Acute Lymphoid Leukemia¶
Chapter 111 | Part 4: Oncology and Hematology · Part 4 – Oncology: Hematologic Malignancies · Chapter 111
Key Clinical Points¶
- ALL arises from hematopoietic progenitors in bone marrow/lymphatic system, causing proliferation of immature leukemic cells.
- L3 morphology (5% of adults) indicates mature B-cell lineage ALL (B-ALL).
- Ph+ ALL occurs in ~50% of elderly B-lineage patients.
- MRD status is the most critical prognostic factor for survival; MRD-negative patients have ~70% DFS vs. <40% for MRD-positive.
- CNS involvement at diagnosis occurs in 5–10% of adults (higher in mature B-ALL [10–15%] and T-ALL [10%]).
- Treatment follows a structured sequence: pre-phase, induction, consolidation, and maintenance.
- TKIs like dasatinib and ponatinib are essential for Ph+ ALL and cross the blood-brain barrier.
- Blinatumomab (anti-CD19/CD3) is highly effective in specific regimens.
- SCT is recommended for high-risk or MRD-positive patients; allogeneic SCT is preferred over autologous.
- Pediatric-inspired therapies improve outcomes in elderly patients by using higher doses of glucocorticoids, vincristine, and asparaginase with fewer anthracyclines/alkylating agents.
1. DEFINITION & OVERVIEW¶
Acute lymphoblastic leukemia (ALL) arises from hematopoietic progenitors in bone marrow or lymphatic system, leading to proliferation of immature leukemic cells.
• Clinical Presentation: Bone marrow infiltration causes anemia, granulocytopenia, and thrombocytopenia. Symptoms include fatigue (70%), infection (50%), and hemorrhage (30%). • Tumor Bulk Manifestations: Lymphadenopathy (20%), hepatosplenomegaly (15%), and CNS involvement (5–10% in adults). • Diagnosis: Confirmed via peripheral blood/bone marrow examination. • Subtype Identification: Immunologic markers (CD19, CD79a, cyCD22) define B-ALL; T-cell markers (CD7, cyCD3) define T-ALL. • Morphology: FAB classification includes L1–L3; only L3 indicates mature B-ALL.
1.1 Classification Systems¶
• Immunologic Classification: ◦ B-cell (CD19+, CD79a+) ◦ T-cell (CD7+, cyCD3+) ◦ Threshold: >20% cell staining with monoclonal antibody defines a positive marker. • Biphenotypic Leukemias: Express both lymphoid/myeloid markers; may require ALL/AML protocols (pediatric studies favor ALL protocols followed by AML consolidation).
2. EPIDEMIOLOGY¶
• Pediatric Incidence: Most common childhood malignancy, peaking at 3–4 years. • Adult Incidence: 0.7–1.8/100,000/year; higher in AYAs and elderly. • Ph+ ALL: Occurs in ~50% of elderly B-lineage patients. • Leukemic Blasts (Peripheral Blood): ◦ 41% WBC <10×10⁹/L ◦ 31% 10–50×10⁹/L ◦ 28% >50–100×10⁹/L ◦ 16% >100×10⁹/L • Leukemic Blasts (Bone Marrow): ◦ 71% cases >90% ◦ 25% 51–90% ◦ 4% <50%
2.1 Risk Factors¶
• Environmental/Chemical: Ionizing radiation and prior chemotherapy (more common in AML). • Secondary ALL: Following alkylating agents or topoisomerase inhibitors (associated with AML, MDS, breast cancer). • Congenital Disorders: Klinefelter’s syndrome, Fanconi’s anemia, Bloom’s syndrome, ataxia-telangiectasia, neurofibromatosis. • Down’s Syndrome: 20× higher leukemia risk.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
• Etiology: Largely unknown; driven by environmental and genetic factors. • Radiation/Chemicals: Increase risk, especially in AML. • Secondary ALL: Linked to alkylating agents/topoisomerase inhibitors. • Congenital Disorders: Klinefelter’s, Fanconi’s, Bloom’s, ataxia-telangiectasia, neurofibromatosis. • Down’s Syndrome: 20× higher leukemia risk. • Infectious Agents: No direct viral causation for ALL; EBV linked to Burkitt’s; HTLV-1 causes adult T-cell leukemia/lymphoma.
4. CLINICAL FEATURES¶
• Hematologic Impact: Bone marrow infiltration → anemia, granulocytopenia, thrombocytopenia. • Symptoms: Fatigue (70%), infection (50%), hemorrhage (30%). • Tumor Bulk: Lymphadenopathy (20%), hepatosplenomegaly (15%), and CNS involvement (5–10% in adults). • Laboratory Findings at Diagnosis: ◦ WBC: 28% are 50–100×10⁹/L; 16% are >100×10⁹/L. ◦ Neutrophils: 27% <100×10⁹/L. ◦ Hemoglobin: 47% >9 g/dL. ◦ Blasts: 71% of bone marrow cases have >90% blasts.
