S1621 CLINICAL EFFICACY OF A NOVEL VALIDATED PROGNOSTIC INDEX FOR TRIAL DESIGN IN ADULT ACUTE LYMPHOBLASTIC LEUKAEMIA.
Authors: Moorman A. , Kirkwood A. , Enshaei A. , Clifton‐Hadley L. , Lawrie E. , Marks D. , McMillan A. , Menne T. , Patrick P. , Wrench B. , Zuborne‐Alapi K. , Rowntree C. , Fielding A. 
Published: June 2019

Background:

The majority of clinical trials in ALL use a combination of binary risk factors to assign patients to different treatment pathways. Examples include age, white cell count (WCC), minimal residual disease (MRD) and genetics. Typically, variables are dichotomised and used sequentially. This approach reduces predictive power by failing to leverage the power of continuous data and predetermines the size of the risk groups due to the skewed distribution of variables. A prognostic index (PIUKALL) using four paediatric clinical trials (UKALL2003, DCOG‐ALL10, NOPHO‐ALL2008 and CoALL‐07–03) was recently developed in childhood ALL (AVM & AE). PIUKALL is based on two, weighted, log‐transformed continuous variables (WCC and end of induction MRD) as well as two weighted binary variables – the presence of good risk and high risk cytogenetics. PIUKALL is readily calculated from a linear model and produces patient specific risk scores.

Aims:

We aimed to determine whether PIUKALL was a valid prognostic marker in adult ALL and, if so, how it could be optimally ultilised to inform future risk stratification algorithms.

Methods:

Using the original linear model, we calculated patient specific risk scores for a representative cohort of 367 Philadelphia‐negative B‐cell precursor and T‐ALL patients, aged 25–65 years, treated on UKALL14. UKALL14 used two induction phases, so we calculated risk scores for each time point: end of phase 1 (PI1, n = 343) and phase 2 (PI2, n = 295). We used the PIUKALL good risk cytogenetic abnormalities (ETV6‐RUNX1, high hyperdiploidy) but added complex karyotype to the list of high risk cytogenetic abnormalities (low hypodiploidy, KMT2A gene fusions and iAMP21). We used standard endpoints and statistical methods to explore the prognostic impact and clinical utility of PIUKALL.

Results:

PIUKALL is a continuous variable ranging, in this study, from −3.37 to 1.82 with higher scores indicating poorer outcome. The median score for PI1 was higher than PI2 (−0.99 v −1.99, p < 0.001) reflecting the lower MRD levels after phase 2. As expected the median PI1 and PI2 scores differed according by baseline risk groups: PI1 standard −2.03 v high −0.77 p < 0.0001; PI2 standard −2.47 v high −1.68 p < 0.0001. Univariate analysis showed that each unit increase in PI1/PI2 resulted in a 50–60% greater risk of event or relapse. Both scores retained significance when adjusting for patient age. Dividing PI1 and PI2 into tertiles produced groups with distinct EFS rates (Figure). On UKALL14, standard risk patients were allocated maintenance chemotherapy while high risk patients were eligible for alloSCT. To gain insight into how PIUKALL could be used prospectively to inform treatement decisions, we examined the prognostic impact of both PI1 and PI2, using a variety of thresholds, according to post induction therapy. The table highlights examples of how PI1 and/or PI2 can be used to identify patients with differential outcomes despite receivng the same therapy. For example, patients with a >90% EFS with maintenance therapy or a 42% relapse risk despite receiving a myeloablative alloSCT.

Summary/Conclusion:

PIUKALL, which was developed and validated using paediatric ALL data, is a valid and powerful biomarker in adult ALL. This intriguing observation highlights the benefit of integrating risk factors as continuous variables. We have demonstrated how PIUKALL could be used to provide additional prognostic information in treatment scenarios previously allocated by binary decision. We plan to use this risk score when designing our next adult ALL trial, UKALL15.

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