Patient-Reported Outcomes in Older Acute Myeloid Leukemia Patients Fit for Intensive Treatment, Who Received Intensified Treatment (DA +/- cladribine) Following No Evidence of Response to Course 1: Results from the NCRI AML18 Trial

Introduction: AML18 was an international program of development in older patients with acute myeloid leukaemia (AML) deemed suitable for intensive chemotherapy. Patients who had received induction course 1 but where evidence of residual disease or failure to achieve a remission was noted, were considered eligible for a randomisation of intensified therapy in treatment courses 2 and 3. The clinical outcome of the randomisation, comparing standard DA (Daunorubicin, AraC) chemotherapy against either FLAG-Ida or DA in combination with cladribine (DAC), has been reported (Russell N, ASH 2023) - here, we consider the effect of treatment intensification on the trial secondary endpoint, patient-reported outcome (PRO). This is the first report of longitudinal PRO results in this context.

Methods:After receiving the first course of treatment within the trial, patients who did not achieve measurable residual disease (MRD) negativity (including those whose MRD status was unknown) were randomised to either continue treatment with up to two courses of standard DA (DA3+8, followed by DA2+5) or to receive up to 2 courses of intensified chemotherapy - either FLAG-Ida or DAC (DA3+8, followed by DA2+5 both including Cladribine 5 mg/m² x 5 days). The randomisation was 1:1:1 between the 3 arms - this analysis focuses on the effect of adding cladribine to DA chemotherapy.

Quality of Life (QoL) questionnaires were provided to patients prior to induction treatment (baseline) and at 3 months (approximately post-course 2), 6 months (approximately post-consolidation) and 12 months after trial entry. The questionnaires included European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) - scores were calculated in line with the respective scoring manuals and reported including mean (95% CI) for each domain. Due to the multiplicity of testing, and the exploratory nature of the analysis, a p-value of 0.0025 was considered statistically significant. Consistent with similar analyses in this patient population, a minimal clinically important difference (MCID) of 10 or more points was selected.

We use the linear mixed model to assess the differences in scores between treatments and logistic regression to estimate the odds ratio of MCID score deterioration at each time point. We also assessed the proportion of patients whose QoL deteriorated by 10 or more points at each timepoint.

Results: 277 patients with a median age of 67 (IQR 64 - 70) years entered the randomisation between November 2014 and January 2023 - 138 were allocated DA treatment and 139 DAC. All characteristics (gender, age, presenting WBC count and induction treatment allocation) were balanced between arms. Clinical outcome data, demonstrating significant benefit of treatment intensification, have been previously presented.

Of these patients, 235 (85%) provided baseline PRO data, with completion (198, 71% at 3 months, 164, 59% at 6 months and 128, 46% at 12 months) remaining acceptable considering the effect of disease progression.

There was evidence for change in all score scales across time, but no evidence that these changes were significantly different between the treatment groups. Global Quality of Life scores were equivalent in the DA and DAC arms at baseline (53.7 and 58.3), 3 months (59.0 and 61.8), 6 months (68.1 and 68.7) and 12 months (68.9 and 73.5). Representative of broader symptom burden, fatigue for DA and DAC at baseline (48.6 and 43.5), 3 months (45.9 and 44.5), 6 months (42.0 and 44.0) and 12 months (43.5 and 41.6) was similarly equivalent.

Deterioration analysis showed no significant difference, in any scoring scales, in the proportion of patients experiencing clinically meaningful deterioration at any time point between the treatment groups.

Conclusions:AML18 is the first trial to use MRD status to direct treatment intensification post-course 1 of intensive therapy - this analysis of PRO data demonstrates that the significant clinical benefit of treatment intensification with DAC is not accompanied by any significant deterioration in patient-reported outcomes. Equivalence in clinical symptoms across arms appear to be mirrored in patient-reported symptom burden.

A 10-point MCID may be too large to detect a signal in this patient population, particularly in scales such as Nausea & Vomiting, Pain, Constipation, Diarrhoea and Financial Difficulties, where scores are significantly lower than in the general population.

Russell:Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Honoraria; Servier: Honoraria. Knapper:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Jazz Pharmacueticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria.