What are the treatment approaches for lymphomas and leukemias in pediatric patients?

Pediatric Lymphomas and Leukemias: Treatment Approaches

Overview of Pediatric Acute Lymphoblastic Leukemia (ALL)

Pediatric ALL should be treated with risk-stratified multiagent chemotherapy at specialized cancer centers, consisting of induction, consolidation, and maintenance phases over 2-3 years, with treatment intensity determined by minimal residual disease (MRD) status and molecular/cytogenetic features. 1, 2

Current Survival Outcomes

• Pediatric ALL has achieved remarkable cure rates of approximately 89-90%, representing one of the most successful treatment paradigms in pediatric oncology 1, 3, 4
• This dramatic improvement from ~10% survival in the 1960s stems from risk-adapted multiagent chemotherapy, effective CNS prophylaxis, molecular understanding of disease biology, and MRD monitoring 3, 4
• Infants younger than 1 year remain an exception with 6-year overall survival of only 58.2%, showing no improvement over 30 years 1
• Adolescent and young adult (AYA) patients have lower survival rates (61% 5-year OS) compared to younger children, though outcomes improve when treated with pediatric-inspired regimens 1, 5

Treatment Structure and Components

Induction Therapy (Weeks 1-4)

Begin with multiagent induction chemotherapy including vincristine, corticosteroids (dexamethasone or prednisone), and asparaginase, with or without anthracycline depending on risk stratification. 1, 2, 4

• Three-drug induction (dexamethasone, asparaginase, vincristine) achieves 70-90% complete remission rates for standard-risk B-ALL 1
• Four-drug induction adding anthracycline is reserved for higher-risk patients 1
• Asparaginase is critical as it is relatively non-myelosuppressive and improves long-term survival to 30-50% when added to two-drug regimens 1, 6

Risk Stratification Based on MRD

MRD assessment after induction is the single most important prognostic factor and determines subsequent treatment intensity. 1, 2, 3

• MRD-negative patients (<0.01% blasts) proceed to standard consolidation and maintenance therapy 1, 2
• MRD-positive patients (≥0.01% blasts) require intensified consolidation with consideration of blinatumomab or tisagenlecleucel 1, 2
• Persistently positive MRD after consolidation warrants immunotherapy (blinatumomab or tisagenlecleucel) before proceeding to hematopoietic stem cell transplantation (HSCT) 1, 2

Consolidation Therapy (Months 2-6)

Consolidation includes high-dose methotrexate (for high-risk and T-ALL), cyclophosphamide, cytarabine, and repeated doses of asparaginase. 1, 4

• High-risk patients receive intermediate-dose methotrexate (1 g/m² over 24 hours) with leucovorin rescue 1
• T-ALL patients benefit from higher cyclophosphamide doses and triple intrathecal therapy 1
• Delayed intensification (re-induction) with dexamethasone, vincristine, and asparaginase improves outcomes, particularly in non-intensive protocols 1

Maintenance Therapy (Up to 2-3 Years Total)

Maintenance consists of daily oral mercaptopurine and weekly methotrexate, with periodic vincristine and corticosteroid pulses, continuing for 2-3 years from diagnosis. 1, 4, 7

• Dexamethasone during maintenance improves systemic and CNS leukemia control 1
• Pharmacogenomic testing for TPMT and NUDT15 variants guides mercaptopurine dosing to prevent toxicity 1

CNS-Directed Therapy

All patients require CNS prophylaxis with intrathecal chemotherapy (methotrexate, cytarabine, and corticosteroid) starting at diagnosis, without routine cranial irradiation. 1, 2

• Triple intrathecal therapy is mandatory for T-ALL and patients with CNS involvement at diagnosis 1
• Prophylactic cranial irradiation is not recommended due to serious long-term complications and lack of survival benefit with effective systemic and intrathecal therapy 1
• Intensified intrathecal chemotherapy prevents both CNS relapse and late bone marrow relapse 2

Special Populations and Molecular Subtypes

Philadelphia Chromosome-Positive (Ph+) B-ALL

Combine intensive chemotherapy with tyrosine kinase inhibitors (imatinib 340 mg/m²/day or dasatinib) to achieve 3-year event-free survival of 80-86%. 1, 2

• TKI therapy should begin during induction and continue throughout all treatment phases 1, 2
• HSCT in first complete remission is no longer routinely required with modern TKI-based regimens 1

BCR::ABL1-Like B-ALL

Identify kinase-activating alterations (ABL1, ABL2, PDGFRB, JAK2, CRLF2 fusions) through molecular testing and consider targeted therapy with appropriate TKIs or JAK inhibitors. 1

• This subtype comprises 15-20% of pediatric B-ALL and requires intensified therapy 1
• FISH probes for ABL1, ABL2, PDGFRB, and JAK2 rearrangements guide targeted therapy selection 1

Infant ALL (Age <12 Months)

Treat with Interfant-based chemotherapy regimens incorporating elements of both ALL and AML protocols, with intensified cytarabine and anthracycline therapy. 1, 2

