Chimeric Antigen Receptor T-cell Therapy, B Cell Acute Lymphoblastic Leukemia (B-ALL), B Cell Lymphoma, Antibiotic Prophylaxis, Immunoglobulin Therapy
Conditions
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.
Interventions
DRUGImmunoglobulin
IgRT 0.4g/Kg IV every 4 weeks for 12 months
DRUGantibiotic prophylaxis
PA following each center's guidelines, for 12 months
Sponsors
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Phase III randomized two-parallel arms, open-label multicentric design in patients treated by CD19-targeted CAR-T Cells for a B-ALL or a BCL, randomly allocated in a 1:1 ratio to receive either IgRT or PA.
Eligibility
Sex/Gender
ALL
Age
16 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Age 16-80 years at inclusion 2. B-cell acute lymphoblastic leukemia or a B-cell lymphoma 3. With gamma globulins \<4g/L at the time of screening 4. Receiving CD19-targeted autologous CAR-T cells (with AMM in their indication) 5. Patients with childbearing potential\* should have reliable contraception for the all duration of the study and another 12 months after CAR-T infusion. 6. Contraceptive measures for concerned patients 7. Informed consent signed by patient or legal representatives
Exclusion criteria
1. Any medical history of intolerance to intravenous immunoglobulin 2. With renal failure calculated glomerular filtrate rate \<30 mL / min; 3. With hepatic failure or hepatitis or bilirubin\> 3 times the upper limit of normal, Serum ALT/AST \>=5N 4. With existing serious acute infection 5. Contraindication to immunoglobulin or to prophylactic antibiotherapy administered in this clinical trial 6. No health insurance coverage 7. Females who are pregnant or breastfeeding 8. Participation in another interventional study or being
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of recurrent infections | At 12 months | Defined by at least 2 episodes requiring a curative systemic antibiotic treatment |
| Occurrence of a severe infection | At 12 months | Defined by the need of hospitalization |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative hazard of severe infections | Up to 12 months | requiring hospitalization |
| Infection-free survival rate | Up to 12 months | — |
| Occurrence of COVID19 infection | Up to 12 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 | IgA, IgG, IgM, CD19/CD4/CD8 lymphocytes counts, at lymphodepletion |
| Quality of life assessment | At 3 months | EQ5D5L : standardized measure of health-related quality of life assessing five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L index score typically ranges from values below 0 (health states considered worse than death) to 1.0 (full health), depending on the country-specific value set. Higher scores indicate better health-related quality of life. |
| Incremental Cost-Effectiveness Ratio (ICER) | Up to 12 months | — |
Contacts
CONTACTFlorence Rabian, MD
CONTACTJérôme Lambert, MD PhD
Outcome results
None listed