Impact of Age on Efficacy and Toxicity of Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP): ENEST1st Sub-Analysis Abstract 479 Giles FJ, Rea D, Baccarani M, Cross NCP, Steegmann JL, Griskevicius L, le Coutre P, Coriu D, Petrov L, Ossenkoppele GJ, Mahon F-X, Müller MC, Hellmann A, Porkka K, Brümmendorf TH, Gastl G, Pellegrino A, Dezzani L, Rosti G, Hochhaus A for the ENEST1st investigators
Introduction Tyrosine kinase inhibitors (TKIs) are the standard of care for the treatment of patients with chronic myeloid leukemia (CML) and substantially improve the life expectancy of patients with early phase disease 1-5 Unlike all prior therapies, imatinib efficacy in chronic phase CML unaffected by age. Age not a component of the EUTOS score 1-5 The ENEST1st (NCT01061177) study was conducted to further examine the efficacy and toxicity of nilotinib in newly diagnosed CML-CP patients 6 An ENEST1st sub-analysis was conducted to assess the impact of age on molecular response (MR) and adverse events (AEs) 1. Cortes J, et al. Cancer. 2003;98:1105 1113. 2. Gugliotta G, et al. Blood. 2011;117:5591-5599. 3. Hasford J, et al. Blood. 2011; 118:686-692. 4. Latagliata R, et al. Drugs Aging. 2013;30:629-37. 5. Sauselle S, et al. Blood. 2015;126:42-49. 6. Hochhaus A, et al. Leukemia. 2015. [Epub ahead of print]
ENEST1st Study Design ENROLL Nilotinib 300 mg BID N = 1089 Nilotinib 300 mg BID Key eligibility criteria: Adults with newly diagnosed CML-CP 3 months prior imatinib and/or 6 months prior hydroxyurea allowed Ph+ or Ph BCR-ABL1+ CML-CP a MR 4 was defined as detectable BCR-ABL1 IS 0.01% or undetectable BCR-ABL1 in cdna with 10,000 ABL1 transcripts. 18 months 6 months Primary endpoint: MR 4 at 18 months a Key exclusion criteria: WHO PS>2 Known impaired cardiac function History of acute or chronic pancreatitis Uncontrolled medical conditions like diabetes, active or uncontrolled infections, acute or chronic liver and renal disease Impaired gastrointestinal function
ENEST1st: Methods Patients were enrolled from 307 sites in 26 European countries All 1089 treated patients were included in the sub-analysis For this subanalysis, patients were stratified according to age at the time of study entry: Young patients (18 to 39 years) n = 243 (22%) Adult patients (40 to 59 years) n = 494 (45%) Elderly patients (60 to 74 years) n = 300 (27%) Very elderly patients ( 75 years) n = 52 (5%) Molecular responses were assessed every 3 months using RQ- PCR in standardized EUTOS laboratories OS and freedom from progression to AP/BP were estimated using Kaplan-Meier product limit estimates according to ITT principles Testing for glucose, cholesterol, and lipids was not routinely performed as it was not specified in the study protocol
ENEST1st: Map of Participating Countries and Network of EUTOS MR 4 Laboratories (N = 1089 Patients Treated and Monitored) Portugal 11 Patients treated (n) Participating EUTOS laboratories 13 Spain 100 4 UK 28 8 France 150 9 BE 30 NL 28 DE 14 Norway 12 Sweden 33 Germany Poland 258 66 3 2 1 11 12 CZ 16 SK 10 10 AU 17 Hungary CH 5 35 7 5 Italy 154 SV 3 CR 4 6 Finland 4 Latvia 3 Lithuania 15 Romania 61 14 14. Bucharest, Romania: Daniel Coriu, Rodica Talmaci AU, Austria; Giles BE, FJ, Belgium; et al. CH, Blood. Switzerland; 2015;126: CR, Croatia; Abstract CZ, 479. Czech Republic; DE, Denmark; ES, Estonia; GR, Greece; NL, The Netherlands; SK, Slovakia; SV, Slovenia. ES 1 GR 10 Bulgaria 21 EUTOS Laboratories and Contacts 1. Mannheim, Germany: Martin Müller 2. Leipzig, Germany: Thoralf Lange 3. Jena, Germany: Janine Ziermann, Andreas Hochhaus 4. Bordeaux, France: François-Xavier Mahon 5. Bologna, Italy: Michele Baccarani, Gianantonio Rosti 6. Naples, Italy: Fabrizio Pane 7. Turin, Italy: Giuseppe Saglio, Enrico Gottardi 8. London, UK: Letizia Foroni 9. Barcelona, Spain: Dolores Colomer 10. Vienna, Austria: Thomas Lion 11. Prague, Czech Republic: Katerina Polakova Machova 12. Krakow, Poland: Tomasz Sacha 13. Bern, Switzerland: Elisabeth Opplinger-Leibundgut
