42 Acute Lymphoblastic Leukemia
Key Points
- Diagnosis: requires immunophenotype, cytogenetics, molecular genetics (IG/TCR, BCR-ABL1, KMT2A)
- Prognosis: genetic subtype & MRD (flow cytometry, qPCR, NGS) key determinants
- Frontline therapy: induction → consolidation → maintenance; CNS prophylaxis essential; age & subtype-driven
- Novel agents: blinatumomab (BiTE), inotuzumab ozogamicin (CD22), CAR-T (tisa-cel, brexu-cel)
- Supportive care: PCP prophylaxis, HCT decisions, toxicity mgmt, fertility counseling, late effects
42.1 Introduction
- Rare, potentially curable clonal lymphoid malignancy; ~50% children, 1/4 AYA (15-39 yrs)
- Prognosis improved w/ newer targeted agents & immunotherapies
- Mgmt evolves by age, genetic subtype, MRD status
42.2 Diagnosis
- Classification: B-ALL (85%), T-ALL (15%); WHO distinguishes ALL (marrow/blood) vs LBL (nodal/extranodal)
- Bone marrow: morphology, cellularity, fibrosis
- Immunophenotype: flow cytometry → CD19, CD20, CD22, CD79a, TdT (B); CD7, CD1a, CD3, CD5 (T)
- Cytogenetics & FISH: BCR-ABL1, KMT2A, hyperdiploidy, hypodiploidy, TCF3-PBX1, complex karyotype
- Molecular: PCR IG/TCR, BCR-ABL1, KMT2A; NGS for emerging subtypes
| Precursor B-cell & T-cell neoplasms | Prognostic significance, if applicable |
|---|---|
| B-lymphoblastic leukemia/lymphoma NOS | Standard |
| B-lymphoblastic leukemia/lymphoma w high hyperdiploidy | Favorable |
| B-lymphoblastic leukemia/lymphoma w hypodiploidy | Unfavorable |
| B-lymphoblastic leukemia/lymphoma w AAMP21 | Unfavorable |
| B-lymphoblastic leukemia/lymphoma w BCR-ABL1 like features | Unfavorable more common in AYA |
| B-lymphoblastic leukemia/lymphoma w ETV6-RUNX1 fusion | Favorable; most common in children |
| B-lymphoblastic leukemia/lymphoma w ETV6-RUNX1-like features | Favorable; more common in children |
| B-lymphoblastic leukemia/lymphoma w TCF3-PBX1 fusion | Standard; most common in children |
| B-lymphoblastic leukemia/lymphoma w TCF3-HLF fusion | Unfavorable |
| B-lymphoblastic leukemia/lymphoma w other defined genetic abnormalities | Unfavorable |
| T-lymphoblastic leukemia/lymphoma NOS | Standard |
| Early T-precursor lymphoblastic leukemia/lymphoma | Unfavorable |
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42.2.1 Clinical workup
- Labs: CBC, CMP, tumor lysis markers (uric acid, LDH, phos), PTT/INR
- CNS: CSF (cell, protein, glucose, cytology) if suspected CNS involvement
- Imaging: CXR or CT for disease extent
- Serology: HIV, HBV; pregnancy test if female
- Fertility: counsel pre-tx (gonadal toxicity risk)
- CNS imaging: MRI/CT w/ contrast before LP (seizure risk)
42.3 Prognosis
- Age: older → worse; AYA intermediate
- WBC: ↑ WBC → worse; peds high-risk >50K; adult ~30K
- Favorable cytogenetics: ETV6-RUNX1 t(12;21), high hyperdiploidy (>50)
- Unfavorable cytogenetics: BCR-ABL1 t(9;22), KMT2A t(4;11), hypodiploidy (<44), complex karyotype (≥3 abnormalities)
- Molecular risk: TP53 mutation, IKZF1 deletion, BCR-ABL1-like features
- Early T-precursor ALL: absent CD1a/CD8, low CD5; myeloid markers → poor outcomes
42.3.1 Measurable Residual Disease (MRD)
- Definition: <5% blasts morphology but residual leukemic cells by sensitive assay (≥10⁻⁴)
- Methods: flow cytometry (10⁻³–10⁻⁴), IG/TCR qPCR (10⁻⁵–10⁻⁶), NGS (10⁻⁶)
- Timing: at diagnosis, post-induction, post-consolidation, post-intensification
- Prognostic impact: detectable MRD post-induction/consolidation → inferior outcomes
- Clinical use: guides escalation, HCT decision, therapy selection
| Assay | Sensitivity in marrow | Advantages | Disadvantages |
|---|---|---|---|
| Flow cytometry | 10⁻³ to 10⁻⁴ | Does not require diagnostic sample; broadly available; provides antigen expression | Limited sensitivity; non-MRD validated flow 10⁻³ to 10⁻⁴ |
| IG/TCR-based qPCR (eg BCR-ABL1) | 10⁻⁵ to 10⁻⁶ | Very sensitive | Requires diagnostic sample for clone identification; requires qPCR equipment |
| Next-generation sequencing (IG/TCR) | 10⁻⁶ | Very sensitive; increasingly commercially available | Requires diagnostic sample |
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MRD of response often used to select treatment, escalate therapy, & guide management in ALL.
