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A Multi-Centre Phase 2 Study of Azacitidine in Chronic Myelomonocytic Leukaemia

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A Multi-Centre Phase 2 Study of Azacitidine in Chronic Myelomonocytic Leukaemia Letters to the Editor 1570 1 1 1 1 1 A Tefferi , TL Lasho , C Finke , AA Belachew , EA Wassie , 4 Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR 2 3 1 RP Ketterling , CA Hanson and A Pardanani mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 1 Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2013; 369: 2391–2405. 2Division of Cytogenetics, Mayo Clinic, Rochester, MN, USA and 5 Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD et al. JAK2 3Division of Hematopathology, Mayo Clinic, Rochester, MN, USA or CALR mutation status defines subtypes of essential thrombocythemia with E-mail: [email protected] substantially different clinical course and outcomes. Blood 2013; e-pub ahead of print 23 December 2013. 6 Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869. 7 Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S et al. DIPSS plus: REFERENCES a refined Dynamic International Prognostic Scoring System for primary myelofi- 1 Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH et al. CALR vs brosis that incorporates prognostic information from karyotype, platelet count, and JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and transfusion status. J Clin Oncol 2011; 29: 392–397. molecular comparisons. Leukemia 2014; 28: 1472–1477. 8 Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E et al. 2 Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, Pieri L et al. New prognostic scoring system for primary myelofibrosis based on a study of the Impact of calreticulin mutations on clinical and hematological phenotype International Working Group for Myelofibrosis Research and Treatment. Blood and outcome in essential thrombocythemia. Blood 2013; e-pub ahead of print 2009; 113: 2895–2901. 26 December 2013. 9 Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A et al. 3 Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114: 2013; 369: 2379–2390. 937–951. Supplementary Information accompanies this paper on the Leukemia website (http://www.nature.com/leu) A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia Leukemia (2014) 28, 1570–1572; doi:10.1038/leu.2014.85 effusions). Of 74 patients pre-screened for eligibility, 32 were registered for trial entry (see CONSORT Flow Diagram, 2 Therapeutic options for chronic myelomonocytic leukaemia Supplementary Figure 1). AZA was administered (75 mg/m for (CMML) remain limited. Azacitidine (AZA) is approved for CMML-2 7 days, 5-2-2 schedule) every 28 days, for a minimum of six cycles. lacking proliferative features (white cell count (WCC) o13 Â 109/l); Responders and patients with stable disease were allowed to however, AZA registration studies for myelodysplasia (MDS) continue therapy until loss of response/progressive disease or contained small numbers of CMML patients (n ¼ 30), preventing development of unacceptable toxicities. Assessment of spleen size definitive conclusions with regards to toxicity and efficacy.1,2 was by clinical examination. Toxicities were determined as per Published retrospective case series of AZA therapy for CMML National Cancer Institute-Common Toxicity Criteria (Version 3.0). document overall response rates (ORR) and complete remission Patients remained on follow-up until 12 months after the last (CR) rates of 39–60% and 11–40%, respectively,3–5 according to patient’s last dose of treatment (median follow-up 12.8 months, International Working Group (IWG) 2006 criteria.6 On behalf of the range 0.6–30.3). UK National Cancer Research Network (UKNCRN) MDS Trial ORR was defined (by central review) as the sum of clinical Subgroup, we conducted a multi-centre phase 2 trial of AZA in remission, good response and minor response determined accord- 8 CMML patients with features of advanced disease, incorporating ing to Wattel et al. (Supplementary Table 1), at day 28 of the sixth mutation analysis and methylation status. or last cycle of AZA (whichever occurred first). These response Between January and August 2010, 32 patients with newly criteria incorporate assessment of proliferative disease, including diagnosed or previously treated CMML7 (hydroxycarbamide and/or leukocytosis, extramedullary involvement and spleen size. Patients supportive care only) were enroled after written informed consent. who received o1 cycle were not considered evaluable. þ Safety and tolerability, and ORR (as defined by Wattel et al.8) were Mutations were analysed (using DNA from CD14 marrow co-primary end points. Secondary end points included response mononuclear cells) in TET2, ASXL1, EZH2, CBL