A Multicentric Phase III Randomized Clinical Trial Open-label, Comparing Immunoglobulin Replacement Therapy (IgRT) and Antibiotic Prophylaxis (AP) in Patients Treated by CD19-targeted Chimeric Antigen Receptor (CAR)T Cells for a B Cell Acute Lymphoblastic Leukemia or a B Cell Lymphoma
Trial Snapshot
- Phase
- Phase 3
- Status
- Not yet recruiting
- Enrollment
- 228
- Primary Endpoint
- Occurrence of recurrent infections
Study Overview
Brief Summary
B cell (CD19) targeted chimeric antigen receptor modified T Cells (CAR-T) has transformed treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) or B-cell lymphoma (BCL).
Because patients receiving CAR-T often present uncontrolled disease and have undergone several lines of treatment, they may be deeply immuno-depressed and prone to infections. Hypogammaglobulinemia were reported in 74% of patients preCAR-T cells infusion (Hill JA, et al. Blood Rev. 2019 Nov). CART cells also results in depletion of normal CD19+ B cells and hypogammaglobulinemia as an on-target, off tumor toxicity.
Because CAR-T cells can persist for years, patients are exposed to infectious complications secondary to long-term Bcell aplasia and severe hypogammaglobulinemia (<4g/l). Data from patients who received rituximab (CD20-specific monoclonal antibody) show that patients with severe hypogammaglobulinemia experienced recurrent bronchitis, sinusitis, pneumonia, and rarely, enteroviral meningoencephalitis. In patients receiving CAR T-cells, infection density is 0.55-0.67 infections/100 days3,5 at risk after the first month with a majority of respiratory and ENT (earsnose-throat) infections. To prevent infections, anti-bacterial prophylaxis (AP) based on local guidelines is often used in patients treated by CAR-T cells, with the risk of subsequent resistance. Otherwise, intravenous immunoglobulin replacement therapy (IgRT) is authorized by the French authorities for patients with secondary antibody deficiencies who developed severe or recurrent infections after appropriate antimicrobial therapy, if IgG levels <4g/l. However, although IgRT as primary prophylaxis (PP) have no approval, they are used as PP after CAR T-cells by many centers, with no data supporting such a strategy. The benefit of IgRT over AP as a primary prophylaxis in the setting of CD19 CAR-T cells therapy should be demonstrated given its burden for patients and care, as well as its cost and the risk of Ig shortage. Therefore, this multi-centric prospective randomized openlabel study aims to assess the benefits of IgRT versus AP as PP in patients with secondary antibody deficiencies.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Prevention
- Masking
- None
Eligibility Criteria
- Ages
- 16 Years to 80 Years (Child, Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age 16-80 years at inclusion
- •B-cell acute lymphoblastic leukemia or a B-cell lymphoma
- •With gamma globulins <4g/L at the time of screening
- •Receiving CD19-targeted autologous CAR-T cells (with AMM in their indication)
- •Patients with childbearing potential* should have reliable contraception for the all duration of the study and another 12 months after CAR-T infusion.
- •Contraceptive measures for concerned patients
- •Informed consent signed by patient or legal representatives
Exclusion Criteria
- •Any medical history of intolerance to intravenous immunoglobulin
- •With renal failure calculated glomerular filtrate rate <30 mL / min;
- •With hepatic failure or hepatitis or bilirubin> 3 times the upper limit of normal, Serum ALT/AST >=5N
- •With existing serious acute infection
- •Contraindication to immunoglobulin or to prophylactic antibiotherapy administered in this clinical trial
- •No health insurance coverage
- •Females who are pregnant or breastfeeding
- •Participation in another interventional study or being
Arms & Interventions
Antibiotic prophylaxis
Intervention: antibiotic prophylaxis (Drug)
Immunoglobulin Replacement therapy
Intervention: Immunoglobulin (Drug)
Outcomes
Primary Outcomes
Occurrence of recurrent infections
Time Frame: At 12 months
Defined by at least 2 episodes requiring a curative systemic antibiotic treatment
Occurrence of a severe infection
Time Frame: At 12 months
Defined by the need of hospitalization
Secondary Outcomes
- Dosage of immune markers(At 1 month)
- Dosage of immune markers(At 3 months)
- Cumulative incidence of readmissions due to infectious episode after hospital discharge following the infusion of CART cells(Up to 12 months)
- Incidence of adverse events due to IgRT and/or PA(Up to 12 months)
- Dosage of immune markers(Up to 12 months)
- Cumulative hazard of severe infections(Up to 12 months)
- Infection-free survival rate(Up to 12 months)
- Occurrence of COVID19 infection(Up to 12 months)
- Dosage of immune markers(At 6 months)
- Dosage of immune markers(At 9 months)
- Dosage of immune markers(At 12 months)
- Quality of life assessment(At 3 months)
- Quality of life assessment(At 6 months)
- Quality of life assessment(At 9 months)
- Quality of life assessment(At 12 months)
- Incremental Cost-Effectiveness Ratio (ICER)(Up to 12 months)