 261 214 170 144 115 71 330 320 314 305 255 203 169 138 105 61 34 27 14 8 2 0 0 0 0 3 6 9 12 15 18 21 24 Months No. at Risk G-Clb R-Clb 1108 m e dic i n e Figure 3. Overall Survival in the Intention-to-Treat ­Population. Overall survival is shown for obinutuzumab–chlorambucil versus chlorambucil alone in Panel A, rituximab– chlorambucil versus chlorambucil alone in Panel B, and obinutuzumab–chlorambucil versus rituximab– chlorambucil in Panel C. P values were calculated with the use of a log-rank test. Clb denotes chlorambucil alone, G-Clb obinutuzumab–chlorambucil, and R-Clb rituximab–chlorambucil. A 0.8 of n engl j med 370;12 previously untreated CLL and coexisting conditions. Most enrolled patients were older than 70 years of age and had clinically meaningful health problems in addition to CLL. Although elderly patients with coexisting conditions represent the majority of patients with CLL,2,3 they have been underrepresented in prior clinical trials. In contrast to treatment in younger, physically fit patients with CLL, chlorambucil monotherapy has remained a standard of care in older patients with coexisting conditions; no treatment has proved to be superior to chlorambucil in this patient population.25,34 Our study shows that the combination of an anti-CD20 antibody with chlor­ambucil results in a better response and prolongation of progression-free survival in these patients. The patients treated with obinutuzumab and chlorambucil had an overall survival advantage over patients receiving chlorambucil alone. Previous trials of various treatments (e.g., fludar­a­ bine [alone or in combination with cyclophosphamide], bendamustine, and alemtuzumab)4,6,8,35 did not show a survival advantage over treatment with chlorambucil alone. To date, targeting of the CD20 antigen is the only therapeutic approach that has been shown to prolong survival among patients with previously untreated CLL.9 New monoclonal antiCD20 antibodies have been developed that were purported to be more efficacious than rituximab on the basis of preclinical studies.36 With the exception of the glycoengineered type 2 antibody obinutuzumab, however, none have been directly compared with rituximab in patients with CLL. This study showed more complete responses and longer progression-free survival with obinutuzumab than with rituximab, when both were given in combination with chlorambucil. The trial met its primary end point (im- nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. Obinutuzumab plus Chlor ambucil in Patients with CLL proved progression-free survival), and this finding was robustly supported by analyses of all secondary end points and various preplanned sensitivity and subgroup analyses. The rate of induction of negative status for minimal residual disease was more than 10 times as high with obinutuzumab–chlorambucil as it was with rituximab–chlorambucil. The capacity of a treatment to result in low levels of minimal residual disease in bone marrow or peripheral blood was recently associated with improved overall survival, irrespective of the clinically assessed response status.37 With longer follow-up, the higher rate of eradication of minimal residual disease that was observed with obinutuzumab as compared with rituximab may lead to an overall survival benefit in addition to the improvement in progression-free survival. Although response rates observed with rituximab–chlorambucil treatment were similar to those reported in previous phase 2 trials,12,13 progression-free survival with rituximab–chlor­ ambucil treatment was shorter in our study than in those trials. Some of the early trials showed longer progression-free survival with chlorambucil-alone treatment than we observed in our study.5,6,35 However, these differences may be attributable to differences in patient populations, chlorambucil dosing schedules, and methods used for rigorous data collection. All these factors were kept constant across our treatment groups and therefore would not account for findings that favored obinutuzumab– chlorambucil over the other two treatments. The dose of obinutuzumab was higher than the dose of rituximab, and it is unclear to what extent this higher dose contributed to the greater activity of obinutuzumab–chlorambucil as compared with that of rituximab–chlorambucil. High-dose rituximab monotherapy in patients with CLL has been shown to have a dose–response relationship.38 In combination with chemotherapy, however, high-dose rituximab did not result in an additional benefit.39 The combination of obinutuzumab or rituxReferences 1. Marti GE, Faguet G, Bertin P, et al. CD20 and CD5 expression in B-chronic lymphocytic leukemia. Ann N Y Acad Sci 1992;651:480-3. 2. Howlader N, Noone AM, Krapcho M, imab with chlorambucil adds not only efficacy but also toxicity to the treatment. An increased incidence of neutropenia was observed with both antibodies but did not result in an increased incidence of infection. Infusion-related reactions, including severe reactions leading to withdrawal of therapy, were identified as a particular risk of obinutuzumab–chlorambucil treatment. Several prophylactic measures were implemented during the conduct of the trial (e.g., premedication with glucocorticoids and administration of the first dose of obinutuzu­ mab over a period of 2 days), with a moderate effect on the frequency of infusion-related reactions. An important observation was that all grade 3 or 4 infusion-related reactions occurred during the first infusion of obinutuzumab but not during subsequent infusions. Rapid and profound B-cell depletion by obinutuzumab40 might be the reason for the greater frequency and intensity of infusion-related reactions during the first dose of obinutuzumab as compared with rituximab. Lymphocyte counts and lymphadenopathy were not strong predictors of infusionrelated reactions. In the absence of validated risk factors, all patients with CLL, irrespective of the leukemic burden, should therefore be closely monitored during the first infusion of obinutuz­ umab. Growing experience with this antibody will be key in reducing the risk of infusion-related reactions. In conclusion, this randomized, phase 3 study showed that the combination of an antiCD20 antibody (obinutuzumab or rituximab) with chlorambucil improves the outcomes in previously untreated patients with CLL and coexisting conditions. Obinutuzumab–chlorambucil provided an overall survival advantage over chlor­ ambucil alone and induced deeper and longer remissions than did rituximab–chlorambucil. Supported by F. Hoffmann–La Roche. