Apperley, JF

Baccarani, M

Chuah, C

Cortes, JE

Deininger, MW

Guilhot, F

Haluska, FG

Hochhaus, A

Hughes, TP

Kantarjian, HM

Khoury, HJ

Le Coutre, PD

Lustgarten, S

Nicolini, FE

Paquette, R

Pinilla-Ibarz, J

Shah, NP

Talpaz, M

Haematologica

Spiral - Imperial College Digital Repository

and Common Terminology Criteria for Adverse Events (CTCAE) liver-relatedlaboratory tests and categories. Those with grade ≥3 ALT/AST elevation wereevaluated for rate of resolution to grade ≤1 ALT/AST, and recurrence of theevent at any time on study. Patients were grouped by use of IDELA alone oras part of a combination regimen.Results: Among patients with any disease type or regimen (N=1073), the inci-dence of any grade ALT/AST elevation was 51%, and the incidence of grade≥3 ALT/AST elevation was 14% (Table). Of patients with transaminase eleva-tion, 73% (398/543) experienced grade 1 or grade 2 events. The incidences ofgrade ≥3 ALT/AST elevations, and outcomes for patients with grade ≥3ALT/AST elevation (Table) were comparable whether IDELA was used aloneor in combination. 92% of patients with grade ≥3 ALT/AST elevation were man-aged with dose interruption and achieved resolution to grade ≤1. The majority(69%) of patients with subsequent IDELA rechallenge experienced no recur-rence of the event; of events that did recur, the vast majority (94%) resolved inthe analysis time period.Summary/Conclusions: These data support the management of ALT/ASTelevation with IDELA using dose interruption at grade 3 with reintroductionafter resolution at the discretion of the treating physician. Studies Included inthis Analysis: 101-02: NCT00710528; 101-07: NCT01088048; 101-08:NCT01203930; 101-09: NCT01282424; 101-10: NCT01306643; 101-11:NCT01393106; 101-99 (extension): NCT01090414; GS-US-312-0116:NCT01539512; GS-US-312-0117 (extension): NCT01539291; GS-US-312-0119: NCT01659021Chronic myeloid leukemia - Clinical 1P227DE-ESCALATION OF TYROSINE KINASE INHIBITOR THERAPY IS SAFEIN CHRONIC MYELOID LEUKAEMIA IN DURABLE MOLECULARRESPONSE (≥ MR3 FOR ≥12 MONTHS): INITIAL RESULTS IN THE BRITISHDESTINY STUDYR Clark1,*, F Polydoros2, J Apperley3, C Pocock4, G Smith5, R Salim6,T Coffey2, S O’Brien7, L Foroni3, M Copland81Haematology/MCCM, 2Liverpool Clinical Trials Unit, University of Liverpool,Liverpool, 3Haematology, Hammersmith Hospital, London, 4Haematology, Kent& Canterbury Hospital, Canterbury, 5Clinical Haematology, St James UniversityHospital, Leeds, 6Haematology, Royal Liverpool University Hospital, Liverpool,7Northern Institute for Cancer Research, University of Newcastle, Newcastle,8Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow,United KingdomBackground: Some chronic myeloid leukaemia (CML) patients with prolongedand deep molecular remissions on tyrosine kinase inhibitor (TKI) therapy candiscontinue treatment. However, study of this has been restricted to patientsin stable MR4 (BCR-ABL1<0.01%), and it is not known whether some patientsin stable major molecular response (MR3; BCR-ABL<0.1%) but not MR4 candiscontinue treatment. In addition, it is plausible that while some patients mightnot be able to completely discontinue TKI therapy, they may be able to maintaingood molecular remissions on TKI doses that are less than standard, with con-current improvement in any TKI-related adverse events; this has not been pre-viously investigated.Aims: The British DESTINY study is examining the safety and efficacy of ini-tially de-escalating therapy to half the standard TKI dose (i.e. imatinib 200mgdaily, nilotinib 200mg twice daily, or dasatinib 50mg daily) for 12 months, thenstopping altogether.Methods: Entrants must be in stable MR3 or better, on all PCR results (mini-mum of 3) in the preceding 12 months, and must have received TKI for at least3 years, and not switched TKI (except that a single switch was permitted ifsolely due to intolerance). The primary endpoint is loss of MR3; monthly molec-ular monitoring is carried out centrally.Results: During 16 months recruitment to April 2015, 174 patients (male 98;female 76) were recruited after giving informed consent by 20 sites. At entry,125 (72%) were in MR4 and 49 (28%) in MR3 but not MR4; 148 were receivingimatinib, 16 on nilotinib and 10 on dasatinib. During 12 months of de-escalationin the first 100 patients, no deaths, disease progressions or losses of cytoge-netic response have been seen, though 7 serious adverse events haveoccurred (6 Grade 3+), all unrelated to TKI. Thirteen patients reported 14 newevents of musculoskeletal disorders since decreasing TKI therapy (all Grade1), comprising pain, stiffness or cramps in the joints, legs, chest, neck and/orback (13) with one additional event of arthritis. Individual side effects (lethargy,diarrhoea, rash, nausea, periorbital oedema, hair thinning) all improve in thefirst 1-2 months of de-escalation but not significantly thereafter, though theFACT-BRM or EQ-5D Quality of Life data are already optimal at trial entry, sug-gesting that TKI side effects in entrants do not impact Quality of Life. Duringthe de-escalation phase in the first 100 patients there have been 7 molecularrelapses (defined as loss of MR3 on 2 consecutive samples), occurring duringthe second (1 case), third (2), seventh (1) and eighth (3) month of de-escalation.Four of these were in the 31 patients in MR3 but not MR4 at trial entry, givinga relapse rate of 12.9%; similarly 3 of 69 patients (4.3%) relapsed in the ‘MR4at entry’ group. No relapses have occurred in the quartile with the shortestduration of prior TKI treatment (less than 4.8 years), while 3 of the 7 relapseshave occurred in the quartile with the longest pre-entry TKI treatment (>10.2years). All 7 patients have regained at least MR3 within 4 months of resumptionof standard dose TKI. Overall, 26 (84%) ‘MR3 but not MR4’ and 64 (93%) ‘MR4at entry’ patients have proceeded to the stopping phase.Summary/Conclusions: In this first DESTINY trial report focussed on de-escalation, halving the standard TKI dose for 12 months in CML patients in atleast MR3 appears safe, does not compromise disease control, and is associ-ated with a rapid improvement in side effects. Mild musculoskeletal symptomsmay occur in about 13% of patients.P228LONG-TERM EFFICACY AND SAFETY OF PONATINIB IN HEAVILYPRETREATED LEUKEMIA PATIENTS: 4-YEAR RESULTS FROM THEPIVOTAL PHASE 2 PACE TRIAL JE Cortes1,*, J Pinilla-Ibarz2, PD le Coutre3, R Paquette4, C Chuah5, FE Nicolini6,JF Apperley7, HJ Khoury8, M Talpaz9, M Baccarani10, S Lustgarten11,FG Haluska11, F Guilhot12, MW Deininger13, A Hochhaus14, TP Hughes15,NP Shah16, HM Kantarjian11The University of Texas MD Anderson Cancer Center, Houston, TX, 2H. LeeMoffitt Cancer Center & Research Institute, Tampa, FL, United States, 3CharitéUniversitätsmedizin Berlin, Berlin, Germany, 4Ronald Reagan UCLA Medical60 | haematologica | 2016; 101(s1)21st Congress of the European Hematology AssociationCenter, University of California, Los Angeles, CA, United States, 5SingaporeGeneral Hospital and Duke-National University of Singapore Graduate MedicalSchool, Singapore, Singapore, 6Centre Hospitalier Lyon Sud, Pierre Bénite,Lyon, France, 7Centre for Haematology, Imperial College, London, United King-dom, 8Winship Cancer Institute of Emory University, Atlanta, GA, 9Comprehen-sive Cancer Center, University of Michigan, Ann Arbor, MI, United States, 10S.Orsola-Malpighi University Hospital, Bologna, Italy, 11ARIAD Pharmaceuticals,Inc., Cambridge, MA, United States, 12Inserm CIC 1402, CHU de Poitiers,Poitiers, France, 13Huntsman Cancer Institute, University of Utah, Salt LakeCity, UT, United States, 14Jena University Hospital, Jena, Germany, 15Instituteof Medicine and Veterinary Science, Adelaide, Australia, 16University of Cali-fornia San Francisco, San Francisco, CA, United StatesBackground: The approved tyrosine kinase inhibitor (TKI) ponatinib is potentlyactive against native and resistant BCR-ABL, including T315I. Aims: The pivotal phase 2 PACE trial (NCT01207440) evaluated the efficacyand safety of ponatinib.Methods: Patients with chronic myeloid leukemia (CML) or Philadelphia-pos-itive acute lymphoblastic leukemia (Ph+ALL) refractory to dasatinib or nilotinib,or with T315I, were enrolled in PACE (starting dose 45 mg once daily). Allpatients gave informed consent. Dose reductions were recommended in Octo-ber 2013 due to observed arterial occlusive events (AOEs). Efficacy and safetyat 4 years, as well as by year for chronic phase (CP) CML patients are reported(data as of 3 August, 2015). Exposure-adjusted incidence rates of new AOEsare reported as the number of events/100 patient-years.Results: Of 449 patients, 59% received ≥3 prior TKIs. At analysis, 30%(133/449) of patients (median follow-up 37.3, range 0.1–58.5 months) and 41%(110/270) of CP-CML pts (48.2, 0.1–58.5 months) remained on study. Primaryreasons for discontinuation were disease progression (22.5% overall, 10.4%CP-CML) and adverse events (AEs) (16.0% overall, 18.5% CP-CML). Respons-es continued to deepen over time (Table 1, CP-CML patients) despite dosereductions. Among CP-CML patients, estimated 4-year rates for PFS, OS, andmaintenance of major cytogenetic response (MCyR) and major molecularresponse (MMR) were 56%, 77%, 82% and 61%, respectively. For acceleratedphase patients, the estimated 4-year OS was 51%; median OS for blastphase/Ph+ALL patients was 6.9 months (95% CI, 5.0-9.2). Common (in ≥30%of patients) treatment-emergent AEs were thrombocytopenia 44%, abdominalpain 43%, rash 42%, constipation 37%, headache 37%, dry skin 36%, fatigueand hypertension 30%. AOE rate/serious AOE rate was 23%/19%, includingcardio- 13%/9%, cerebro- 9%/7%, and peripheral-vascular 9%/7%. Of patientswith AOEs (n=104), 38% remained on study. Exposure-adjusted incidence ratesof new AOEs fell after the first 2 years: 15.5 Year 1, 15.7 Year 2, 10.4 Year 3,and 9.6 Year 4. Nearly 2 years after recommended dose reductions, 87%(114/131) and 74% (70/95) of CP-CML pts were estimated to maintain MCyRand MMR, respectively, and 8% (6/75) of all dose-reduced pts without a priorAOE on trial had an AOE. Table 1.Summary/Conclusions: After 4 years, heavily pretreated patients continue toshow deep and lasting responses on ponatinib, and approximately 2 years postrecommended dose reductions, maintenance of response is high, and the inci-dence of newly occurring AOEs has decreased. P229SUCCESSFUL TREATMENT FREE REMISSION IN CML AFTER 2 YEARCONSOLIDATION WITH NILOTINIB OF AN MR4.5 RESPONSE LEVELACHIEVED ORIGINALLY WITH IMATINIB TREATMENT: FIRST REPORTFROM STAT2 TRIAL IN JAPANN Takahashi1,*, K Nishiwaki2, C Nakaseko3, H Wakita4, K Sano2, C Ohwada3,N Aotsuka4, J Kuroki5, H Kimura6, H Noji7, M Tokuhira8, K Mitani9,K Fujikawa10, O Iwase11, K Ohishi12, F Kimura13, T Fukuda14, S Tanosaki15,M Miura16, K Sawada11Hematology, Akita University Graduate School of Medicine, Akita, 2Oncologyand Hematology, Jikei University Kashiwa Hospital, Kashiwa, 3Hematology,Chiba University Hospital, Chiba, 4Hematology and Oncology, Japanese RedCross Narita Hospital, Narita, 5Internal Medicine, Yuri General Hospital, Yuri-honjo, 6Hematology, Northern Fukushima Medical Center, Date, 7Hematology,Fukushima Medical University, Fukushima, 8Hematology, Saitama Medical Cen-ter, Saitama Medical University, Kawagoe, 9Hematology and Oncology, DokkyoMedical University, Mibu-machi, 10Hematology, Chibaken Saiseikai NarashinoHospital, Narashino, 11Hematology, Tokyo Medical University Hachioji MedicalCenter, Hachioji, 12Transfusion Service, Mie University Hospital, Mie, 13Hema-tology, National Defense Medical College, Tokorozawa, 14Hematology, TokyoMedical and Dental University, 15Hematology, The Fraternity Memorial Hospital,Tokyo, 16Pharmacy, Akita University Hospital, Akita, JapanBackground: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI)that exhibits significant efficacy as