Acute Lymphoblastic Leukemia (ALL) — Detailed

Acute lymphoblastic leukemia (ALL) is an aggressive hematologic malignancy resulting from clonal proliferation of immature lymphoid precursor cells (lymphoblasts) in bone marrow with peripheral blood, organ, and central nervous system involvement. ALL is the most common pediatric cancer (25-30% of childhood malignancies) but uncommon in adults (1-2 per 100,000 incidence), with bimodal distribution: highest incidence in children 2-5 years old (peak childhood ALL with excellent prognosis, 90%+ cure rate), second peak in adults >50 years (poorer prognosis, 30-50% cure rate). The 2017/2022 WHO classification recognizes B-cell ALL (75-85% of cases) and T-cell ALL (15-25%) with multiple molecular subtypes important for prognosis and treatment.

B-cell ALL molecular subtypes: high hyperdiploidy (chromosome count >50) — favorable prognosis, common in children; ETV6-RUNX1 fusion — favorable, common in children; BCR-ABL1 fusion (Philadelphia chromosome positive Ph+ ALL with t(9;22)(q34;q11)) — historically poor prognosis dramatically improved with tyrosine kinase inhibitors (TKIs), 25-30% of adult ALL, increases with age; KMT2A (MLL) rearrangements — poor prognosis especially in infants; hypodiploidy (chromosome count <44) — poor prognosis; iAMP21 intrachromosomal amplification of chromosome 21 — adverse; Ph-like ALL (BCR-ABL1-like) — gene expression profile similar to Ph+ ALL with various kinase activating lesions (CRLF2, JAK1/2, ABL-class fusions including PDGFRA, PDGFRB, NTRK3) — comprises 15-25% of childhood and 25-30% of young adult B-ALL, poor prognosis but responsive to targeted TKIs; TCF3-PBX1, MEF2D, ZNF384 rearrangements; DUX4-rearranged with ERG deletion (favorable). T-cell ALL: early T-cell precursor ALL (ETP-ALL — distinct subtype with stem cell features and poor prognosis, 10-15% of T-ALL), classical T-ALL with NOTCH1 mutations (60%), FBXW7 mutations, PTEN deletions, mediastinal involvement common.

Clinical presentation, diagnosis, and treatment: rapid onset over weeks of bone marrow failure symptoms (fatigue, pallor, dyspnea from anemia; bleeding/petechiae/bruising from thrombocytopenia; fever and infections from neutropenia), B-symptoms (fever, night sweats, weight loss), hepatosplenomegaly, lymphadenopathy, bone pain (especially in children — characteristic), testicular involvement (sanctuary site), CNS symptoms (headache, vomiting, cranial neuropathy from CNS leukemia, 5-10% at diagnosis, more in T-ALL), mediastinal mass with respiratory compromise (T-ALL, 50-60%), tumor lysis syndrome at presentation (hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, AKI), gum hypertrophy, skin involvement (rare). Diagnosis: bone marrow biopsy and aspirate showing >20% lymphoblasts (often >80%), characteristic morphology (small to medium cells with high N:C ratio, scant cytoplasm, fine chromatin), comprehensive immunophenotyping (B-ALL: CD19, CD22, CD79a positive with CD10, CD20, surface immunoglobulin expression by maturation stage, TdT positive; T-ALL: CD2, CD3, CD5, CD7 positive, TdT positive, ETP-ALL: CD7+ with myeloid/stem cell markers CD34, CD117, MPO), comprehensive cytogenetics and molecular testing (karyotyping, FISH, RT-PCR, NGS panels for BCR-ABL1, MLL/KMT2A, ETV6-RUNX1, TCF3-PBX1, IKZF1, JAK2, CRLF2, NOTCH1), CSF analysis with cytology and flow cytometry. Treatment: pediatric protocols (BFM, COG, NOPHO) with prolonged intensive multi-agent chemotherapy (induction with vincristine, dexamethasone/prednisone, asparaginase, anthracycline; consolidation with cyclophosphamide, cytarabine, mercaptopurine; CNS prophylaxis with intrathecal methotrexate; maintenance with mercaptopurine, methotrexate, vincristine for 2-3 years). Adult protocols: pediatric-inspired (CALGB 10403, GMALL) for younger adults — improved outcomes; hyper-CVAD for older patients. Ph+ ALL: addition of TKI (imatinib, dasatinib, ponatinib) — dramatic improvement from 30% to 70-80% cure rate. Targeted/immune therapies: blinatumomab (CD19/CD3 BiTE) for MRD positive disease and relapsed/refractory; inotuzumab ozogamicin (CD22 ADC); CAR-T cell therapy (tisagenlecleucel for pediatric/young adult B-ALL up to age 25, brexucabtagene autoleucel for adult B-ALL); allogeneic stem cell transplantation in first complete remission for high-risk adults, second remission for relapsed disease; CNS-directed therapy with intrathecal chemotherapy and cranial irradiation in selected cases. Outcomes: pediatric ALL 5-year overall survival >90% in standard risk, 80-85% in high risk; adult ALL 30-50% with conventional chemotherapy, 60-70% with pediatric-inspired protocols, 70-80% in Ph+ with TKI.