Acute Lymphoblastic Leukemia (ALL)

Epidemiology & Impact

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, accounting for approximately 25% of pediatric malignancies, with peak incidence between ages 2 and 5. In adults, ALL is relatively rare, representing less than 1% of adult cancers, with a second peak in incidence after age 50. Approximately 6,500 new cases are diagnosed annually in the United States. The disease demonstrates notable racial disparities, with Hispanic children experiencing the highest incidence rates. Outcomes have improved dramatically in pediatric populations, where 5-year survival now exceeds 90%, but adult ALL remains challenging with survival rates around 40%. Key risk factors include certain genetic syndromes (Down syndrome, Li-Fraumeni), prior chemotherapy or radiation exposure, and specific germline variants in IKZF1 and CDKN2A.

Molecular Biology & Biomarkers

ALL is broadly classified into B-cell ALL (approximately 75% of cases) and T-cell ALL (approximately 25%). The genomic landscape of ALL is now understood to be highly diverse, with over 30 recognized subtypes defined by specific chromosomal alterations and gene fusions. The Philadelphia chromosome (BCR-ABL1 fusion) is present in approximately 25% of adult ALL cases and was historically associated with poor outcomes before the advent of tyrosine kinase inhibitors. Philadelphia-like (Ph-like) ALL, harboring ABL-class fusions or JAK-STAT pathway alterations, has emerged as a high-risk subtype amenable to targeted therapy. In pediatric ALL, hyperdiploidy and ETV6-RUNX1 fusion define favorable-risk groups, while KMT2A rearrangements and hypodiploidy confer poor prognosis. Minimal residual disease (MRD) assessment by flow cytometry or PCR has become the single most important prognostic factor, with MRD negativity after induction strongly predicting long-term survival.

Evolving Treatment Landscape

The treatment paradigm for ALL has been transformed by immunotherapy. Blinatumomab, a bispecific T-cell engager targeting CD19, was the first bispecific antibody approved in oncology and has shown remarkable efficacy in MRD-positive and relapsed/refractory B-cell ALL. Inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, provides another targeted option for relapsed disease. CAR-T cell therapy with tisagenlecleucel (Kymriah) has achieved complete remission rates exceeding 80% in pediatric and young adult patients with relapsed/refractory B-ALL, fundamentally changing the salvage treatment landscape. For Ph-positive ALL, the combination of chemotherapy with tyrosine kinase inhibitors (imatinib, dasatinib, ponatinib) has dramatically improved outcomes. The integration of MRD-driven therapy, where treatment intensity is tailored based on residual disease levels, represents the current frontier in optimizing outcomes while minimizing toxicity.

EMA-Approved Therapies for Acute Lymphoblastic Leukemia

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key approvals with comparative timelines to FDA, demonstrating regulatory differences between regions.

For complete European approval details, visit ema.europa.eu ↗