Cavenagh, J

Craddock, C

Dennis, M

Ferguson, P

Gbandi, E

Houlton, A

Metzner, M

Pillai, S

Quek, L

Roberts, C

Siddique, S

Vyas, P

Wheatley, K

Haematologica

Oxford University Research Archive (ORA)

Molecular predictors of response to azacitidine therapy: the results of the UK trials acceleration programme RAVVA study

Quek, Lynn

Metzner, Marlen

Vyas, Paresh

Oxford University Research Archive

Background: AML is a heterogeneous disease based on genetic characteris-tics with impact on prognosis. So, it becomes necessary to treat patients accord-ing to risk-adapted therapies.Aims: To analyze the results of intensive induction and post-remission treatmentin 868 patients with the novo AML enrolled into the CETLAM-03 trial between2003 and 2012 with a prolonged follow-up (results reported at 10 years).Methods: Patients received 1 or 2 induction chemotherapy courses of IDICE-G (idarubicin, intermediate cytarabine (IDC), VP-16 and priming with G-CSF)followed by mitoxantrone and IDC as consolidation therapy. Further treatmentwas assigned according to the CETLAM risk groups as follows: Favorable risk(FR) defined as favorable cytogenetics according to MRC: autologous stemcell transplantation (ASCT) if leukocyte index [LI=leucocytes x (BM blasts/100)]≥20 or high dose cytarabine (HDAC) (one course) if LI <20. Intermediate risk(IR), defined as patients in CR after a single induction course, <50x10E9/l whiteblood cells at diagnosis, normal karyotype and absence of FLT3 internal tandemduplication (FlT3-ITDwt) and no MLL rearrangement: ASCT . Adverse risk (AR),patients not included in FP or IP: ASCT or allogeneic stem cell transplantation(allo-SCT) depending on donor availability (HLA-identical sibling or unrelateddonor if high risk of relapse).Results: There were enrolled 868 patients. Median age was 53 years-old (16-70). According to MRC cytogenetics, available in 802 patients, 99 belonged tothe favorable (12%), 581 (73%) to the intermediate and 122 (15%) to theadverse groups. 66 patients with no metaphases. FLT3-ITD was present in 128patients with normal karyotype (36%). Four patients died before treatment and864 patients received induction therapy. 77% of patients achieved a CR (88%with a single course), 11% were refractory and 12% died during induction. CRrate was 92% in CBF leukemia, 91% in NPM1 mutation without FLT3-ITD, 77%in intermediate cytogenetic and no mutations, 74% if FLT3-ITD, 70% in adversecytogenetics and 62% if monosomal karyotype was present (p<0.001). Themultivariate analysis showed that mutational status (adverse cytogenetics,FLT3-ITD and absence of NPM1 mutation) had an adverse impact on CRachievement. Overall survival (OS), event free survival (EFS) and cumulativeincidence of relapse (CIR) of the whole series at 10 years were: 36±2%, 29±2%and 44±5% respectively. Post-remission results of OS, EFS and CIR accordingto the different CETLAM risk groups at 10 years follow up were: FR (n=85,14%): 85±4%, 70±6% and 22±1%; IR (n=99, 17%): 64±6%, 51±5% and 47±2%;AR (n=417, 69%): 41±3%, 33±3% and 52±16% respectively. In FR there wereno differences in OS, EFS and CIR depending if intention to treat was HDACor ASCT. In AR statistical differences were observed at 10 years in EFS andCIR when comparing ASCT vs allo-SCT (27±4% vs 39±4%, p=0.026 and66±6% vs 39±1%, p<0.001). In IR intention to treat was ASCT, but in 21% mobi-lization failed and most of them received HDAC. Forty-nine patients receivedan ASCT and 21 relapsed, 9 of them were rescued with an allo-SCT.Summary/Conclusions: In this large cooperative experience CR rate was above75%, in most cases after a single course. In patients with favorable MRC cyto-genetics, the adverse impact of high LI observed in our previous protocol wasabrogated with autologous transplantation. In IR group, a remarkable proportionof patients allocated to ASCT had mobilization failure. In HR group, allo-SCTimproves