first- or second-line treatment in patientswith chronic myeloid leukemia (CML). Superior rates of deeper molecularresponses (DMR) were achieved with nilotinib vs imatinib in patients newlydiagnosed with CML in chronic phase (CML-CP) in the ENESTnd trial. Recently,treatment free remission (TFR) is one of the goals in CML treatment. Indeed,prospective trials suggest that imatinib therapy may be safely and successfullydiscontinued in 40% of CML patients with DMR (Mahon et al, Lancet Oncol2010, Ross et al, Blood 2013). Aims: The purpose of this study is to evaluate the efficacy of two-year consol-idation by nilotinib for successful TFR in patients with CML-CP who hadachieved MR4.5 with imatinib.Methods: Patients with CML-CP who had achieved MR4.5 (BCR-ABL1≤0.0032% on the International Scale [IS]) by real- time quantitative poly-merase chain reaction (RQ-PCR) on imatinib were eligible. At study entry,patients treatment was switched from imatinib to nilotinib and nilotinib wastaken twice daily (600mg/day) for 2 years as a consolidation phase. Patientswho had sustained MR4.5 for 2 years after initiation of the study were able tostop nilotinib in TFR phase. Thirty-three institutions in STAT study group par-ticipated. The study was conducted in accordance with the principles of theDeclaration of Helsinki. Informed consent was written by all patients accordingto institutional guidelines. The study was approved by all institutional reviewboards and registered with ClinicalTrials.gov (number UMIN000005904). Theprimary objective of this multicenter phase II, single-treatment arm, open-label clinical study was to identify the MR4.5 rate at 12 months after discon-tinuation of nilotinib treatment in patients who have sustained MR4.5 for 2years after initiation of the study. The molecular response was evaluatedusing IS-PCR (Molecular MD One-Step qRT-PCR BCR-ABL kit) at a centrallaboratory (BML, Inc., Kawagoe, Japan) upon study entry, every 3 monthsduring the consolidation phase, every month the first year in TFR phase,every 2 months the second year in TFR phase, and every 3 months the thirdyear in TFR phase thereafter. Molecular recurrence of CML was defined asconfirmed loss of MR4.5 (2 consecutive BCR-ABL1 IS >0.0032%) accordingto STIM criteria (Mahon Lancet Oncol 2010).Results: Between July, 2011 and December, 2012, 96 Japanese patients wereenrolled, and 75 patients who had sustained MR4.5 during the consolidationphase were eligible to discontinue nilotinib. The median age was 56 years. Theratio of men to women was 60:36 and the risk groups according to Sokal Scorewere low: 56, intermediate: 20, high: 18, respectively. Sixteen patients weretreated with interferon prior to imatinib therapy. All patients showed MR4.5 atthe time of entry into the study and the median time to DMR on imatinib therapywas 50.8 months. Median follow up duration in TFR phase of STAT2 trial was16 month (range: 3 - 30 months). Among the 75 patients who entered the TFRphase, 52 patients (69.4%, 95%CI: [58.9% to 79.8%]) remained without molec-ular recurrence the first 12 months (Figure 1). TFR rate at 12M was 69.4%,which was superior to the previous reports, although we have to carefully val-idate that the population baseline characteristics are similar to those from othertrials. Furthermore, the 23 patients with molecular recurrence who were treatedwith nilotinib again achieved MR4.5 within 6 months.Figure 1.Summary/Conclusions: 2-year consolidation by nilotinib is associated withsuccessful TFR in CML patients with MR4.5 on imatinib.haematologica | 2016; 101(s1) | 61Copenhagen, Denmark, June 9 – 12, 2016

English

LONG-TERM EFFICACY AND SAFETY OF PONATINIB IN HEAVILY PRETREATED LEUKEMIA PATIENTS: 4-YEAR RESULTS FROM THE PIVOTAL PHASE 2 PACE TRIAL

LONG-TERM EFFICACY AND SAFETY OF PONATINIB IN HEAVILY PRETREATED LEUKEMIA PATIENTS: 4-YEAR RESULTS FROM THE PIVOTAL PHASE 2 PACE TRIAL

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