ALL Assembly 2017

Dr Boer speaks with ecancer about the genetic subtypes of ALL, and how to best treat BCR-ABL-like patients. She outlines the network of mutations that can drive leukaemia through JAK, ABL and RAS pathways, and describes Philidelphia-like genetic signatures. Dr Boer also considers how druggable these pathways may be, including the use of tyrosine kinases.

Dr Mohty about poor prognosis, comorbities and genetically distinct lineage of elderly ALL, and the ongoing role of stem cell transplant in treatment. He describes allogeneic HSCT as feasible in improving MRD, and encourages the incorporation of novel immunotherapies and tyrosine kinase inhibitors for differing patient subtypes.

Prof Boissel speaks with ecancer about results from the GRAALL-2005 study, which assessed the response of adolescent and young adult patients to HSCT and consolidation therapy. He identifies Ph-like and ABL-like subgroup of patient genotypes which indicate a sensitivity to TKI therapy, and considers the case of a patient who, initially unresponsive to prednisone, responded well to blinatumomab and dasatinib therapy before stem cell transplant, and is now in remission.

Prof Dombret speaks with ecancer about recent advances in ALL, and his vision of future care schema. He highlights chemotherapy intensification and the identification of Philadelphia-positive ALL as significant steps in understanding and treating disease, and considers the new modalities progressing towards clinical application. Overall, Prof Dombret considers the benefits of balancing targetted therapies with a tailored dose of chemotherapy, though notes the rarity of some mutations prove a challenge to current trial design, and the need for collaborative evaluation.

Dr Grupp speaks with ecancer about managing cytokine release syndrome, an adverse event associated with CAR T cell therapy, with IL-6R agonist tocilizumab. He considers the growing availability and avenues of research in immunotherapy, and looks forward to identifying the most potent combinations or sequences of treatments once approval criteria has been met.

Dr Locatelli speaks with ecancer about the state of care for paediatric ALL. He considers the past, present and future of treatment modalities, with the advent of TKI therapy for a range of patient subtypes, and stem cell transplant improving overall survival and duration of survival. Dr Locatelli encourages ongoing collaboration between international institutes, especially when working with rare mutational subtypes, and looks forward incorporating the promise of immunotherapy into care.

Prof Cools speaks with ecancer about the molecular pathways through which early T precursor ALL may be treated. He describes the origin of ETP-ALL and cell surface markers which characterise its near-stemness, and introduces mutations which drive tumourigenesis. These include JAK-STAT, IL7 and BCL2 pathways, and Prof Cools introduces XPO1, an organelle shuttling protein, which may also be a useful target for treating HIV.

Dr Topp speaks with ecancer about BiTE antibody constructs; engineered antibodies in which the variable heavy and light chains are designed to bridge host immune responses and tumours. He describes the mechanism and design of blinatumomab, a CD19 engager which has been approved in Europe, and compares other antibody formats including dual-affinity re-targeting (DART) arrangements and bispecific tandem diantibodies (TandAbs).

Dr Mullighan about genetic subtypes within ALL, considering how classifications change in frequency across different age groups. He highlights chromosonal gains, and mutations in RUNX and ABL pathways as known drivers, and considers the role of new diagnostics in screening patients. Dr Mullighan identifies Ph-like B ALL as a newly identified subtype, largely druggable through tyrosine kinase inhibitors, and describes results from a recent study of ~1000 adults with ALL which found 20-25% of patients fit this subtype, and introduces ongoing studies into alternative treatment modalities including targeting cell adhesion. Considering genomic sequencing to identify which patients fit within known subtypes, he considers cost and feasibility in different disease indications, and for limited clinic availability.

Prof Ottman speaks with ecancer about the past and future management of Ph ALL. He describes the impact of TKI therapy on prognosis, and how this has gone on to modulate chemotherapy regimens towards less intensive courses, but highlights the difficulty of treating relapsed patients. Prof Ottman also highlights the GRAAPH-2005 trial as confirming indications and patients who respond strongly to allogeneic or autologous stem cell transplant, with age as a major disposing factor. With this in mind, he considers a future in which 3rd generation TKIs, stem cell transplant and immunotherapy might offer a chemo-free treatment regimen for patients.

Dr Cazzaniga speaks with ecancer about the prenatal origin of acute lymphoblastic leukaemia. He describes how Guthrie card analysis has identified mutations in utero, 1% of which manifests as ALL, and compares this to the rate of concordant mutations in twins. Dr Cazzaniga emphasises that such mutations are seemingly unpreventable, and do not reflect the genotype of either parent, though ongoing monitoring of a concordant and discordant twins is encouraged.

Dr Giebel speaks with ecancer about the need for stem cell donation in treating adult acute lymphoblastic leukaemia. Comparing autologous transplant to chemotherapy, he notes previous studies which found no benefit compared to chemotherapy were not conducted with consideration of minimal residual disease (MRD), and that there are some who would consider an ongoing role for autologous transplant in treating ALL, alongside consolidation and maintenance therapies. Dr Giebel also considers the results of the GRAAPH trial, discussed by Dr Ottman, and weighs the advantages of autologous stem cell transplant in the age of tyrosine kinase inhibitors.