Letters to the Editor 1602 2,7,8 malignancy with reported hazard ratios of 10.1–12.89. In 2 Laurie CC, Laurie CA, Rice K, Doheny KF, Zelnick LR, McHugh CP et al. Detectable addition to conferring a risk of subsequent disease development, clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet which our data suggest might be refined by analysis of different 2012; 44:642–650. blood cell types, findings such as these clearly have implications 3 Jacobs KB, Yeager M, Zhou W, Wacholder S, Wang Z, Rodriguez-Santiago B et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet for the interpretation of whole exome or genome sequencing in 2012; 44:651–658. elderly individuals, and introduce some uncertainty into the 4 Forsberg LA, Rasi C, Malmqvist N, Davies H, Pasupulati S, Pakalapati G et al. Mosaic assumption that the mutational landscape of the peripheral blood loss of chromosome Y in peripheral blood is associated with shorter survival and is representative of that of the germline. higher risk of cancer. Nat Genet 2014; 46: 624–628. 5 Busque L, Patel JP, Figueroa ME, Vasanthakumar A, Provost S, Hamilou Z et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal 44 – CONFLICT OF INTEREST hematopoiesis. Nat Genet 2012; : 1179 1181. 6 Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related The authors declare no conflict of interest. mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 20: 1472–1478. J Score1,2, A Chase1,2, LA Forsberg3, L Feng1, K Waghorn1,2, 7 Genovese G, Kahler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF et al. AV Jones1,2, C Rasi3, DC Linch4, JP Dumanski3, Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 2014; 371: 2477–2487. RE Gale4 and NCP Cross1,2 1 8 Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Wessex Regional Genetics Laboratory, Salisbury, UK; Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2 Faculty of Medicine, University of Southampton, Southampton, UK; 2014; 371: 2488–2498. 3 Department of Immunology, Genetics and Pathology, Rudbeck 9 Pang WW, Price EA, Sahoo D, Beerman I, Maloney WJ, Rossi DJ et al. Human bone Laboratory, Uppsala University, Uppsala, Sweden and marrow hematopoietic stem cells are increased in frequency and myeloid-biased 4Department of Haematology, UCL Cancer Institute, London, UK with age. Proc Natl Acad Sci USA 2011; 108: 20012–20017. E-mail: [email protected] 10 Gale RE, Fielding AK, Harrison CN, Linch DC. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br J Haematol 1997; 98:512–519. REFERENCES 11 Score J, Cross NC. Acquired uniparental disomy in myeloproliferative neoplasms. Hematol Oncol Clin North Am 2012; 26: 981–991. 1 Forsberg LA, Rasi C, Razzaghian HR, Pakalapati G, Waite L, Thilbeault KS et al. 12 Ernst T, Chase AJ, Score J, Hidalgo-Curtis CE, Bryant C, Jones AV et al. Inactivating Age-related somatic structural changes in the nuclear genome of human mutations of the histone methyltransferase gene EZH2 in myeloid disorders. blood cells. Am J Hum Genet 2012; 90:217–228. Nat Genet 2010; 42: 722–726.

Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study

Leukemia (2015) 29, 1602–1604; doi:10.1038/leu.2015.14 or Clb alone. Diagnosis of CLL was according to the criteria of the International Workshop on Chronic Lymphocytic Leukemia.5 The Obinutuzumab is a novel glycoengineered, humanized, type II comorbidity burden was assessed by the Cumulative Illness Rating anti-CD20 antibody. In preclinical studies, obinutuzumab Scale (CIRS) and by calculating creatinine clearance (CrCl) using showed greater antileukemic activity than the type I and the Cockcroft–Gault formula (with CIRS greater than 6 and/or CrCl non-glycoengineered anti-CD20 antibodies rituximab and of 30–69 ml/min used as eligibility criteria).6,7 Obinutuzumab was ofatumumab.1–3 Obinutuzumab recently became available for infused at 1000 mg on days 1, 8 and 15 of cycle 1 and on day 1 of the treatment of patients with chronic lymphocytic leukemia cycles 2–6 (each 28 days in duration). The first infusion of (CLL). Approval of the antibody in this indication was based on obinutuzumab was split over 2 days. Rituximab was administered primary results of the CLL11 study (NCT01010061), which at 375 and 500 mg/m2 body surface area on day 1 of cycle 1 and compared obinutuzumab (also known as GA101) plus chlorambu- cycles 2–6, respectively. Clb was given orally at 0.5 mg/kg body cil (G-Clb) with rituximab plus chlorambucil (R-Clb) and with weight on days 1 and 15 of cycles 1–6. PFS was the primary chlorambucil alone (Clb) in patients with previously untreated CLL endpoint of the trial. Secondary endpoints included OS and time and comorbidities.4 In an analysis with a data cutoff in May 2013, to next antileukemic treatment. Kaplan–Meier methodology and a G-Clb demonstrated superiority over R-Clb with regard to two-sided log-rank test were used to estimate and compare progression-free survival (PFS) and treatment response. The survival times. addition of obinutuzumab to Clb resulted in prolonged overall The treatment arms were well balanced for patient demographics survival (OS) compared with treatment with Clb alone, whereas and disease characteristics. The median age of enrolled patients was rituximab added to Clb compared with Clb alone did not result in 73 years with cardiovascular, pulmonary, metabolic, renal and a statistically significant OS benefit. There was also no difference in musculoskeletal disorders being the most frequent comorbidities OS between G-Clb and R-Clb treatment at the time. As survival (median CIRS 8, range 0–22). Deletions of 17p or 11q, and data can change with longer patient follow-up, we report here unmutated IGHV were present in 8, 16 and 61% of the patients, updated results on PFS and OS from an analysis with a data cutoff respectively. The present analysis did not reveal any new safety in April 2014. signals. Figure 1 shows updated PFS and OS data. PFS was Study methods were as previously published.4 In brief, 781 remarkably longer with G-Clb compared with R-Clb treatment treatment-naive patients with CLL in need of therapy and with (median PFS 29.2 versus 15.4 months, hazard ratio (HR) 0.40, 95% significant comorbidity burden were enrolled from April 2010 to confidence interval (CI) 0.33–0.50, Po0.001). Time to next July 2012 and randomly assigned for treatment with G-Clb, R-Clb antileukemic treatment was also longer with G-Clb than with

Accepted article preview online 30 January 2015; advance online publication, 17 February 2015

Leukemia (2015) 1600 – 1618 © 2015 Macmillan Publishers Limited Letters to the Editor 1603

G-Clb 1.0 R-Clb 1.0 0.9 HR: 0.40 0.9 0.8 95% CI, 0.33-0.50 0.8 0.7 p<0.001 0.7 0.6 0.6 0.5 0.5 G-Clb 0.4 0.4 R-Clb 0.3 HR: 0.70 Overall survival 0.3 0.2 0.2 95% CI, 0.47-1.02

Progression-free survival p=0.0632 0.1 0.1 0.0 15.4 29.2 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Time (months) No. at risk No. at risk G-Clb: 333 307 302 288 267 243 221 172 124 99 75 45 25 12 1 0 G-Clb: 333 317 311 306 300 296 289 257 205 169 141 105 72 38 9 2 0 R-Clb: 330 317 309 273 204 160 128 82 59 38 26 20 13 4 1 0 R-Clb: 330 320 314 309 302 293 279 238 198 161 134 105 65 29 12 0 0

G-Clb 1.0 Clb 1.0 0.9 HR: 0.18 0.9 0.8 95% CI, 0.14-0.24 0.8 0.7 p<0.0001 0.7 0.6 0.6 0.5 0.5 G-Clb 0.4 0.4 Clb 0.3 Overall survival 0.3 HR: 0.47 29.9 0.2 0.2 95% CI, 0.29-0.76 Progression-free survival 0.1 11.1 0.1 p=0.0014 0.0 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Time (months) No. at risk No. at risk G-Clb: 238 220 218 207 189 174 161 146 124 99 75 45 25 12 1 0 G-Clb: 238 227 224 222 217 214 208 206 198 169 141 105 72 38 9 2 0 Clb: 118 101 89 68 36 19 13 12 10 5 4 2 1 0 0 0 Clb: 118 110 107 105 104 98 93 92 89 69 56 47 29 14 5 0 0

1.0 1.0 R-Clb 0.9 Clb 0.9 0.8 0.8 HR: 0.44 0.7 95% CI, 0.34-0.56 0.7 0.6 p<0.0001 0.6 0.5 0.5 R-Clb 0.4 0.4 Clb 0.3 0.3 Overall survival HR: 0.60 0.2 11.1 0.2 95% CI, 0.38-0.94 Progression-free survival 0.1 0.1 p=0.0242 0.0 16.3 0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Time (months) Time (months) No. at risk No. at risk R-Clb: 233 225 219 191 146 120 94 72 58 38 26 20 13 4 1 0 R-Clb: 233 227 223 218 216 210 204 193 190 161 134 105 65 29 12 0 0 Clb: 118 101 89 68 36 19 13 12 10 5 4 2 1 0 0 0 Clb: 118 110 107 105 104 98 93 92 89 69 56 47 29 14 5 0 0 Figure 1. Updated PFS and OS for G-Clb versus R-Clb (a, b), G-Clb versus Clb (c, d) and R-Clb versus Clb (e, f) comparisons. G-Clb, obinutuzumab/chlorambucil; R-Clb, rituximab/chlorambucil; Clb, chlorambucil alone; HR, hazard ratio; 95% CI, 95% confidence interval.