ENEST1st: Patients / Assessment Populations Screened (n = 1164) Enrolled (n = 1091) Screening failure (n = 73) ITT/safety population (N = 1089) Reason for exclusion: Did not receive 1 dose of study drug (n = 2) Molecular analysis population (n = 1052) Reason for exclusion: Typical BCR-ABL1 transcripts not detected at baseline (n = 33)* Received > 3 mo imatinib therapy prior to enrollment (protocol violation; n = 4) Young Patients (n = 243) Adult Patients (n = 494) Elderly Patients (n = 300) Very Elderly Patients (n = 52) Patients not in the molecular analysis population were distributed in the age groups as follow 9 pts in young: 18 to 39 years 10 pts in adults: 40 to 59 years old 10 pts in elderly: 60 to 74 years old ITT, intent-to-treat 4 pts in very elderly: 75 or more years old
ENEST1st: Demographics / Baseline Characteristics ITT population (N = 1089) Median age (range), years 53 (18-91) Median time since diagnosis (range), mo 0.9 (< 0.1-6.6) a Prior treatment for CML, n (%) 766 (70.3) Imatinib (< 3 months) 188 (17.3) Hydroxyurea (< 6 months) 576 (52.9) Other 2 (0.2) Median prior treatment duration (range), mo 0.9 (0.1-7.6) a EUTOS risk, n (%) Low 900 (82.6) High 94 (8.6) Missing 95 (8.7) Sokal risk, n (%) Low 377 (34.6) Intermediate 408 (37.5) High 197 (18.1) Missing 107 (9.8) BCR-ABL1 transcript type, n (%) b2a2 and/or b3a2 1056 (97.0) Other b 16 (1.5) Inadequate sample, not evaluated, or not reported 17 (1.6) a One patient was pretreated with hydroxyurea while awaiting confirmation of CML diagnosis and, therefore, had a longer prior treatment duration than time since diagnosis. Four patients with > 3 mo of prior exposure to imatinib were excluded. b Including e1a2, e19a2, e14a3, e18a2, e8a2, and e13a3.
ENEST1st: Demographics/Baseline Characteristics Young (n = 243) a One patient was pretreated with hydroxyurea while awaiting confirmation of CML diagnosis and, therefore, had a longer prior treatment duration than time since diagnosis. Four patients with > 3 mo of prior exposure to imatinib were excluded. Adults (n = 494) Figure: EUTOS score at baseline Low High Missing Elderly (n = 300) Very elderly (n = 52) Median age (range), years 32.0 (18.0, 39.0) 50.0 (40.0, 59.0) 66.0 (60.0, 74.0) 78.0 (75.0, 91.0) Median time since diagnosis (range), months a 0.84 (0.07, 5.86) 0.92 (0.07, 6.61) 0.92 (0.03, 6.41) 0.86 (0.07, 6.02) Mean (SD) spleen size 5.0 (6.2) 3.22 (4.9) 1.49 (2.8) 1.5 (3.1) Proportion of patients (%) 100 90 80 70 60 50 40 30 20 10 0 78.2 83.4 84 88.5 12.8 9.1 7.9 8.7 7.3 8.7 7.7 3.8 Young (n = 243) Adults (n = 494) Elderly (n = 300) Very elderly (n = 52)
ENEST1st: Patient Disposition / Treatment Exposure Patients, n (%) Safety population (N = 1089) Completed 24 mo of treatment 881 (80.9) Discontinued treatment a 208 (19.1) AEs 117 (10.7) Withdrew consent b 27 (2.5) Disease progression/treatment failure 17 (1.6) Abnormal laboratory value 6 (0.6) Other c 41 (3.8) Median duration of exposure (25th-75th percentile), days d 722 (691-734) Median dose intensity (25th-75th percentile), mg/day 600 (588-600) a Reasons for discontinuation are listed as reported by the investigator. b Withdrawal of consent was due to treatment failure in 2 (1.8%) patients. c Includes discontinuations due to protocol deviation (n = 11), loss to follow-up (n = 9), new cancer therapy (n = 9; CML [n = 7], and endometrial cancer and non-hodgkin lymphoma [n = 1 each]), administrative problems (n = 4), abnormal test procedure results (n = 4), and death (n = 4). d Excluding periods of drug interruption.