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank all the study patients and investigators. (A complete list of investigators and other persons acknowledged is provided in the Supplementary Appendix.) et al. SEER Cancer Statistics Review, 1975-2010: based on November 2012 SEER data submission, posted to the SEER website. April 2013 (http://seer.cancer.gov/csr/ 1975_2010). n engl j med 370;12 nejm.org 3. Thurmes P, Call T, Slager S, et al. Co- morbid conditions and survival in unsel­ ected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma 2008;49:49-56. march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1109 Obinutuzumab plus Chlor ambucil in Patients with CLL 4. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlor­ ambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000; 343:1750-7. 5. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 2006;107:88591. 6. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007;370:230-9. 7. Flinn IW, Neuberg DS, Grever MR, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 2007;25: 793-8. 8. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:4378-84. 9. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010;376:1164-74. 10. Tam CS, O’Brien S, Wierda W, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 2008;112:975-80. 11. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005;105:49-53. 12. Hillmen P, Gribben JG, Follows GA, et al. Rituximab plus chlorambucil in patients with CD20-positive B-cell chronic lymphocytic leukemia (CLL): final response analysis of an open-label Phase II study. Blood 2010;116:697. abstract. 13. Foa R, Ciolli S, Di Raimondo F, et al. Rituximab plus chlorambucil as initial treatment for elderly patients with chronic lymphocytic leukemia (CLL): effect of pre-treatment biological characteristics and gene expression patterns on response to treatment. Blood 2011;118:294. abstract. 14. Cartron G, Watier H, Golay J, SolalCeligny P. From the bench to the bedside: ways to improve rituximab efficacy. Blood 2004;104:2635-42. 15. Owen C, Stewart DA. Obinutuzumab for the treatment of lymphoproliferative 1110 disorders. Expert Opin Biol Ther 2012;12: 343-51. 16. Mössner E, Brünker P, Moser S, et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 2010;115:4393402. 17. Patz M, Isaeva P, Forcob N, et al. Comparison of the in vitro effects of the antiCD20 antibodies rituximab and GA101 on chronic lymphocytic leukaemia cells. Br J Haematol 2011;152:295-306. 18. Dalle S, Reslan L, Besseyre de Horts T, et al. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101. Mol Cancer Ther 2011;10:178-85. 19. Alduaij W, Ivanov A, Honeychurch J, et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosomemediated cell death in B-cell malignancies. Blood 2011;117:4519-29. 20. Herter S, Herting F, Mundigl O, et al. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther 2013;12:2031-42. 21. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 2008;111: 5446-56. [Erratum, Blood 2008;112:5259.] 22. Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness Rating Scale in a geriatric residential population. J Am Geriatr Soc 1995;43: 130-7. 23. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41. 24. Goede V, Fischer K, Busch R, et al. Chemoimmunotherapy with GA101 plus chlorambucil in patients with chronic lymphocytic leukemia and comorbidity: results of the CLL11 (BO21004) safety run-in. Leukemia 2013;27:1172-4. 25. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 2009;114:3382-91. 26. Morschhauser F, Salles G, Cartron G, et al. Dose selection for phase III studies of the monoclonal anti-CD20 antibody obinutuzumab (GA101) — a rational approach. Haematologica 2011;96:Suppl 2: 935. abstract. 27. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 2000;343:1910-6. n engl j med 370;12 nejm.org 28. Kröber A, Seiler T, Benner A, et al. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 2002;100:1410-6. 29. Salvi F, Miller MD, Grilli A, et al. A manual of guidelines to score the modified Cumulative Illness Rating Scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc 2008;56:192631. 30. Common Terminology Criteria for Adverse Events v4.03 (CTCAE) (http://evs.nci .nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06 -14_QuickReference_5x7.pdf). 31. Rawstron AC, Villamor N, Ritgen M, et al. International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia. Leukemia 2007;21:956-64. 32. Ritgen M, Böttcher S, Stilgenbauer S, et al. Quantitative MRD monitoring identifies distinct GVL response patterns after allogeneic stem cell transplantation for chronic lymphocytic leukemia: results from the GCLLSG CLL3X trial. Leukemia 2008; 22:1377-86. 33. Böttcher S, Stilgenbauer S, Busch R, et al. Standardized MRD flow and ASO IGH RQ-PCR for MRD quantification in CLL patients after rituximab-containing immunochemotherapy: a comparative analysis. Leukemia 2009;23:2007-17. 34. Woyach JA, Ruppert AS, Rai K, et al. Impact of age on outcomes after initial therapy with chemotherapy and different chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia: results of sequential cancer and leukemia group B studies. J Clin Oncol 2013;31:440-7. 35. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25: 5616-23. 36. Robak T. Emerging monoclonal antibodies and related agents for the treatment of chronic lymphocytic leukemia. Future Oncol 2013;9:69-91. 37. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 2012;30:980-8. 38. O’Brien SM, Kantarjian H, Thomas DA, et al. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 2001;19:2165-70. 39. O’Brien S, Wierda WG, Federl S, et al. FCR-3 as frontline therapy for patients with chronic lymphocytic leukemia. Blood 2005;106:2117. abstract. 40. Morschhauser F, Cartron G, Lamy T, et al. Phase I study of RO5072759 (GA101) in relapsed/refractory chronic lymphocytic leukemia. Blood 2009;114:884. abstract. Copyright © 2014 Massachusetts Medical Society. march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org on October 9, 2023. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.