R-Clb (42.7 versus 32.7 months, HR 0.54, 95% CI 0.40–0.72, many patients treated frontline with Clb alone received active next- Po0.001). No statistically significant OS benefit for G-Clb over line treatments including chemoimmunotherapy (Table 1). R-Clb could be demonstrated at current follow-up (HR 0.70, 95% CI These updated results are likely to have clinical implications. 0.47–1.02, P = 0.0632). This OS result is not yet mature owing to the Our observation that the addition of both antibodies (obinutuzu- small number of death events in the antibody arms (45 of 333 mab or rituximab) to frontline chemotherapy is life prolonging patients died in the G-Clb arm and 63 of 330 patients died in the and thus could change the course of CLL in elderly patients is R-Clb arm.) However, the previously observed OS benefitofG-Clb consistent with OS results obtained from chemoimmunotherapy studies in younger patients.8,9 A recently published trial compar- over Clb monotherapy was confirmed (HR 0.47, 95% CI 0.29–0.76, ing ofatumumab plus Clb with Clb alone as frontline treatment of P = 0.0014; of the patients randomized over the same period, 37 of elderly patients has not yet reported a statistically significant OS 238 and 34 of 118 died in the G-Clb and Clb arms, respectively). benefit for chemoimmunotherapy,10 which possibly could arise R-Clb treatment also prolonged OS compared with treatment with with longer patient follow-up in the future, however. On the basis Clb alone (HR 0.60, 95% CI 0.38–0.94, P = 0.0242; of the patients of the growing evidence, chemoimmunotherapy with anti-CD20 randomized over the same period, 44 of 233 and 34 of 118 patients antibody therefore should be considered a current standard of died in the R-Clb and Clb arms, respectively). Of note, OS was longer care across patients in all age groups, with previously untreated with G-Clb or R-Clb compared with Clb monotherapy although CLL requiring therapy. Although benefits from using anti-CD20

