ALL is divided into B-cell (85%) and T-cell lineages (10–15%).
Survival rates in children are excellent, while in adults they remain poor. 
The treatment landscape has been transformed by the incorporation of immunotherapy and potent tyrosine kinase inhibitors into frontline regimens, resulting in meaningful improvements in long-term survival. 
Immunotherapy is now central to treating B‑cell acute lymphoblastic leukemia (ALL), especially in relapsed/refractory disease and in patients who cannot tolerate more intensive chemotherapy or transplant.
The main modalities are monoclonal antibodies/antibody–drug conjugates, bispecific T‑cell engagers (BiTEs), and CD19‑directed CAR T‑cell therapy.
Key Immunotherapy Approaches:
Bispecific T-Cell Engagers (BiTEs) — Blinatumomab Blinatumomab, the first bispecific T-cell engager (BiTE), has been approved for relapsed/refractory ALL.
It is more effective and better tolerated than conventional chemotherapy, and is the first antileukemic drug approved for the treatment of minimal residual disease. 
FDA approved blinatumomab for earlier treatment of adults and children with CD19-positive B-cell precursor ALL.
Both children and adults who have completed induction therapy can now receive blinatumomab during consolidation, leading to deeper and more durable responses.
Approximately 80% of patients who received blinatumomab plus chemotherapy were still alive versus approximately 63% treated with chemotherapy alone. 
Antibody-Drug Conjugates — Inotuzumab Ozogamicin
Agents including inotuzumab ozogamicin and blinatumomab are being incorporated into chemotherapy regimens to improve measurable residual disease (MRD) negativity rates and long-term outcomes.
Inotuzumab ozogamicin (anti‑CD22 ADC) is approved for relapsed/refractory (R/R) B‑ALL; it delivers a calicheamicin payload to CD22‑positive blasts and achieves high complete remission and MRD‑negative rates, but with notable veno‑occlusive disease risk, especially around transplant.
With these immunotherapy-chemotherapy regimens, 4-year survival rates have improved to 80–85% among patients who are able to receive them. 
CAR T-Cell Therapy The recent emergence of targeted therapies, including antibody-drug conjugates, bispecific antibodies, and CD19 CAR T-cell therapy, revolutionized B-ALL management, allowing optimism about gradually replacing chemotherapy and stem cell transplantation in the first remission. 
Tisagenlecleucel and brexucabtagene autoleucel are approved CAR T products for R/R B‑ALL (pediatric/young adult and some adults), achieving complete response rates >80% with durable remissions in a subset of heavily pretreated patients.
Autologous T cells are collected, transduced to express a CD19‑targeting CAR, expanded ex vivo, then reinfused; patients generally receive lymphodepleting chemotherapy beforehand.
Monoclonal antibodies (mAbs)
Rituximab (anti‑CD20) is added to chemotherapy in CD20‑positive B‑ALL to deepen remission, often in induction or consolidation.
Bispecific T‑cell engagers (BiTEs)
Blinatumomab (anti‑CD19×CD3) links CD3+ T cells to CD19+ B‑lineage blasts, driving T‑cell–mediated cytotoxicity.
Immunotherapy is increasingly integrated into front‑line regimens, particularly for:
Ph+ ALL (e.g., TKIs plus blinatumomab instead of intensive chemotherapy in some adult protocols.
Patients with persistent or re‑emergent MRD after chemotherapy, where blinatumomab improves MRD‑negative conversion and survival and may allow deferral or optimization of transplant.
Relapsed/refractory B‑ALL
For first or later relapse, especially after prior HSCT or intensive chemo:
Inotuzumab and blinatumomab are standard antibody‑based options for cytoreduction and MRD clearance.
CD19 CAR T‑cell therapy is used in patients with chemo‑refractory disease or multiple relapses and can serve either as: Definitive therapy for some pediatric/AYA patients with durable remissions, or A bridge to allogeneic HSCT in higher‑risk adults.
Most immunotherapies are designed for B‑lineage ALL (CD19, CD20, CD22), and their efficacy depends on antigen expression by blasts.
Blinatumomab (BiTE)
Major toxicities include cytokine release syndrome (CRS), neurologic events (confusion, aphasia, seizures), and infection risk due to B‑cell aplasia and lymphodepletion.
Management involves step‑up dosing, premedication with steroids, inpatient monitoring during initial cycles, and tocilizumab/steroids for higher‑grade CRS.
Inotuzumab ozogamicin (ADC)
Myelosuppression and hepatotoxicity are common; hepatic sinusoidal obstruction/veno‑occlusive disease is the most feared toxicity, particularly when followed by myeloablative transplant.
Fractionated dosing and careful transplant timing/conditioning intensity mitigate risk.
CAR T‑cell products (tisagenlecleucel, brexucabtagene)
CRS is the most frequent serious AE; incidence with tisagenlecleucel in ALL is around three‑quarters of treated patients.
Neurotoxicity (ICANS) occurs in a substantial minority (≈40%) within the first 8 weeks, often after CRS.
Long‑term issues include prolonged B‑cell aplasia and hypogammaglobulinemia, often requiring IVIG replacement, and increased infection risk.
Trials are exploring sequencing inotuzumab → blinatumomab → CAR T or combinations with TKIs for Ph+ ALL to maximize MRD‑negative remission while minimizing cumulative toxicity and transplant need.
Novel bispecifics and CAR constructs target CD22, CD20, and dual antigens to mitigate CD19 escape; NK‑cell and off‑the‑shelf allogeneic CAR platforms aim to reduce manufacturing time and cost.