Haploidentical Hematopoietic Stem Cell Transplantation With Ex Vivo TCR Alpha/Beta and CD19 Depletion in Pediatric Hematologic Malignancies
Study Details
Study Description
Brief Summary
This single arm pilot phase I study with safety run-in is designed to estimate the safety and efficacy of a familial mismatched or haploidentical hematopoietic stem cell transplantation (haplo-HSCT) using a novel graft modification technique (selective αβ-TCR and CD19 depletion).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ex vivo αβ-TCR/CD19 depleted haplo-hematopoietic stem cell infusion (HSCT) Patients will undergo standard of care conditioning regiment prior to HSCT On Day 0, patients will undergo infusion of the ex vivo αβ-TCR/CD19 depleted haplo-HSCT from a stimulated peripheral stem cell source per institutional standard of care. Patients whose graft has a residual CD20+ count > 1.0 x 10^5 will receive a single infusion of rituximab on Day +1 at a dose of 375 mg/m2. |
Device: Ex Vivo T-cell receptor alpha-beta and CD19+ Depletion using CliniMACs Plus
Once pheresed, the product will be washed to remove platelets and the cell concentration will be adjusted per laboratory and ClinicMACS technology recommendations. It is then labeled using the CliniMACS αβ-TCR Biotin Kit and CD19+ immunomagnetic microbeads. After labeling, the cells are washed to remove unbound microbeads. The partially processed product is loaded on the CliniMACS device where labeled cells are depleted and the negative fraction is eluted off the device. The negative fraction is centrifuged and volume reconstituted to obtain the final product
|
Outcome Measures
Primary Outcome Measures
- Safety as measured by the number of events occurring within the first 100 days post-transplant [Through 100 days post-transplant]
-Events are death, disease recurrence or progression, and graft failure
- Engraftment as measured by time to neutrophil count recovery [From day of transplant (day 0) to 42 days (+/- 14 days) post transplant]
Time to neutrophil recovery is defined as the first of 3 measurements on different days when the patient has an absolute neutrophil count of >500/μL after conditioning.
- Engraftment as measured by time to platelet count recovery [From day of transplant (day 0) to 75 days (+/- 14 days) post transplant)]
Time to platelet recovery is defined as the first day of a minimum of 3 measurements on different days that the patient has achieved a platelet count > 50,000/μL AND did not receive a platelet transfusion in the previous 7 days. The exception is the case in which a patient receives platelet transfusions specifically to achieve a higher platelet threshold to allow for an invasive procedure or protection if determined to be at elevated bleeding risk.
- Donor cell chimerism as measured by short tandem repeat analysis [Through day +100]
Can use peripheral blood samples or bone marrow samples The percent of donor-derived cells are sequentially followed.
Secondary Outcome Measures
- Event free survival (EFS) [At 2 years post transplant]
-Death, disease recurrence or progression, and graft failure are considered events
- Change in Lansky/Karnofsky performance score [Day +14, Day +30, Day +60, Day +100, Day +180, Day +365, +18 months, and +24 months]
Lansky is used for participants <15.99 years of age Karnofsky is used for participants >16.00 years of age
- Incidence and severity of acute GVHD [Weekly through day +100]
-Incidence and severity of acute GVHD as graded according to the NIH consensus criteria. Severe aGVHD (Grades III-IV) is considered an event.
- Incidence and severity of chronic GVHD [Day 101 through 24 months]
Incidence and severity of acute GVHD as graded according to the NIH consensus criteria. Severe cGHVD is considered an event.