ENEST1st: Treatment Exposure by Age Group 18 1 dose reduction 2 dose reductions >2 dose reductions 16 15.4 15.3 Proportion of patients (%) 14 12 10 8 6 4 13.2 9.9 6.2 6.1 8.1 8 6.7 11.5 9.6 5.8 2 0 Young (n = 243) Adults (n = 494) Elderly (n = 300) Very Elderly (n = 52)
ENEST1st: Rates of MMR, MR4, and MR4.5 at 3, 12, 18, and 24 Months Patients, % a 29.7 MMR MR 4 MR 4.5 56.3 30.8 15.3 65.8 38.4 20.9 Primary endpoint 61.2 40.4 22.0 6.3 1.9 At 3 mo At 12 mo At 18 mo At 24 mo MMR, major molecular response (BCR-ABL1 IS 0.1%); MR 4.5, detectable BCR-ABL1 IS 0.0032% or undetectable BCR-ABL1 in cdna with 32,000 ABL1 transcripts. a Molecular analysis population (n = 1052)
ENEST1st: Cumulative Incidence of MMR, MR4, and MR4.5 Cumulative Incidence of Response, % a 100 90 80 70 60 50 40 30 20 10 0 a Molecular analysis population (n = 1052). By 12 mo By 18 mo By 24 mo 68.9% 37.1% 20.7% 77.2% 48.7% 31.7% 80.4% 55.2% 38.6% 0 3 6 9 12 15 18 21 24 Time Since Study Entry, mo MMR MR 4 MR 4.5
ENEST1st: Cumulative Rates of MR4 by 6, 12, 18, and 24 Months by Age Group 100.0 Young (n = 233) Adults (n = 482) Elderly (n = 289) Very elderly (n = 48) 90.0 Proportion of patients (%) 80.0 70.0 60.0 50.0 40.0 30.0 20.0 12.4 16.2 15.9 12.5 28.8 39.2 39.8 39.6 42.1 49.8 52.9 43.8 50.2 57.1 57.4 47.9 10.0 0.0 6 months 12 months 18 months 24 months Time Since Study Entry
ENEST1st: Cumulative Rates of MR4.5 by 6, 12, 18, and 24 Months by Age Group 100.0 Young (n = 233) Adults (n = 482) Elderly (n = 289) Very elderly (n = 48) 90.0 Proportion of patients (%) 80.0 70.0 60.0 50.0 40.0 30.0 20.0 25.0 21.8 22.1 15.9 33.2 32.9 31.3 27.5 39.4 39.8 37.5 35.6 10.0 0.0 5.2 6.2 6.9 2.1 6 months 12 months 18 months 24 months Time Since Study Entry
ENEST1st: Landmark Analysis: Cumulative Incidence of MR4 by BCR-ABL1 IS Levels at 3 Months (n = 783) 100 By 12 mo By 18 mo By 24 mo Cumulative Incidence of MR 4, % 90 80 70 60 50 40 30 20 10 0 0 3 6 9 12 15 18 21 24 Time Since Study Entry, mo 67.6% 59.0% 47.0% 20.0% 24.1% 8.3% 0% 0% 0% BCR-ABL1 IS 1% at 3 mo (n = 615) BCR-ABL1 IS > 1% to 10% at 3 mo (n = 145) BCR-ABL1 IS > 10% at 3 mo (n = 23)
Cumulative Incidence of MR 4.5, % ENEST1st Landmark Analysis: Cumulative Incidence of MR4.5 by BCR-ABL1 IS Levels at 3 Months By 12 mo By 18 mo By 24 mo 100 BCR-ABL1 IS 1% at 90 3 mo (n = 615) 80 BCR-ABL1 IS > 1% to 10% at 3 mo 70 60 50 47.0% (n = 145) BCR-ABL1 IS > 10% at 3 mo (n = 23) 40 39.5% 30 26.5% 20 14.5% 10 9.0% 4.1% 0% 0% 0% 0 0 3 6 9 12 15 18 21 24 Time Since Study Entry, mo