42.4 Management
42.4.1 General Principles
- Structure: induction → consolidation → maintenance; ± HCT
- Core agents: steroids, asparaginase, vincristine, doxorubicin, cyclophosphamide, MTX, Ara-C
- CNS prophylaxis: systemic + intrathecal chemotherapy
- Adult regimens: ↑ cumulative traditional cytotoxic vs peds
42.4.2 Front-line Therapy
Ph-negative B-ALL - Pediatric: asparaginase, vincristine, doxorubicin, cyclophosphamide, MTX, Ara-C; ± rituximab (CD20+) - AYA (CALGB 10403): Hyper-CVAD alternating w/ high-dose MTX/Ara-C; ± rituximab, ± TKI - Adult: GOALL/JALSG regimens; multiple intensive blocks; daunorubicin ± dexamethasone
Ph+ ALL (BCR-ABL1 t(9;22)) - All ages: TKI + intensive chemotherapy (Hyper-CVAD) mandatory - TKIs: imatinib (1st-gen), dasatinib, nilotinib, ponatinib (2nd-gen) - Goal: improve EFS vs chemotherapy alone; dasatinib may ↑ EFS vs imatinib - Consolidation & maintenance: continued TKI ± reduced-intensity chemotherapy
42.4.3 Allogeneic Hematopoietic Cell Transplantation (HCT)
- Indications in CR1:
- BCR-ABL1: standard (↓ relapse, ↑ OS)
- Intermediate/high-risk cytogenetics: generally recommended
- KMT2A, hypodiploidy, complex karyotype: HCT benefit
- ETV6-RUNX1, favorable risk: no clear HCT benefit
- Outcomes: vs intensive chemo alone → ↑ OS 45–52% (intermediate/poor-risk)
- Conditioning: myeloablative (MAC) or reduced-intensity (RIC)
- Graft source: matched sibling, matched unrelated donor (MUD), haploidentical
- Considerations: disease risk, comorbidities, donor availability
42.4.4 Treatment for Medically Ill/Older Adults
- Fitness assessment: HCT-CI, APACHE, frailty score
- Options: intensive (Hyper-CVAD), reduced-intensity, or palliative-focused chemotherapy
- Cardiac disease, renal impairment, organ dysfunction: may limit intensive therapy
- Goal-directed approach: balance curability vs toxicity
42.4.5 Treatment of MRD & Relapsed/Refractory ALL
MRD-positive after induction/consolidation - Consider intensification, escalate to immunotherapy/CAR-T, or allogenic HCT - Novel agents routinely used
Blinatumomab (BiTE CD3/CD19) - Mechanism: bispecific T-cell engager - Indications: R/R B-ALL, MRD+ CD19+ ALL - Efficacy: CR ~80% (INNOVATE trial); ↑ OS vs chemo - Toxicities: CRS, neurologic (ICANS) - Front-line role: emerging benefit for early response
Inotuzumab ozogamicin (CD22-ADC) - Mechanism: anti-CD22 antibody-drug conjugate - Indications: R/R CD22+ (>50%) B-ALL - Efficacy: CR ~80%; ↑ OS vs chemo - Toxicities: cytopenia, sinusoidal obstruction syndrome (SOS/VOD), hepatotoxicity
CAR-T Therapies - Tisagenlecleucel (tisa-cel): CD19-CAR, ages ≤26, R/R B-ALL - Brexucabtagene (brexu-cel): CD19-CAR, ages ≥18, R/R B-ALL - Both: high response rates; toxicities = CRS, ICANS, cytopenia
| Agent | Mechanism of action | Indication of use | Notable toxicities |
|---|---|---|---|
| Blinatumomab | Bispecific (CD3/CD19) T-cell engager | t/r B-ALL; MRD+ CD19+ B-ALL | CRS; neurologic toxicity |
| Inotuzumab ozogamicin | Antibody-drug conjugate targeting CD22 | t/r CD22+ (>50%) B-ALL | Cytopenia; SOS/VOD |
| CAR T cell-transduced & brentuximab autoleucel | CD19-directed CAR T-cell therapies | t/r CD19+ B-ALL | CRS; ICANS |
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42.5 Supportive Care, Toxicities, & Late Effects
42.5.1 Infection Prophylaxis
- PCP: TMP-SMX (all steroids ≥3 wks)
- CMV: monitor for reactivation; prophylaxis if high-risk
- Fungal: monitor; no routine prophylaxis if not severe immunosuppression
- Blood products: irradiate if HCT planned (prevent alloimmunization)
42.5.2 Acute Toxicity Management
- Nausea/vomiting: aggressive antiemetics (5-HT3, NK1 antagonists)
- Thromboembolic disease: DVT prophylaxis; monitor for PE risk
- Central line infection: surveillance; early intervention
- Psychosocial support: patient & family counseling throughout
42.5.3 Late Effects (5–10+ yrs post-Tx)
- Metabolic: ↑ glucose intolerance/DM (high-dose glucocorticoids, asparaginase)
- Cardiac: cardiomyopathy (anthracyclines); monitor ejection fraction
- Neurologic: peripheral neuropathy (vincristine)
- Fertility: gonadal dysfunction (alkylating agents); counsel + sperm/egg cryopreservation
- Secondary malignancy: ALL (etoposide), solid tumors (radiation); ↑ risk w/ intensified Tx
- Survivor education: late effects monitoring, screening programs