5. DIFFERENTIAL DIAGNOSIS¶
• Immunologic Markers: ◦ B-ALL: CD19+, CD79a+, cyCD22+. ◦ T-ALL: CD7+, cyCD3+. • Morphology (FAB): L1–L3; only L3 indicates mature B-ALL. • Biphenotypic: Express both lymphoid/myeloid markers → may require ALL/AML protocols.
5.1 B-Cell Lineage ALL (B-ALL)¶
• Overall: 76% of adult ALL. • Subtypes: ◦ Common ALL (CD10+) ◦ Pro B-ALL (cyIg+) ◦ Pro-B-ALL (HLA-DR+, TdT+, CD19+) ◦ Mature B-ALL (sIgM+, TdT–, CD34–) → Burkitt’s leukemia (3–4% of adults).
5.2 T-Cell Lineage ALL (T-ALL)¶
• Overall: 24% of adult ALL; CD7+, cyCD3+. ◦ Early pro/pre-T-ALL (CD1a–, CD8–) ◦ Cortical T-ALL (CD1a+) ◦ Mature T-ALL (sCD3+) ◦ ETP-ALL: CD1a–, CD8–, weak CD5, myeloid/stem cell markers.
6. INVESTIGATIONS & DIAGNOSIS¶
• Bone Marrow Examination: ◦ Aspirates/biopsies confirm ALL and distinguish from AML. ◦ Criteria: >90% blasts in ~70% of patients; normal elements reduced/absent. • Lumbar Puncture (LP): ◦ Essential for CNS leukemia diagnosis (Criteria: ≥5 cells/μL or morphology-positive blasts). ◦ Timing: Debated pre-treatment vs. post-remission. ◦ Action: Administer intrathecal methotrexate at first LP to eliminate transferred blasts. • Cytogenetic and Molecular Analysis: ◦ Standard cytogenetics, FISH, RT-PCR → detect Ph+ (t(9;22)), MLL-AF4, PBX-E2A. ◦ Gene expression profiling → identify ETP-ALL/Ph-like ALL.
7. MANAGEMENT & TREATMENT¶
- Pre-phase Therapy: ◦ Glucocorticoids (prednisone 20–60 mg/d or dexamethasone 6–16 mg/d) ± vincristine/cyclophosphamide for 5–7 days. ◦ Goals: Reduce tumor lysis risk, initiate support (transfusions), allow time for cytogenetics/molecular analysis.
- Induction Therapy: ◦ Regimens: Vincristine, glucocorticoids, anthracyclines ± cyclophosphamide/cytarabine. ◦ Asparaginase: Now standard in adults; pegylated asparaginase preferred for prolonged depletion. ◦ Dexamethasone: Preferred over prednisone for CNS penetration.
- Consolidation: ◦ High-dose (HD) methotrexate (1–5 g/m²). ◦ HD cytarabine (4–12 doses at 1–3 g/m²).
- Maintenance Therapy: ◦ Drugs: 6-mercaptopurine, methotrexate + intrathecal therapy. ◦ Duration: 2–2.5 years (except in Burkitt cases).
- Ph+ ALL Specific Treatment: ◦ TKIs (imatinib, dasatinib, ponatinib) during induction, consolidation, and maintenance; continue post-SCT.
- CNS Prophylaxis & Treatment: ◦ Intrathecal methotrexate 3–5x/week until CSF clear. ◦ CNS relapse → local/systemic therapy; allogeneic SCT + salvage chemotherapy. ◦ CAR-T cells (CD19-targeting) for CNS relapse.
- Stem Cell Transplantation (SCT): ◦ Indicated: High-risk or MRD-positive patients; survival ~50% in first CR. ◦ Preference: Allogeneic over autologous; peripheral blood stem cells used when no sibling available.
- Targeted Therapies: ◦ TKIs (imatinib, dasatinib, ponitinib) for Ph/BCR-ABL+ ALL. ◦ Blinatumomab (anti-CD19/CD3) → 98% CR in chemotherapy-free regimens.
Treatment Algorithm (Figure 111-1)¶
• Stepwise Pathway: 1. Diagnosis → Baseline MRD Evaluation. 2. Induction Phase I → Induction Phase II → Consolidation Phase I. 3. Consolidation Phase I → Maintenance Therapy. • Monitoring: ◦ MRD evaluation performed every 3 months during consolidation and maintenance phases. • CNS Prophylaxis: ◦ Intrathecal MTX or triple MTX (MTX, AraC, Dexa/Pred) + optional cranial irradiation (24 Gy). • Maintenance Duration: ≈ 2 years (except in Burkitt cases).
