What is the role of CAR-T (Chimeric Antigen Receptor T-cell) therapy in treating pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL)?

CAR-T Therapy in Pediatric Patients

CAR-T cell therapy, specifically tisagenlecleucel, is FDA-approved and highly effective for pediatric and young adult patients (up to 25 years of age) with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), achieving overall remission rates of approximately 81-90%, with the majority being MRD-negative. 1, 2

Primary Indications and Patient Selection

FDA-Approved Indication

• Tisagenlecleucel (KYMRIAH) is indicated for patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. 1
• The therapy has demonstrated remarkable efficacy with overall remission rates of 81-90% within 3 months of infusion, with all responses being MRD-negative. 2

Eligibility Criteria

Patients must meet specific clinical criteria before proceeding:

• ECOG performance status <2, Karnofsky >60%, or Lansky >60% 3
• Life expectancy >6-8 weeks minimum 3
• Hemodynamically stable and able to tolerate fluid shifts during leukapheresis 2
• Free from active bacterial or fungal infection, active viremia, or active uncontrolled infection 3, 1
• No active graft-versus-host disease (GVHD) 1

Treatment Algorithm and Procedure

Pre-Treatment Phase: Leukapheresis

• Pediatric patients typically require a leukapheresis central venous catheter rather than peripheral venous cannula for collection. 2
• Close monitoring for hypotension, hypocalcemia, and catheter-related pain is imperative during pediatric leukapheresis, particularly among infants and younger children who might not verbalize symptoms. 2

Lymphodepletion Chemotherapy

The recommended lymphodepletion regimen for pediatric B-ALL is:

• Fludarabine 30 mg/m² intravenously daily for 4 days 1
• Cyclophosphamide 500 mg/m² intravenously daily for 2 days starting with the first dose of fludarabine 1
• Confirm availability of KYMRIAH prior to starting the lymphodepleting regimen 1
• Exceptions to cyclophosphamide-fludarabine regimens should be considered in cases of hemorrhagic cystitis and/or resistance to prior cyclophosphamide-based regimens. 2

CAR-T Cell Dosing

Based on patient weight at time of leukapheresis:

• Patients ≤50 kg: administer 0.2 to 5.0 × 10⁶ CAR-positive viable T cells per kg body weight 1
• Patients >50 kg: administer 0.1 to 2.5 × 10⁸ CAR-positive viable T cells 1

Timing of Infusion

• Infuse KYMRIAH 2 to 14 days after completion of lymphodepleting chemotherapy 1
• Delay infusion if patient has unresolved serious adverse reactions from preceding chemotherapies, active uncontrolled infection, active GVHD, or worsening leukemia burden following lymphodepleting chemotherapy. 1

Post-Infusion Monitoring and Management

Hospitalization and Initial Monitoring

• Consider inpatient admission for a minimum of 3-7 days following infusion based on published experience with tisagenlecleucel in pediatric and young adult patients. 2
• Given the potential for rapid clinical deterioration, maintain a low threshold for patient admission upon development of fever and/or signs or symptoms suggestive of CRS and/or CRES. 2
• Patients require close monitoring for at least 4 weeks post-infusion. 3, 4

Specific Monitoring Parameters

• Perform CRS grading at least once every 12 hours and more often if changes are noted or concerns exist. 2
• Assess vital signs at least every 8 hours during and after infusion. 3, 4
• Conduct neurological evaluations at least twice daily. 4
• Monitor complete blood count, comprehensive metabolic panel, C-reactive protein, and ferritin levels regularly. 4
• Address parent and/or caregiver concerns because early signs or symptoms of CRS can be subtle and best recognized by those who know the child best. 2

Activity Restrictions

• Patients should refrain from driving or hazardous activities for at least 8 weeks following infusion. 4

Toxicity Recognition and Management

Cytokine Release Syndrome (CRS)

CRS should be suspected if at least one of the following is present during the first 2 weeks following CAR-T infusion:

• Fever ≥38°C 2
• Hypotension (for patients aged 1-10 years: systolic blood pressure <[70 + (2 × age in years)] mmHg; for those aged >10 years: SBP <90 mmHg) 2
• Hypoxia with arterial oxygen saturation <90% on room air 2
• Evidence of organ toxicity as determined by CTCAE grading system (version 5.0) 2

Key monitoring points:

• Maintain high vigilance for sinus tachycardia as an early sign of CRS (based on age-specific normal range or baseline values). 2
• Apply PALICC at-risk P-ARDS criteria for CRS grading of hypoxia. 2

Treatment approach:

• Grade 1 CRS: manage with fever reduction and supportive care 3
• Grade 2-4 CRS: administer tocilizumab and corticosteroids as needed 3, 1
• Tocilizumab pediatric dosing: patients weighing <30 kg receive 12 mg/kg; those weighing ≥30 kg receive 8 mg/kg 2

CAR-T Cell-Related Encephalopathy Syndrome (CRES)