• KMT2A (MLL) rearrangements occur in 70-80% of infant ALL and confer poor prognosis 1
• These patients require more intensive therapy but avoid prolonged maintenance due to different disease biology 1, 2

T-Cell ALL/Lymphoblastic Lymphoma

Use intensified chemotherapy backbones with higher cyclophosphamide doses, extended asparaginase, and consideration of bortezomib addition. 1

• Modern T-ALL protocols achieve outcomes nearly equivalent to B-ALL (5-year OS ~85%) 1
• Early T-cell precursor (ETP) ALL requires identification by flow cytometry (lacks CD5, CD8, CD1a; expresses myeloid markers) but does not necessarily require treatment modification 1
• Bortezomib added to BFM backbone chemotherapy improves event-free survival and overall survival specifically in T-lymphoblastic lymphoma 1

Pediatric Aggressive Mature B-Cell Lymphomas

Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma

Treat sporadic Burkitt lymphoma and DLBCL with short-duration, high-intensity multiagent chemotherapy regimens (typically 3-6 months) rather than prolonged ALL-type therapy. 1

• These are highly aggressive but curable malignancies requiring treatment at centers with specific expertise 1
• Regimens include high-dose methotrexate, cyclophosphamide, cytarabine, and rituximab for CD20-positive disease 1
• Treatment duration is much shorter (3-6 months) compared to ALL (2-3 years) 1

Relapsed/Refractory Disease Management

Risk Stratification at Relapse

Classify relapse timing as very early (<18 months from diagnosis), early (18-36 months), or late (>36 months or >6 months off therapy), with site of relapse (bone marrow vs. extramedullary) determining treatment intensity. 1

• Very early bone marrow relapse has the worst prognosis and requires HSCT in second complete remission 1
• All T-ALL relapses are considered high-risk regardless of timing or site 1
• Isolated extramedullary relapse (CNS or testicular) still requires systemic chemotherapy to prevent subsequent bone marrow relapse 2

Immunotherapy Options

For relapsed/refractory B-ALL, use blinatumomab (bispecific T-cell engager) or tisagenlecleucel (CAR T-cell therapy) to achieve MRD-negative remission before proceeding to HSCT or as definitive therapy. 1, 2

• Blinatumomab achieves 88% complete MRD response in patients with MRD ≥10⁻³ 8
• Tisagenlecleucel produces long-term remissions without subsequent HSCT in some patients, with 3-year relapse-free survival of 52% and only 22% proceeding to HSCT 1, 2
• Inotuzumab ozogamicin (anti-CD22 antibody-drug conjugate) is an alternative for CD22-positive disease 1, 2

Reinduction Chemotherapy

Use bortezomib-based reinduction regimens for first relapse, achieving 68% second complete remission rates for B-ALL and 63-72% for early relapses. 1

• Standard reinduction includes vincristine, anthracycline, corticosteroid, and asparaginase with added bortezomib 1
• For T-ALL relapse, consider myeloid-type consolidation (ADE/MAE regimens) for patients with MRD ≥5×10⁻⁴ after induction 1

Resource-Stratified Approaches

Basic Resources

In resource-limited settings, use two-drug induction (vincristine and corticosteroid) achieving 50-70% remission with 20% cure rate, adding asparaginase if affordable to improve survival to 30-50%. 1

• Two-drug induction is less toxic, requires minimal supportive care, and reduces treatment abandonment rates 1
• Twinning programs with institutions in developed countries facilitate training and difficult case management 1

Limited Resources

Implement three-drug induction (dexamethasone, asparaginase, vincristine) with risk-adapted intensification, achieving up to 60% cure rates. 1

• Add daunorubicin and extended asparaginase for poor early responders based on day 8 peripheral blood or day 15 bone marrow evaluation 1
• Use intermediate-dose methotrexate (1 g/m² over 24 hours) for high-risk cases rather than high-dose protocols 1

Enhanced/Maximum Resources

Adopt comprehensive risk-directed protocols from major cooperative groups (COG, BFM, DFCI) featuring early intrathecal therapy, high-dose methotrexate consolidation, delayed intensification, and continuation therapy. 1

Critical Pitfalls to Avoid

• Never delay treatment at non-specialized centers: The complexity of ALL therapy with required supportive care (tumor lysis prophylaxis, infection management, transfusion support) necessitates treatment at specialized cancer centers 1
• Never proceed to HSCT with detectable MRD when avoidable: Additional immunotherapy or chemotherapy to achieve MRD negativity before HSCT significantly improves post-transplant outcomes 1, 2
• Never omit CNS prophylaxis: Intrathecal chemotherapy must begin at diagnosis to prevent CNS relapse, which has poor salvage rates 1, 2
• Never use chronologic age alone for treatment decisions: AYA patients (ages 15-39) benefit from pediatric-inspired regimens rather than adult protocols, yet only 21-31% treated at adult centers receive appropriate therapy 5
• Never ignore pharmacogenomic testing: TPMT and NUDT15 variants require mercaptopurine dose adjustments to prevent life-threatening myelosuppression 1