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221 A Comparison of 1 or 2 Courses of High Dose Cytarabine As Consolidation in Younger Patients with AML: First Results of the UK NCRI AML17 Trial

Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemia: Commercially available Therapy, excluding Transplantation: New Approaches Using Older Drugs
Sunday, December 6, 2015: 10:30 AM
W109, Level 1 (Orange County Convention Center)

Nigel H. Russell, MD1, Robert K Hills, DPhil2, Sylvie Freeman, PhD FRCPath3*, Steven Knapper4, Lars Kjeldsen, MD, PhD5, Ian Thomas6*, Jamie Cavenagh7, Paul Cahalin8*, Mary Frances McMullin, MD, FRCPath, FRCP9 and Alan K. Burnett, MD, FRCP10

1Centre for Clinical Haematology, Nottingham University Hospital, Nottingham, United Kingdom
2Department of Haematology, Cardiff University School of Medicine, Cardiff, United Kingdom
3Immunity and Infection, University of Birmingham, Birmingham, United Kingdom
4Cardiff University, Cardiff, United Kingdom
5Department of Hematology, Rigshospitalet, Copenhagen, Denmark
6HCTU, Cardiff University, Cardiff, United Kingdom
7Dept. of Hematology, St. Bartholomew's Hospital, London, United Kingdom
8Blackpool Victoria Hospital, Blackpool, United Kingdom
9Queen's University Belfast, Belfast, United Kingdom
10Blackwaterfoot, Isle of Arran, United Kingdom

On behalf of the UK NCRI AML Working Party

Introduction

Outcomes in younger patients with AML have steadily improved over the last 4 decades. However, the question of the optimal chemotherapy schedule remains open. As outcomes improve attention turns from survival to survivorship: can similar or better outcomes be obtained with less cost to the patient. We have previously shown in our MRC AML12,15 trials that a fifth course of chemotherapy did not improve outcomes in these younger patients. A retrospective analysis of patients who received 3 or 4 courses of treatment showed that, while patients with poor risk disease had better outcomes with four courses, any effect of a fourth course was much less clear for patients with good or standard risk disease.

Methods

The UK NCRI AML17 trial (ISRCTN: 55675535) was designed for patients with AML or high risk MDS up to the age of 60. Following their first course of treatment, patients were allocated a risk group based upon a validated score (comprising cytogenetics, WBC, age, secondary disease and blast response to course 1)[1]; additionally, patients who failed to achieve at least a 50% reduction in blasts were considered poor risk. A protocol amendment included patients who were otherwise standard risk, but were FLT-3 ITD mutant/NPM1c wild type in the poor risk group. Remaining adults who were either good or standard risk could be randomised after 2 courses of treatment (DA or ADE, with or without GO at 3/6 mg/m2) to receive 1 or 2 courses of consolidation (3 or 4 courses in total). Before mid-2010 patients were randomised between MACE/MidAC vs MACE; based on the results of AML15 [2], a protocol amendment changed consolidation to 1 or 2 courses of Ara-C 3g/m2/d for 5 days. Follow-up is complete to 1st March 2015, with median follow-up of 28.8 months (range 0.1-68.2).

Results

From July 2009 to June 2015, 1017 patients were randomised. Median age was 48 (range 16-72); 45% were male; 24% had core binding factor leukaemia; 76% intermediate risk disease; 1% had secondary disease, and 3% high risk MDS; WHO PS was 2+ in 4% of patients. Overall survival at 5 years was 57%.  An additional course of consolidation reduced relapse (CIR 53% vs 57%; HR 0.81 (0.67-0.99) p=0.04), with no difference in death in remission (7% vs 6%; HR1.10 (0.61-2.00) p=0.8), leading to some evidence of improved relapse free survival (41% vs 37%, HR 0.84 (0.70-1.01) p=0.06). Survival however, did not differ significantly between the arms (58% vs 55%, HR 0.90 (0.71=1.14) p=0.4), reflecting the effect of salvage: 3 year survival from relapse was 32% vs 31% (HR 0.97 (0.75-1.26) p=0.8). In stratified analyses, there was no difference in the effect of the extra course by cytogenetics (p-values for interaction between cytogenetics and treatment p=1.0 for survival); while relapse was reduced more in CBF leukaemias (HR 0.63 (0.40-1.00), p=0.05) than in others (HR 0.91 (0.73-1.13) p=0.4), the test for interaction was not significant (p=0.16). Information on minimal residual disease (by immunophenotype to a sensitivity of up to 1 in 104) was available for 353 patients post course 1 and 265 patients post course 2. There was no evidence of a differential effect of an extra course of consolidation by MRD status after either course (p=1.0 for survival post course 1; p=0.3 for survival post course 2). In stratified analyses, there was no interaction between treatment and age, sex, performance status or diagnosis. However, there was a significant benefit for FLT3-ITD WT patients (OS: 63% vs 54%, HR 0.75 (0.57-0.99) p=0.04), which was not present for ITD mutant patients (41% vs 58%; HR 1.38 (0.84-2.26) p=0.2; p=0.04 for interaction), and evidence of greater benefit for 4 courses in patients with lower WBC at diagnosis (p=0.04 for trend). There was no heterogeneity by induction therapy (p=0.7), in particular the use of gemtuzumab ozogamicin or not (p=0.2).

Conclusions

These data in good and standard risk patients (as defined comprising 63% of patients diagnosed) suggests no overall survival benefit of a 4th course of chemotherapy in younger patients with AML, although relapse was significantly reduced. With respect to subgroups, there was a suggestion that 4 courses of treatment was beneficial for FLT3 wild type patients. Attention now turns to whether the use of more intensive induction regimens such as FLAG-Ida can improve outcomes while delivering fewer courses.

[1] Burnett et al. Blood 2006:108 (11): Abstract 18

[2] Burnett et al. JCO 2013: 31(27);3360-8

 

Disclosures: Russell: Therakos: Other: shares . Cavenagh: Celgene: Consultancy , Speakers Bureau ; Janssen: Consultancy , Speakers Bureau ; Novartis: Consultancy , Speakers Bureau ; Amgen: Consultancy , Speakers Bureau .

*signifies non-member of ASH