• Neurotoxicity can occur 1-2 weeks post-infusion, with late onset possible up to a month later. 4
• The incidence of CRES may be lower with second-round CAR-T therapy (11.1%) compared to first-round therapy (33.3%). 5
• Perform delirium screening using the CAPD tool. 2
• Provide close neurological monitoring and prompt intervention for patients with neurotoxicity. 3

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

• CAR-T cell-related HLH and/or MAS have been shown to resolve following administration of anti-IL-6 therapy and corticosteroids. 2
• Refractory cases can require further therapy, including consideration of systemic and/or intrathecal therapy based on HLH-2004 management guidelines or use of the IL-1 receptor antagonist anakinra. 2

Hematologic Toxicity

• Acute kidney injury in children can be graded according to CTCAE using pRIFLE and KDIGO definitions of oliguria. 2
• Patients with grade 3-4 neutropenia, anemia, and thrombocytopenia should receive supportive care and transfusions as needed. 3
• ANC and platelet counts are reduced obviously post-CAR-T, with severe thrombocytopenia and severe anemia potentially more common after first-round therapy. 5

Infections

• Early and late infection rates may be higher after first-round CAR-T therapy compared to second-round therapy. 5
• Monitor for infections and provide appropriate antimicrobial therapy. 3

Long-Term Outcomes and Considerations

Efficacy and Survival

• At median follow-up of 29 months, overall survival was 12.9 months (95% CI, 8.7-23.4 months) in adult studies, with 6-month OS rates of 90% and 12-month OS rates of 76% in pediatric populations. 2
• Event-free survival at 6 months was 78% (95% CI, 51%-88%) in pediatric studies. 2
• Long-term remissions have been reported after tisagenlecleucel without subsequent HSCT, with 3-year relapse-free survival of 52% and only 22% proceeding to HSCT. 6

Relapse Patterns and Management

• Approximately 40-60% of patients will relapse within the first year after CAR-T therapy. 2
• Blinatumomab-exposed patients, particularly non-responders, have lower CR rates (64.5%) and lower 6-month EFS rates (27.3%) compared to blinatumomab-naïve patients (93.5% CR, 72.6% EFS). 2
• Blinatumomab-exposed patients are more likely to have CD19-dim or -partial expression before CAR-T infusion (13.3% versus 6.5%), which is associated with shorter EFS and RFS. 2
• Prior inotuzumab ozogamicin therapy may confer inferior CAR-T outcomes. 2

Role of Consolidative Allogeneic HSCT

The decision regarding consolidative HSCT after CAR-T therapy remains controversial:

• No clinical trials of allo-HSCT versus 'watch and wait' have been carried out to demonstrate superiority of one approach over the other. 2
• Some studies report no EFS difference in adults undergoing allo-HSCT consolidation after CD28 CAR-T therapy, while others report superior RFS (61% at 24 months) with allo-HSCT. 2
• The 1-year non-relapse mortality rate with post-CAR-T HSCT was 21%, with factors predictive of higher mortality including delayed allo-HSCT (>80 days after CAR-T therapy) and high HSCT comorbidity index score. 2
• Research to define pretreatment factors, disease and patient factors, and product factors predisposing to CAR-T failure is key to help inform discussions on the role of allo-HSCT after CAR-T therapy. 2

Long-Term Monitoring

• Monitor for B-cell aplasia and hypogammaglobulinemia, and provide IVIG replacement as needed. 3
• Monitor for antigen escape and diminished CAR-T expansion on re-treatment. 3
• T-cell malignancies have occurred following treatment with CD19-directed genetically modified autologous T-cell immunotherapies, including KYMRIAH. 1

Second-Round CAR-T Therapy

Safety Profile

• Second-round CAR-T therapy (CART2) demonstrates excellent safety regarding CRS, CRES, infections, and organ injury, though the remission rate (44.4% MRD-negative CR) is lower than first-round therapy (100% MRD-negative CR) due to disease severity. 5
• No differences in incidence and grade of CRS were found between first-round and second-round CAR-T therapy. 5
• The incidence of CRES was lower for CART2 (11.1%) compared to CART1 (33.3%). 5
• CART2 remains a viable option for treating pediatric relapsed B-ALL despite lower remission rates. 5

Critical Pitfalls to Avoid

• Do not administer KYMRIAH to patients with active infection or inflammatory disorders. 1
• Do not proceed with lymphodepletion until KYMRIAH availability is confirmed. 1
• Do not underestimate the importance of specialized center care—treatment should preferably be delivered at a specialized cancer center with CAR-T therapy expertise. 6
• Do not dismiss subtle early signs of CRS—parent/caregiver concerns should be addressed promptly as they may recognize changes best. 2
• Do not delay admission for fever or concerning symptoms—maintain a low threshold given potential for rapid deterioration. 2

REMS Program Requirements

• KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the KYMRIAH REMS. 1
• Providers are encouraged to adhere to product information labels and guidance from REMS programs as approved by the FDA. 2