the outcome compared to ASCT. In our experience, molecular charac-terization and MRD studies are helpful to decide post-remission therapy.S791MOLECULAR PREDICTORS OF RESPONSE TO AZACITIDINE THERAPY:THE RESULTS OF THE UK TRIALS ACCELERATION PROGRAMMERAVVA STUDYC. Craddock1,*, L. Quek2, A. Houlton3, P. Ferguson4, E. Gbandi3, C. Roberts5,M. Metzner2, K. Wheatley 6, S. Siddique6, S. Pillai7, M. Dennis8, J. Cavenagh9,P. Vyas101Centre for Clinical Haematology, University of Birmingham, University of Birm-ingham, Birmingham, 2Haematology, Weatherall Institute of Molecular Medi-cine, Oxford, 3Cancer Research UK Clinical Trials Unit, University of Birming-ham, 4Haematology, Centre for Clinical Haematology, Queen Elizabeth Hospi-tal, Birmingham, 5Haematology, Oxford, Oxford, 6CRCTU, University of Birm-ingham, Birmingham, 7Haematology, University Hospital of North Staffordshrire,Stoke on Trent, 8Haematology, The Christie NHS Foundation Trust, Manchester,9Department of Haemato-Oncology, St Bartholomews Hospital, London, 10MRCMolecular Haematology Unit, Weatherall Institute of Molecular Medicine,Oxford, United KingdomBackground: Azacitidine (AZA) represents an important therapeutic advancein patients with acute myeloid leukaemia (AML) and high risk myelodysplasia(MDS) ineligible for intensive chemotherapy. However disease progressionappears inevitable and a number of strategies aimed at improving outcome,including co-administration of histone deacetylase inhibitors such as vorinostat(VOR), have been proposed. Leukaemic stem/progenitor cells (LSC) have beenpostulated to represent a reservoir of resistant disease but the impact of AZAbased therapy on LSC numbers has not been studied. An additional factor lim-iting the rational use of AZA based therapy in AML and MDS is imprecision inthe identification of patients likely to achieve a significant clinical benefit andmolecular predictors of outcome would improve the rational utilisation of thsiimportant new agent. Aims: We wished to study the impact of AZA based therapy on LSC numbersaswell as identify molecular predictors of outcome in patients treated on therecently completed UK Trials Acceleration Programme RAVVA randomised PhaseII trial which compared AZA monotherapy with AZA/VOR combination therapy.Methods: The RAVVA trial randomized 259 adults with AML (n=217) and MDS(n=42) to receive AZA monotherapy (AZA (75 mg/m2) x 7 days every 28 days)or AZA combined with VOR (300 mg bd days 3-9) po for a minimum of 6 cycles.Next generation sequencing was performed on 42 genes commonly mutatedin AML and MDS in 250 patients treated on the RAVVA trial and correlated withresponse. Separately serial immunophenotypic quantitation of leukaemicstem/progenitor cells (LSC) was performed in 44 patients. Results: Co-administration of VOR did not increase overall survival (OS) (1year OS AZA 43% versus 41% p=0.32) as previously reported (Blood 2016Absract No 1065). The mean number of mutations per patient in the 250 geno-typed patients was 3.4. The presence of mutations in CDKN2A (p=0.0001),IDH1 (p=0.004) and TP53 (p=0.003), NPM1 (p=0.037) and FLT3-ITD (p=0.04)were associated with reduced OS in univariate analysis. In multivariate analysisadjusted for all clinical variables mutations in CDKN2A, IDH1 and TP53remained predictive of decreased OS. No mutations were associated withimproved OS. The presence of ASXL1 (p=0.035) and ETV6 (p=0.033) mutationswere found to be associated with a reduced duration of response. AZA basedtherapy had no significant impact on LSC numbers in patients who failed toachieve a CR. LSC numbers were reduced but not eradicated in patientsachieving a CR and observed to expand at relapse.Summary/Conclusions: In this, the largest such study reported to date, thedemonstration that mutations in CDKN2A, IDH1 and TP53 are associated witha decreased OS in patients treated with AZA not only can inform patient