and NRAS by high- according to modified IWG criteria (incidence of CR, partial resolution melt and/or direct sequence analysis (n ¼ 21) as 9–11 remission and haematological improvement),6 overall and previously described. Global levels of DNA methylation were progression-free survival (OS, PFS), time to transformation or determined for eight patients analysed at baseline and post death and biological correlates (mutation analysis of TET2, ASXL1, course six using Illumina Infinium human 454 BeadChip oligo EZH2, CBL and NRAS genes, and gene methylation status). The trial arrays, which determine the % DNA methylation at 450 000 was approved by the UK National Research Ethics Service (EudraCT individual CG sequences. Analyses were performed by Gen-Probe 2008-006349-23 and ISRCTN 21428905). Inclusion criteria were: Life Sciences (Manchester, UK). OS, PFS, time to acute (1) CMML-2 and (2) CMML-1 patients with symptomatic marrow myelogenous leukemia (AML) transformation and death, and failure or proliferative disease, intermediate or high Dusseldorf duration of response were based on available data on 21st score (for WCC 412 Â 109/l) or int-2 or high IPSS score (for WCC January 2013. OS was defined as the time from registration to o12 Â 109/l), and/or symptomatic splenomegaly or systemic death from any cause or last follow-up. Patients discontinuing symptoms (including weight loss of 10% from baseline over the protocol treatment were still followed for OS. Analyses were previous 6 months with no other explanation) or symptomatic carried out using SAS version 9.2 (SAS Institute Inc., Cary, NC, USA). extramedullary disease (including skin infiltration and serous Baseline characteristics are summarized in Table 1. Accepted article preview online 26 February 2014; advance online publication, 18 March 2014 Leukemia (2014) 1543 – 1572 & 2014 Macmillan Publishers Limited Letters to the Editor 1571 Table 1. Baseline patient characteristics Table 2. Response to treatment as determined by the criteria of Wattel et al. (2A) or the IWG (2B) Characteristic (n ¼ 30) Value Total, n ¼ 30 (%) Median age (range) 70 years (57–85) Sex, M/F, n (%) 20 (67)/10 (33) (A) Response according to Wattel et al. Prior hydroxycarbamide, n (%) Yes: 13 (43.3), no: 17 (56.7) CLR 1 (3%) CMML-1 or -2a, n (%) 21/30 (70%), 8/30 (27%) GR 2 (7%) WHO performance status, n (%) 0–8 (26%) MR 10 (33%) 1–16 (53%) Stable disease 2 (7%) 2–6 (20%) Progression 11 (37%) Extramedullary diseaseb, n (%) 5 (17%) Not evaluable (died before completion of last cycle) 2 (7%)a c Splenomegaly , n (%) 14 (47%) Not evaluable (o1 cycle) 2 (7%) Abnormal karyotype, n (%) 5 (17%) ORR 43% (25%, 63%) Median Hb, g/dl (range) 10.1 (6.6–14.3) Median WCC, Â 109/l (range) 15.9 (5.0–124.7) (B) Response using IWG criteria Median plt count, Â 109/l (range) 43 (15–462) CR 2 (7%) Median blood monocytesd, Â 109/l (range) 2.7 (0.3–21.9) PR 0 (0%) Median blood neutrophils, Â 109/l (range) 7.9 (1.2–71.7) Marrow CR 2 (7%) Median marrow blasts, % (range) 4.5 (0–15) Marrow CR, HI-P 1 (3%) Red cell transfusion dependent, n (%) 17 (57%) Stable disease 5 (17%) Median red cell units transfused, n (range)e 6 (0–34) Fail 8 (27%)a Plt transfusion dependent, n (%) 5a (17%) Progressive disease 9 (30%) Median plt units transfused, n (range)e 3 (1–15) HI-E, HI-P 1 (3%) TET2, n mutated/n evaluable (%) 17/27 (63) Not evaluable (o1 cycle) 2 (7%) ASXL1, n mutated/n evaluable (%) 8/21 (38) Incidence of CR/PR 7% (0.8–22) EZH2, n mutated/n evaluable (%) 1/25 (4) CBL, n mutated/n evaluable (%) 2/26 (8) Abbreviations: CR, complete remission; CLR, clinical remission; E, erythroid; NRAS, n mutated/n evaluable (%) 1/21 (5) GR, good response; HI, haematological improvement; IWG, international working group; MR, minor response; ORR, overall response rate; P, platelets; Abbreviations: CMML, chronic myelomonocytic leukaemia; F, female; PR, partial remission. (A) Response to azacitidine (AZA) according to the Hb, haemoglobin; M, male; Plt, platelets; WCC, white cell count. Overall 32 criteria of Wattel et al.8 (see Supplementary Table 1 for definitions). patients were registered for the study. Two patients received no treatment B: response to AZA according to modified IWG 2006 criteria.6 Response at and were not included in the final analysis (one was found to be in day 28 of the sixth or last cycle of AZA is shown. ORR for Wattel et al. criteria transformation to acute myelogenous leukemia before therapy and another is calculated from the combination of CLR, GR and MR (brackets represent had an unexpected rise in creatinine precluding treatment). Median time 95% confidence interval). The majority of MR represented leucoreduction from diagnosis to trial entry was 6.7 months.
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