Targeted Therapy Options¶
• Tyrosine Kinase Inhibitors (TKIs): ◦ Ph/BCR-ABL+ ALL: Imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib. ◦ Ph/BCR-ABL-like ALL: Dasatinib, ponatinib; JAK2: ruxolitinib. • Immunologic Approaches: ◦ Monovalent and Bivalent antibodies (e.g., blinatumomab). ◦ Adoptive cellular therapy (T cells engineered to kill leukemic cells). • Checkpoint Inhibitors: ◦ PD-1 inhibitors: pembrolizumab, nivolumab. ◦ CTLA-4 inhibitors: ipilimumab. • Other Targeted Agents: ◦ Proteasome inhibitors: bortezomib, ixazomib. ◦ BCL-2 inhibitors: venetoclax, navitoclax.
Clinical Outcomes by Subtype (Table 111-4)¶
• Burkitt’s leukemia: Short intensive chemotherapy + rituximab; no SCT/maintenance → 80–90% OS. • Ph BCR-ABL: Intensive chemotherapy + TKI ± SCT → 60–70% OS. • Ph-like ALL: Chemotherapy + dasatinib/JAK inhibitors → ≤50% OS.
COMPLICATIONS & PROGNOSIS¶
• MRD Status: Most important prognostic factor. ◦ MRD-negative → ~70% DFS. ◦ MRD-positive → <40% DFS. • CNS Involvement: ◦ 5–10% of adults; higher in mature B-ALL (10–15%) and T-ALL (10%). • Relapsed ALL: Allogeneic SCT is curative option; CAR-T cells effective for CNS relapse. • Elderly Patients: Palliative regimens → 40% CR, 24% early death, poor OS.
SPECIAL POPULATIONS¶
• Elderly Patients: ◦ Less intensive protocols (glucocorticoids, vincristine, asparaginase). ◦ Avoid anthracyclines/alkylating agents to reduce toxicity. ◦ Ph+ ALL occurs in ~50% of elderly B-lineage patients. • AYAs: 70–80% OS with optimized treatment. • Pediatric-Inspired Therapies: ◦ Higher glucocorticoids/vincristine/asparaginase doses, fewer anthracyclines/alkylating agents. ◦ Strict adherence to time-dose intensity reduces SCT reliance.
KEY PEARLS & HIGH-YIELD POINTS¶
• L3 morphology indicates mature B-ALL (5% of adults). • Ph+ ALL occurs in ~50% of elderly B-lineage patients. • MRD status is the most important prognostic factor. • Dasatinib/ponatinib cross blood-brain barrier for CNS leukemia. • SCT recommended for high-risk or MRD-positive patients. • Pediatric-inspired therapies improve outcomes in elderly patients.
Reference Tables¶
TABLE 111-1 Laboratory Values at Diagnosis of Acute Lymphoblastic Leukemia (ALL) NO. Initial white blood cell count (×…¶
Harrison's 22e, p.844
| 111 | Acute Lymphoid Leukemia Dieter Hoelzer |
|---|---|
TABLE 111-1 Laboratory Values at Diagnosis of Acute Lymphoblastic Leukemia (ALL)
| ALL | ||
|---|---|---|
| NO. | 1273 | |
| Initial white blood cell count (× 109/L) | <10 10–50 >50–100 >100 |
41% 31% 28% 16% |
| <50–100 <100,000 |
||
| Platelets (× 109/L) | <20 21–40 41–100 >100 |
22% 22% 29% 27% |
| <7 7–9 >9 |
||
| Leukemic blasts in peripheral blood | 0% 25–75% >75% |
8% 34% 36% |
| <50% 51–90% >90% |
TABLE 111-2 Immunologic, Cytogenetic, Molecular, and Clinical Characteristics of Adult Acute Lymphoblastic Leukemia¶
Harrison's 22e, p.845
| SUBTYPES | MARKER | INCIDENCE | FREQUENT CYTOGENETIC ABERRATIONS |
GENETIC ABERRATIONS AND FUSION TRANSCRIPTS |
CLINICAL CHARACTERISTICS | RELAPSE KINETICS AND LOCALIZATION |
|---|---|---|---|---|---|---|
| B-lineage ALL (B-ALL) |
HLA-DR+, TdT+, CD19+, and/or CD79a+, and/or cyCD22+ |
76% | ||||
| No additional differentiation markers Frequent myeloid coexpression (>50%) CD10– |
112% | t(4;11) (q21;q23) |
70% ALL1-AF4 (20% Flt3 in MLL+) |
High WBC (>100,000/μL) (26%) | ||
| Common ALL | CD10+ | 49% | t(9;22)(q34;q11) del(6q) |
