Acute Lymphoblastic Leukemia

B-cell and T-cell ALL — Ph+ disease and TKI therapy, pediatric-inspired regimens in adults, blinatumomab, inotuzumab, and CAR-T for B-ALL

Key Points

• ALL is the most common pediatric cancer (~75% of childhood leukemia) and is highly curable in children (~90% OS); adult outcomes are significantly worse (~40–50% OS at 5 years) though improving rapidly.
• Ph+ ALL (BCR-ABL1+, t(9;22)) occurs in ~25% of adult B-ALL; tyrosine kinase inhibitor (TKI) therapy — dasatinib or ponatinib — added to chemotherapy has transformed outcomes.
• Ph-like ALL (BCR-ABL1-like) has Ph+ gene expression profile with kinase-activating alterations (JAK-STAT, CRLF2, ABL-class); TKI or JAK inhibitor therapy may be beneficial.
• Pediatric-inspired regimens (CALGB 10403, GRAALL-2003) improve outcomes in AYA patients (15–40 years), achieving survival approaching pediatric rates (~70–75% at 5 years).
• MRD negativity after induction is the strongest predictor of outcome and guides consolidation decisions, including alloSCT indication.
• Blinatumomab (CD19×CD3 BiTE) and inotuzumab ozogamicin (anti-CD22 ADC) are approved for relapsed/refractory B-ALL and are increasingly incorporated into frontline therapy.
• Tisagenlecleucel (CD19-directed CAR-T) is FDA approved for relapsed/refractory B-ALL in patients up to 25 years; adult CAR-T approvals expanding.

Epidemiology & Biology

Acute lymphoblastic leukemia accounts for approximately 6,550 new cases and 1,330 deaths annually in the United States (2024 estimates). ALL is the most common cancer in children, comprising ~75% of childhood leukemia, with a peak incidence between ages 2–5 years. A second smaller peak occurs in adults >50 years. Overall, approximately 60% of ALL cases occur in patients 40 years: ~40–50% overall; 60 years with standard chemotherapy • Ph+ ALL: Previously dismal in adults (<20% OS at 5 years without TKI); now approaches 50–70% with TKI + immunotherapy combinations and alloSCT.

Molecular Subtypes & Risk Stratification

Molecular characterization is now mandatory for all ALL diagnoses. Key subtypes with clinical implications: High-risk molecular subgroups in B-ALL: • Ph+ ALL (BCR-ABL1+): t(9;22)(q34;q11.2); ~25% of adult B-ALL; ~3% of pediatric ALL; requires TKI added to chemotherapy; TKI choice increasingly guided by mutation profile (dasatinib for unmutated BCR-ABL1; ponatinib or asciminib for T315I-mutated). • Ph-like ALL (BCR-ABL1-like ALL): ~25–30% of adult B-ALL; has gene expression profile similar to Ph+ ALL but lacks BCR-ABL1; harbors kinase-activating alterations — ABL-class fusions (responsive to…

Clinical Presentation

ALL presents acutely with symptoms of marrow failure and leukemic infiltration, often evolving over days to weeks: Bone marrow failure (universal): • Anemia: Fatigue, pallor, dyspnea • Thrombocytopenia: Petechiae, mucosal bleeding, easy bruising; intracranial hemorrhage in severe thrombocytopenia • Neutropenia: Fever, infections — bacterial and fungal Organ infiltration (distinguishes ALL from AML): • Lymphadenopathy: Cervical, axillary, inguinal; painless, firm, rubbery • Splenomegaly and hepatomegaly: Very common in B-ALL • Mediastinal mass (anterior mediastinum): Classic of T-ALL…

Treatment: Induction & Consolidation

ALL treatment consists of three main phases: Induction, Consolidation/Intensification, and Maintenance (total 2–3 years of therapy in adults). Induction therapy (achieves CR in ~85–95% of adults): • Pediatric-inspired regimens (recommended for AYA ≤40 years and increasingly up to age 55–60 in fit patients): CALGB 10403 (rituximab + vincristine + prednisone + doxorubicin + PEG-asparaginase + cyclophosphamide + 6-MP + MTX); GRAALL-2003/2014. These regimens improve 3-year OS from ~40% with adult regimens to ~70–75% in AYA patients. • Hyper-CVAD (cyclophosphamide + vincristine + doxorubicin +…

Relapsed/Refractory ALL & Novel Therapies

Outcomes for relapsed/refractory B-ALL with standard chemotherapy are dismal (<10% long-term survival). Novel immunotherapies have transformed this landscape: Blinatumomab (CD19×CD3 BiTE antibody construct): • Mechanism: Simultaneously binds CD19 on B blasts and CD3 on T cells; redirects cytotoxic T cells to kill blasts. • Approved for R/R Ph-negative B-ALL (TOWER trial: OS 7.7 vs. 4.0 months vs. standard chemotherapy) and MRD-positive B-ALL in CR. • ECOG-ACRIN E1910 trial: Adding blinatumomab after consolidation chemotherapy to standard induction/consolidation in Ph-negative B-ALL…