- Number of neurologic toxicities [Through 24 months]
-As evidence by clinical assessment and/or imaging at physician discretion
- Number of pulmonary toxicities [Through 24 months]
-As determined by clinical context and serial assessment of TLC, FVC, FEV1, DLCO, or high-resolution CT Chest
- Number of cardiac toxicities [Through 24 months]
-As determined by clinical assessment and EKG and/or echocardiogram
- Number of renal toxicities [Through 24 months]
-As determined by clinical assessment and BUN, creatinine, urinalysis, estimated GFR, or renal scintigraphy
- Number of hepatic toxicities [Through 24 months]
-As determined by clinical assessment and liver function tests
- Number of participants with infections [Through 24 months]
- Number of metabolic toxicities [Through 24 months]
-Metabolic toxicities will be collected using a complete metabolic panel
- Number of thyroid toxicities [Through 24 months]
-Thyroid toxicities will be collected using a thyroid function test
- Immune reconstitution as measured by recovery of absolute neutrophil count [Over 24 months]
- Immune reconstitution as measured by recovery of absolute monocyte count [Over 24 months]
- Immune reconstitution as measured by regain of function of NK cell populations [Over 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry
- Immune reconstitution as measured by regain of function of T cell populations [Through 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry
- Immune reconstitution as measured by regain of function of B cell populations [Through 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via flow cytometry
- Immune reconstitution as measured by regain of function of immunoglobulin G (IgG) [Over 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis
- Immune reconstitution as measured by regain of function of immunoglobulin A (IgA) [Over 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis
- Immune reconstitution as measured by regain of function of immunoglobulin M (IgM) [Over 24 months]
Immune reconstitution is defined as regain of function of donor-derived immunogenic cells. Immune reconstitution is to be measured by recovery of individual cellular compartments Via serum analysis
Eligibility Criteria
Criteria
Recipient Inclusion Criteria:
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Must meet at least one of the following disease criteria:
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ALL in CR (defined by < 5% blasts in adequate bone marrow specimen) AND at least one of the following:
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Induction failure
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Relapsed or refractory disease
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AML in CR (defined by < 5% blasts on an adequate bone marrow specimen) with one of the following high-risk cytogenetic features:
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High allelic FLT3/ITD ratio
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Monosomy 7
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Monosomy 5 or Del(5q)
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Relapsed or refractory disease
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Any acute leukemia in CR ≥ 2
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Mixed phenotype or undifferentiated leukemia in any CR
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Secondary to therapy-associated leukemia in any CR
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NK cell lineage leukemia in any CR
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Myelodysplastic syndrome (MDS)
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Juvenile myelomonocytic leukemia (JMML)
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May have undergone a prior hematopoietic stem cell transplant provided one of the criteria in Inclusion Criterion #1 are met AND the patient does not have active GVHD (has been off immunosuppression for at least 3 months).
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Available familial haploidentical donor.
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Donor and recipient must be identical at a minimum of one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum of 5/10 match is required and will be considered sufficient evidence that the donor and recipient share one HLA haplotype.
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No more than 30 years of age
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Lansky or Karnofksy performance status > 50%
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Adequate organ function as defined below:
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Cardiac: LVEF ≥ 40% at rest or SF ≥ 26%
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Hepatic:
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Total bilirubin < 3 x IULN for age
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AST(SGOT)/ALT(SGPT) < 5 x IULN
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Renal: GFR ≥ 60 mL/min/1.73m2 as estimated by updated Schwartz formula for ages 1-17 years (see Appendix B), 24 hour creatinine clearance, or renal scintigraphy. If GFR is abnormal for age based on updated Schwartz formula, accurate measurement should be obtained by either 24 hour creatinine clearance or renal scintigraphy. Renal function may also be estimated by serum creatinine based on age/gender. A minimum serum creatinine of 2x upper limit of normal is required for inclusion on this protocol.
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Pulmonary:
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O2 saturation ≥ 92% on room air without positive pressure support
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FEV1, FVC, and DLCO ≥ 50% of predicted (for children unable to perform a pulmonary function test, a high-resolution CT chest may be obtained)
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The effects of these treatments on the developing human fetus are unknown. For this reason, patients of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for 24 months following transplant. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
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Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Recipient Exclusion Criteria:
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Available matched related donor. A patient with a matched unrelated donor is eligible if urgent transplantation is required. A prior unrelated donor search is not required for enrollment.
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Active non-hematologic malignancy. History of other malignancy is acceptable as long as therapy has been complete and there is no evidence of disease.
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Currently receiving any other investigational agents.
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Active CNS or extramedullary disease. History of CNS or extramedullary disease now in remission is acceptable.
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A history of allergic reactions attributed to compounds of similar chemical or biologic composition to conditioning agents used in the study.
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Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (bacterial, viral with clinical instability, or fungal), symptomatic congestive heart failure, or unstable cardiac arrhythmia.
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Presence of significant anti-donor HLA antibodies per institutional standards. Anti-donor HLA Antibody Testing is defined as a positive crossmatch test of any titer (by complement dependent cytotoxicity or flow cytometric testing) or the mean fluorescence intensity (MFI) of any anti-donor HLA antibody by solid phase immunoassay.
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Presence of a second major disorder deemed a contraindication for HSCT.
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Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of the start of conditioning.
Donor Eligibility Criteria:
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At least 6 months of age
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Meets the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FACT).
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The following criteria, in order of importance, should be considered for donor selection:
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Medically and psychologically fit and willing to donate
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ABO compatibility (in order of priority)
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CMV status
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For a CMV seronegative recipient, use a CMV seronegative donor.
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For a CMV seropositive recipient, use a CMV seropositive donor.
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Younger adults and non-obese donors should be preferred.
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If all else is equal, male donors may be preferred over nulliparous female donors who may be preferred over multiparous female donors
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Agree to donate PBSC.
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Able to understand and willing to sign an IRB-approved written informed consent document (or that of legally authorized representative, if applicable).
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
Sponsors and Collaborators
- Washington University School of Medicine
Investigators
- Principal Investigator: Jeffrey Bednarski, M.D., Ph.D., Washington University School of Medicine
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- 202203051