33% BCR::ABL1 with 54% IKFZ1 del >25% CDKN2A/B |
Higher age >50 years (24%) | Mainly BM (>90%) Prolonged relapse kinetics (up to 5–7 years) |
| CD10±, cyIg+ | 12% | t(9;22)(q34;q11) t(1;19)(q23;p13) |
4% t(1;19)/PBX-E2A | |||
| Mature B-ALL | TdT–, CD34–, sIg+ | 4% | t(8;14)(q24;q32) t(2;8)(p12;q24) t(8;22)(q24;q11) |
Higher age >55 years (27%) Frequent organ involvement (32%) and CNS involvement (13%) |
Frequent CNS (10%) Short relapse kinetics (up to 1–1.5 years) |
|
| TdT±, cyCD3, CD7+ | 24% | t(10;14)(q24;q11) t(11;14)(p13;q11) |
50% NOTCH1B 33% HOX11b 5% HOX11L2b 4% NUP213-ABL1 |
Younger age (90% <50 years) Frequent mediastinal tumors (60%) Frequent CNS involvement (8%) High WBC (>50/μL) (46%) |
||
| Early Pro/Pre T-ALL Cortical T-ALL Mature T-ALL |
No additional differentiation markers, mostly CD2–/(+), SCD3–, CD1a– CD1a+, sCD3± sCD3+, CD1a– |
6% 12% 6% |
TABLE 111-3 Response Parameters According to Minimal Residual Disease¶
Harrison's 22e, p.846
| TERMINOLOGY | DEFINITION |
|---|---|
| Complete hematologic remission (CHR) |
Leukemic cells not detectable by light microscopy (<5% blast cells in bone marrow [BM]) |
| Molecular failure/MRD positivity |
Patient in complete hematologic remission, but not in molecular complete remission >0.01% |
| Hematologic relapse | >5% blast cells in BM/blood |
TABLE 111-4 Best Results in Recent Studies for Adult Acute Lymphoblastic Leukemia¶
Harrison's 22e, p.847
| SUBTYPE | TREATMENT | OVERALL SURVIVAL |
|---|---|---|
| Burkitt’s leukemia | Short intensive chemotherapy + rituximab; no SCT; no maintenance |
80–90% |
| Pediatric inspired, few/no SCT | ||
| Intensive chemotherapy +/– SCT | ||
| Less intensive chemotherapy + immunotherapy |
||
| Various | ||
| B-lineage ALL, Ph+ | ||
| Ph BCR-ABL | Intensive chemotherapy + TKI +/– SCT |
60–70% |
| Ph-like ALL | Chemotherapy + dasatinib/JAK inhibitors |
≤50% |
| Intensive chemotherapy + nelarabine + SCT |
||
| Intensive chemotherapy + nelarabine, no SCT |
||
| Intensive chemotherapy + nelarabine + SCT |
TABLE 111-5 Targeted Therapies in Adult Acute Lymphoblastic Leukemia (ALL) Tyrosine Kinase Inhibitors (TKIs)…¶
Harrison's 22e, p.848
- Tyrosine Kinase Inhibitors (TKIs)
- Ph/BCR-ABL+ ALL
TKIs
Imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib
Ph/BCR-ABL-like ALL
ABL1, ABL2: dasatinib, ponatinib; JAK2: ruxolitinib - Immunologic Approaches
- Antibodies directed against leukemia surface antigens
Monovalent antibodies
Bivalent antibodies against the tumor and CD3 (e.g., blinatumomab)
Adoptive cellular therapy
T cells engineered to kill leukemic cells - Checkpoint Inhibitors
- PD-1 inhibitors: pembrolizumab, nivolumab
CTLA-4 inhibitors: ipilimumab - Targeted Agents
- Proteasome inhibitors: bortezomib, ixazomib
BCL-2 inhibitors: venetoclax, navitoclax
TABLE 111-6 Expression of Antigens in B-Cell Lineage Acute Lymphoblastic Leukemia (ALL) for Potential Antibody Therapy¶
Harrison's 22e, p.848
| SURFACE ANTIGEN |
ALL SUBTYPES | EXPRESSION ON LBCa |
MONOCLONAL ANTIBODY |
|---|---|---|---|
| CD20 | Burkitt’s lymphoma/ leukemia B-precursor |
86–100% 30–40% |
Rituximab Ofatumumab |
| B-precursor Mature B-ALL |
93–98% ~100% |
||
| CD19 | B-precursor Mature B-ALL |
95–<100% 94–<100% |
T cell–activating therapies Blinatumomab Bispecific CD3/CD19 Chimeric antigen receptor modified T cells (CAR T cells) |