40 ENEST1st: Most Frequent Adverse Events by Age Group a Young (n=243) Adults (n=494) Elderly (n=300) Very Elderly (n=52) Proportion of patients (%) 30 20 10 0 24.9 21.4 21 17.3 17.4 11.5 8.3 7.7 14.8 14.8 10.3 8.9 9.3 3.8 9.3 5.8 18.3 16.8 17.3 15 15 15.4 13.6 13.6 15.4 12.8 13.7 5.8 13.5 11.1 11.9 10.7 10.3 10.3 9.9 10.5 6.3 7.3 8 5.7 3 3.8 3.8 1.9 a AEs reported in 10% of patients at any grade in any group ALT, alanine aminotransferase
ENEST1st: Adverse Events by Age Group Young (n=243) Adults (n=494) Elderly (n=300) Very Elderly (n=52) Proportion of patients (%) 16 14 12 10 8 6 4 2 0 14.3 11.5 11.5 10.5 5 4.3 3.7 3.8 2.1 1.6 1.2 1.3 1.7 0.8 0 0 0.8 1 0.2 0 13.5 10 5.3 0.8 7.7 7.7 4.5 4.3 1.9 0.8 0.4 1.7 0.7 0 0.4 0.4
ENEST1st: Cardiovascular Adverse Events by Age Group Young (n = 243) Adults (n = 494) Elderly (n = 300) Very elderly (n = 52) P value by Fisher's Exact Test* Cardiovascular events 2 (0.8%) 26 (5.3%) 30 (10%) 7 (13.5%) <.0001 Ischemic heart disease (IHD) Peripheral arterial occlusive disease 1 (0.4%) 14 (2.8%) 17 (5.7%) 5 (9.6%).0002 1 (0.4%) 9 (1.8%) 9 (3.0%) 1 (1.9%).12 Ischemic cerebrovascular event 0 4 (0.8%) 4 (1.3%) 1 (1.9%).19 Overall test is significant at P <.05 *P values provided are nominal, post hoc, and provided for descriptive purpose only; no multiplicity adjustments were made
ENEST1st: Progression and Survival KM-estimated rate at 24 mo, % (95% CI) ITT population (N = 1089) Freedom from progression to AP/BP a 99.4 (98.7-99.7) Overall survival 98.9 (98.0-99.4) 6 patients (0.6%) (2 in young patient group and 4 in adult patient group) progressed to AP/BP on study 13 patients (1.2%) died on study (5 in adult patients group, 5 in elderly patients group and 3 in very elderly patients group) 1 patient died of CML b 12 patients died due to other causes, including infections (n = 4), secondary cancers (n = 3), heart failure (n = 2), and one each due to pulmonary embolism, cerebral infarction, and thrombocytopenia considered not due to CML KM, Kaplan-Meier. a Freedom from progression to AP/BC considered only transformation events (deaths unrelated to CML were excluded). b Laboratory data to confirm progression to AP/BP not provided by the investigator.
ENEST1st Sub-Analysis on Age Effect Conclusions According to the EUTOS score, high-risk CML more frequent among younger patients Molecular response rates and rates of progression to AP/BP were comparable across age groups The distribution of some AEs was significantly different depending on age Understanding of variations in disease characteristics and TKI AE profiles in terms of patient age may help in improving CML therapy