© 2015 Macmillan Publishers Limited Leukemia (2015) 1600 – 1618 Letters to the Editor 1604 2Oncology Practice, Würzburg, Germany; Table 1. Next-line therapies received by patients initially treated with 3Department of Hematology, Centre Henri Becquerel, Rouen, France; G-Clb, R-Clb or Clb 4Department of Hematology, Hospital Virgen de la Salud, Initial study treatment Toledo, Spain; 5Department of Hematology and Oncology, Ospedale Niguarda Ca’ G-Clb R-Clb Clb Granda, Milan, Italy; 6Department of Hematology, University Hospital of Wales, Patients per treatment arm (N, %) 333 (100) 330 (100) 118 (100) Cardiff, UK; Patients with at least one new treatment 76 (23) 117 (35) 70 (59) 7F. Hoffmann-La Roche Ltd, Basel, Switzerland; (n, %) 8F. Hoffmann-La Roche Ltd, Welwyn, UK and 9 Types of administered new treatments (n, %)a Cluster of Excellence ‘Cellular Stress Responses in Aging Associated FC or F 3 (1) 8 (2) 4 (3) Diseases’ (CECAD), University of Cologne, Cologne, Germany FC or F+rituximab 14 (4) 20 (6) 7 (6) E-mail: [email protected] FC or F+ofatumumab 0 (0) 2 (1) 0 (0) FC or F+obinutuzumab 0 (0) 0 (0) 0 (0) B 10 (3) 6 (2) 3 (3) B+rituximab 17 (5) 33 (10) 18 (15) B+ofatumumab 0 (0) 0 (0) 0 (0) B+obinutuzumab 2 (1) 1 (o1) 0 (0) REFERENCES Clb 13 (4) 12 (4) 7 (6) 1 Patz M, Isaeva P, Forcob N, Muller B, Frenzel LP, Wendtner CM et al. Clb+rituximab 2 (1) 0 (0) 2 (2) Comparison of the in vitro effects of the anti-CD20 antibodies rituximab and Clb+ofatumumab 0 (0) 0 (0) 0 (0) GA101 on chronic lymphocytic leukaemia cells. Br J Haematol 2011; 152: Clb+obinutuzumab 0 (0) 0 (0) 30 (25) – CHOP(-like) 0 (0) 3 (1) 0 (0) 295 306. CHOP(-like)+rituximab 4 (1) 3 (1) 2 (2) 2 Mossner E, Brunker P, Moser S, Puntener U, Schmidt C, Herter S et al. Increasing COP(-like) 0 (0) 3 (1) 2 (2) the efficacy of CD20 antibody therapy through the engineering of a new type II COP(-like)+rituximab 0 (0) 6 (2) 3 (3) anti-CD20 antibody with enhanced direct and immune effector cell-mediated Rituximab without chemo 8 (2) 6 (2) 0 (0) B-cell cytotoxicity. Blood 2010; 115: 4393–4402. o Ofatumumab without chemo 1 ( 1) 4 (1) 0 (0) 3 Herter S, Herting F, Mundigl O, Waldhauer I, Weinzierl T, Fauti T et al. Preclinical Obinutuzumab without chemo 0 (0) 0 (0) 0 (0) Alemtuzumab without or with chemo 2 (1) 6 (2) 1 (1) activity of the type II CD20 antibody GA101 (obinutuzumab) compared with Experimentalb 4 (1) 12 (4) 1 (1) rituximab and ofatumumab in vitro and in xenograft models. Mol Cancer Ther Other 3 (1) 7 (2) 3 (3) 2013; 12: 2031–2042. 4 Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM et al. Abbreviations: B, bendamustine; C, cyclophosphamide; Clb, chlorambucil; Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. fl F, udarabine; G-Clb, obinutuzumab plus chlorambucil; H, adriamycin; O, N Engl J Med 2014; 370: 1101–1110. vincristine; P, prednisolone; R-Clb, rituximab plus chlorambucil. aIncludes 5 Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H et al. new treatment received after initial study therapy plus any new treatment Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a received after first next-line therapy. Multiple treatments of the same report from the International Workshop on Chronic Lymphocytic Leukemia category are counted once per patient. bIncludes treatments containing updating the National Cancer Institute-Working Group 1996 guidelines. Blood lenalidomide, ibrutinib, idelalisib or other experimental compounds. 2008; 111: 5446–5456. 6 Parmelee PA, Thuras PD, Katz IR, Lawton MP. Validation of the Cumulative Illness 43 – antibodies in combination with novel targeted drugs need to be Rating Scale in a geriatric residential population. J Am Geriatr Soc 1995; : 130 137. 11–14 7 Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. further studied, the presented results indicate that the efforts Nephron 1976; 16:31–41. to optimize CD20 targeting by use of novel or engineered anti- 8 Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J et al. Addition CD20 antibodies could have great potential in CLL. In our trial, of rituximab to fludarabine and cyclophosphamide in patients with chronic median PFS was nearly doubled and extended to almost lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 2010; 376: 30 months by adding obinutuzumab instead of rituximab to Clb. 1164–1174. Efficacy of this regimen compares well with that of other frontline 9 Tam CS, O'Brien S, Wierda W, Kantarjian H, Wen S, Do KA et al. Long-term results treatments currently offered to elderly patients with CLL. Ongoing of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of patient follow-up and future analyses of OS will reveal whether chronic lymphocytic leukemia. Blood 2008; 112: 975–980. obinutuzumab produces OS advantage over rituximab in this 10 Hillmen P, Robak T, Janssens A, Govindbabu K, Grosicki S, Mayer J et al. treatment setting. Ofatumumab+chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). Blood 2013; 122: 528. CONFLICT OF INTEREST 11 Burger JA, Keating MJ, Wierda WG, Hartmann E, Hoellenriegel J, Rosin NY et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic VG, MM, CF and MH received honoraria from Roche. VG, KF and MH received research lymphocytic leukaemia: a single-arm, phase 2 study. Lancet Oncol 2014; 15: funding from Roche. AE received travel grants from Roche. VG, SL, MM, CF and MH – declared consultancy or board membership for Roche. EA, KH and GF are paid 1090 1099. employees and stockholders of Roche. The other authors declare no conflict of 12 Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM et al. Ibrutinib interest. versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014; 371:213–223. 1 1 1 2 3 13 Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P et al. Idelalisib V Goede , K Fischer , A Engelke , R Schlag , S Lepretre , 370 4 5 6 7 8 and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; : LFC Montero , M Montillo , C Fegan , E Asikanius , K Humphrey , 997–1007. 7 1,9 G Fingerle-Rowson and M Hallek 14 O'Brien S, Furman RR, Coutre SE, Sharman JP, Burger JA, Blum KA et al. Ibrutinib as 1 German CLL Study Group (GCLLSG), Department I of Internal initial therapy for elderly patients with chronic lymphocytic leukaemia or small Medicine, Center of Integrated Oncology Cologne-Bonn, University of lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol Cologne, Cologne, Germany; 2014; 15:48–58.

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