Methotrexate-related central neurotoxicity: clinical characteristics, risk factors and genome-wide association study in children treated for acute lymphoblastic leukemia

Symptomatic methotrexate-related central neurotoxicity (MTX neurotoxicity) is a severe toxicity experienced during acute lymphoblastic leukemia (ALL) therapy with potential long-term neurologic complications. Risk factors and long-term outcomes require further study. We conducted a systematic, retrospective review of 1,251 consecutive Australian children enrolled on Berlin-Frankfurt-Münster or Children's Oncology Group-based protocols between 1998-2013. Clinical risk predictors for MTX neurotoxicity were analyzed using regression. A genome-wide association study (GWAS) was performed on 48 cases and 537 controls. The incidence of MTX neurotoxicity was 7.6% (n=95 of 1,251), at a median of 4 months from ALL diagnosis and 8 days after intravenous or intrathecal MTX. Grade 3 elevation of serum aspartate aminotransferase (P=0.005, odds ratio 2.31 [range, 1.28–4.16]) in induction/consolidation was associated with MTX neurotoxicity, after accounting for the only established risk factor, age ≥10 years. Cumulative incidence of CNS relapse was increased in children where intrathecal MTX was omitted following symptomatic MTX neurotoxicity (n=48) compared to where intrathecal MTX was continued throughout therapy (n=1,174) (P=0.047). Five-year central nervous system relapse-free survival was 89.2±4.6% when intrathecal MTX was ceased compared to 95.4±0.6% when intrathecal MTX was continued. Recurrence of MTX neurotoxicity was low (12.9%) for patients whose intrathecal MTX was continued after their first episode. The GWAS identified single-nucletide polymorphism associated with MTX neurotoxicity near genes regulating neuronal growth, neuronal differentiation and cytoskeletal organization (P<1x10-6). In conclusion, increased serum aspartate aminotransferase and age ≥10 years at diagnosis were independent risk factors for MTX neurotoxicity. Our data do not support cessation of intrathecal MTX after a first MTX neurotoxicity event.Marion K. Mateos, Glenn M Marshall, Pasquale M. Barbaro, Michael C.J. Quinn, Carly George, Chelsea Mayoh, Rosemary Sutton, Tamas Revesz, Jodie E Giles, Draga Barbaric, Frank Alvaro, Françoise Mechinaud, Daniel Catchpoole, John A. Lawson, Georgia Chenevix-Trench, Stuart MacGregor, Rishi S.Kotecha, Luciano Dalla-Pozza, and Toby N. Traha

Prospective longitudinal evaluation of treatment-related toxicity and health-related quality of life during the first year of treatment for pediatric acute lymphoblastic leukemia

Background Pediatric acute lymphoblastic leukemia (ALL) therapy is accompanied by treatment-related toxicities (TRTs) and impaired quality of life. In Australia and New Zealand, children with ALL are treated with either Children's Oncology Group (COG) or international Berlin-Frankfurt-Munster (iBFM) Study Group-based therapy. We conducted a prospective registry study to document symptomatic TRTs (venous thrombosis, neurotoxicity, pancreatitis and bone toxicity), compare TRT outcomes to retrospective TRT data, and measure the impact of TRTs on children's general and cancer-related health-related quality of life (HRQoL) and parents' emotional well-being. Methods Parents of children with newly diagnosed ALL were invited to participate in the ASSET (Acute Lymphoblastic Leukaemia Subtypes and Side Effects from Treatment) study and a prospective, longitudinal HRQoL study. TRTs were reported prospectively and families completed questionnaires for general (Healthy Utility Index Mark 3) and cancer specific (Pediatric Quality of Life Inventory (PedsQL)-Cancer Module) health related quality of life as well the Emotion Thermometer to assess emotional well-being. Results Beginning in 2016, 260 pediatric patients with ALL were enrolled on the TRT registry with a median age at diagnosis of 59 months (range 1-213 months), 144 males (55.4%), majority with Pre-B cell immunophenotype, n = 226 (86.9%), 173 patients (66.5%) treated according to COG platform with relatively equal distribution across risk classification sub-groups. From 2018, 79 families participated in the HRQoL study through the first year of treatment. There were 74 TRT recorded, reflecting a 28.5% risk of developing a TRT. Individual TRT incidence was consistent with previous studies, being 7.7% for symptomatic VTE, 11.9% neurotoxicity, 5.4% bone toxicity and 5.0% pancreatitis. Children's HRQoL was significantly lower than population norms throughout the first year of treatment. An improvement in general HRQoL, measured by the HUI3, contrasted with the lack of improvement in cancer-related HRQoL measured by the PedsQL Cancer Module over the first 12 months. There were no persisting differences in the HRQoL impact of COG compared to iBFM therapy. Conclusions It is feasible to prospectively monitor TRT incidence and longitudinal HRQoL impacts during ALL therapy. Early phases of ALL therapy, regardless of treatment platform, result in prolonged reductions in cancer-related HRQoL.Clarissa E. Schilstra, Karen McCleary, Joanna E. Fardell, Mark W. Donoghoe, Emma McCormack, Rishi S. Kotecha, Richard De Abreu Lourenco, Shanti Ramachandran, Ruelleyn Cockcroft, Rachel Conyers, Siobhan Cross, Luciano Dalla, Pozza, Peter Downie, Tamas Revesz, Michael Osborn, Frank Alvaro, Claire E. Wakefield, Glenn M. Marshall, Marion K. Mateos, and Toby N. Trahai

Outcomes for Australian children with relapsed/refractory acute lymphoblastic leukaemia treated with blinatumomab

We report on the Australian experience of blinatumomab for treatment of 24 children with relapsed/refractory precursor B‐cell acute lymphoblastic leukaemia (B‐ALL) and high‐risk genetics, resulting in a minimal residual disease (MRD) response rate of 58%, 2‐year progression‐free survival (PFS) of 39% and 2‐year overall survival of 63%. In total, 83% (n = 20/24) proceeded to haematopoietic stem cell transplant, directly after blinatumomab (n = 12) or following additional salvage therapy (n = 8). Four patients successfully received CD19‐directed chimeric antigen receptor T‐cell therapy despite prior blinatumomab exposure. Inferior 2‐year PFS was associated with MRD positivity (20%, n = 15) and in KMT2A‐rearranged infants (15%, n = 9). Our findings highlight that not all children with relapsed/refractory B‐ALL respond to blinatumomab and factors such as blast genotype may affect prognosis.Rosemary Sutton, Luciano Dalla Pozza, Seong Lin Khaw, Chris Fraser, Tom Revesz, Janis Chamberlain, Richard Mitchell, Toby N. Trahair, Caroline M. Bateman, Nicola C. Venn, Tamara Law, Erika Ong, Susan L. Heatley, Barbara J. McClure, Claus Meyer, Rolf Marschalek, Michelle J. Henderson, Siobhan Cross, Deborah L. White, Rishi S. Kotech