Apperley, J

Clark, R

Coffey, T

Copland, M

Foroni, L

O'Brien, S

Pocock, C

Polydoros, F

Salim, R

Smith, G

Haematologica

English

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 Association

DE-ESCALATION OF TYROSINE KINASE INHIBITOR THERAPY IS SAFE IN CHRONIC MYELOID LEUKAEMIA IN DURABLE MOLECULAR RESPONSE (>= MR3 FOR >= 12 MONTHS): INITIAL RESULTS IN THE BRITISH DESTINY STUDY

http://spiral.imperial.ac.uk/bitstream/10044/1/40113/2/75.pdf

DE-ESCALATION OF TYROSINE KINASE INHIBITOR THERAPY IS SAFE IN CHRONIC MYELOID LEUKAEMIA IN DURABLE MOLECULAR RESPONSE (>= MR3 FOR >= 12 MONTHS): INITIAL RESULTS IN THE BRITISH DESTINY STUDY

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