Paediatric inspired regimens have improved survival in AYA ALL. However, results remain inferior when compared to children likely associated with the poorer tolerability of paediatric regimens and unique biology of ALL in the AYA population.
The objective of ALL06 was to assess whether a BFM based protocol could be administered to patients (pts) aged 15–40 years (yrs) in a comparable time frame to paediatric pts (aged <15 yrs) treated using the same induction therapy as part of the ANZCHOG Study 8 protocol. The primary outcome was the proportion of pts commencing protocol M or High Risk (HR) Block 1 by day 94. The study design permitted direct comparison of dose delivery during induction between the ALL06 and Study 8 cohorts.
Previously untreated pts with Ph-negative ALL were eligible for enrolment. Treatment consisted of 2 years of therapy including induction phase I and II, protocol M, reinduction phase I and II and maintenance therapy. Minimal Residual Disease (MRD) was assessed centrally using RQ-PCR assays with a sensitivity of 10–4 or greater at day 33 and day 79 of induction and reported according to EuroMRD criteria. Stratification to HR therapy was based on diagnostic and treatment response criteria with the aim of eliminating MRD prior to allogeneic transplantation if a suitable donor was available or further intensive chemotherapy.
86 pts were enrolled on ALL06 from 07/12 to 06/18. 3 were considered ineligible. Median age was 24 (16 – 38) yrs. Most had B-cell ALL (72.3%) and were male (72.0%). Considering the primary objective, 41.0% (95%CI 30.3 – 52.3%) of the ALL06 cohort commenced protocol M or HR1 by day 94 vs 39.3% in Study 8 (p = 0.77). For ALL06, median time to protocol M/HR1 was 97 (78 – 139) days vs 98 days in Study 8 (p = 0.85). CR rates at day 33 and day 79 were 90.4% and 97.6%. To date there have been 19 deaths (n = 9 due to relapse) and 19 relapses. Of 10 treatment related deaths, 4 (4.8%) occurred during induction (1 = pancreatitis, 1 = cerebral venous thrombosis, 2 = sepsis). 13 pts remain on therapy. With median follow up of 27.4 months, 2 yr DFS and OS was 75.6% (95%CI 65.6 – 85.5%) and 78.4% (95% CI 68.9 – 87.9%). 2 yr DFS and OS for the standard/medium risk group was 89.6% (95%CI 78.4–100%) and 97.1% (95%CI 91.4–100%) vs 66.3% (95%CI 49.1–83.5%) and 67.3% (95%CI 49.5–85%) for higher risk groups (p = 0.012 and 0.002 respectively). MRD results were available in 66 pts at day 33 and 70 pts at day 79. Day 33 and day 79 MRD results were as follows: MRDneg 18.2% and 58.6%, MRDlow pos (<5 x 10–4) 33.3% and 18.6% and MRDhigh pos (≥5 x 10–4) 48.5% and 22.9%. 2 yr DFS and OS for the day 79 MRDneg cohort was 91.4% (95%CI 82.1–100%) and 97.5% (95%CI 92.7–100%) vs 57.7% (95%CI 37.3–78%) and 57.8% (95%CI 36.3–79.2%) for the combined MRDlow pos/MRDhigh pos group (p
= 0.003 and <0.001 respectively). T vs B phenotype was associated with improved 2yr DFS 94.7% (95%CI 84.7–100%) vs 66.2% (95%CI 52.3–80%, p = 0.036) but not 2 yr OS (90.5% vs 72.0%, p = 0.117).
BFM style induction is equally as deliverable in an AYA population as in children with ALL. 2 yr DFS and OS compares favourably with other study group outcomes in this population. Risk stratification incorporating centralised MRD testing was feasible in the context of a national multicentre trial. Our findings suggest that intolerance to induction therapy is not a major contributor to inferior outcomes in the AYA cohort. This first ALLG study using a BFM regimen will be used to incorporate novel therapies targeting the unique biology of AYA ALL.