riskstratification but also provides insights into the mechanism of action of AZA.Specifically, the observation that mutations in the cell cycle regulator CDKN2Awas associated with a markedly decreased overall survival is consistent withthe hypothesis that induction of cell cycle arrest represents at least one of themechanisms by which AZA exerts an anti-tumour activity. Furthermore our dataidentify serial quantitation of LSC populations as a potentially important bio-marker of response to AZA based therapies which may assist in the evaluationof novel treatment combinations. S792SORAFENIB MAINTENANCE IN FLT3-ITD MUTATED ACUTE MYELOIDLEUKEMIA AFTER ALLOGENEIC STEM CELL TRANSPLANTS. Ahmed1, R. Saliba1, G. Rondon1, A. Alousi1, Q. Bashir1, S. Ciurea1,G. Al-Atrash1, K. Patel2, A. Olson1, D. Marin1, K. Rezvani1, P. Kebriaei1,U. Popat1, E. Shpall1, R. Champlin1, B. Oran1,*1Stem cell transplant and cellular therapy, 2Hematopathology, University ofTexas, MD Anderson Cancer Center, Houston, United StatesBackground: The fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is a genetic alteration found in approximately 30% of patientswith acute myeloid leukemia (AML). Although patients with FLT3-ITD AMLachieve remission rates similar to those with FLT3 wildtype status with inductionchemotherapy regimens; patients with FLT3-ITD have significantly shorterremission durations and increased rates of relapse. Even though allogeneicSCT improves outcomes, patients still have higher rates of relapse compara-tively with poor prognosis post relapse. Sorafenib(SFB) is a TKI with activityagainst RAF, VEGF and FLT3-ITD and its use as maintenance therapy afterallogeneic SCT has been shown as a promising approach to decrease relapse.Several studies report that SFB maintenance post SCT provides durable com-plete responses; however, there are also descriptions of sorafenib post SCTtriggering acute GVHD, cytopenias, rash and diarrhea. Aims: To assess the outcomes, including progression free survival (PFS) andoverall survival (OS), in patients with FLT3-ITD mutated AML who receive SFBmaintenance after allogeneic SCT. Methods: We analyzed adult patients (age≥18) with a diagnosis of FLT3-ITDmutated AML who received an allogeneic SCT between 1/1/2010 and 10/28/16at our institution. Using a case control analysis and matching patients whoreceived maintenance SFB (maintenance group) with control patients, FLT3-ITDmutated AML who did not receive maintenance post SCT(control group); wematched each case to two control patients accounting for disease status, type ofconditioning, donor type, cytogenetic risk factors and age. To be considered asmaintenance, SFB had to be started within 101 days of the SCT. To reduce biasfrom disease risks and transplant-related mortality (TRM), all patients wererequired to be in complete remission (CR) at study entry - defined as the date ofSFB initiation for cases and the same time point after SCT for their matched con-trols without maintenance. Actuarial OS and PFS were estimated from studyentry using Kaplan-Meier method. OS and PFS were compared between casesand controls using log rank test and cox proportional hazards regression analysis.Patient-, transplant- and disease characteristics were compared between casesand controls using chi square and Fisher exact tests.Results: Among the 214 AML patients with FLT3-ITD mutation that underwentSCT during study period, we identified 13 cases (maintenance) and 26 controls(no maintenance). Median follow-up of survivors were 12 months and 30months for maintenance and control group respectively. Disease and transplanthaematologica | 2017; 102(s2) | 323Madrid, Spain, June 22 – 25, 2017

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Molecular predictors of response to azacitidine therapy: the results of the UK trials acceleration programme RAVVA study

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