Sickle Cell Disease, Thalassemia, Beta, Thalassemia
Conditions
Keywords
allogeneic hematopoietic cell transplantation, Sickle Cell Disease, Beta Thalassemia, Thalassemia, 23-009, Memorial Sloan Kettering Cancer Center
Brief summary
Hematopoietic Cell Transplantation/HCT involves receiving healthy blood-forming cells (stem cells) from a donor to replace the diseased or damaged cells in participants' bone marrow. The researchers think giving participants treatment with fludarabine and dexamethasone, drugs that lower the activity of the body's immune system (immune suppression), before standard conditioning therapy and HCT may help prevent serious side effects, including graft failure and GvHD. In this study, depending on how participants' body responds to the fludarabine and dexamethasone, the study doctor may decide participants should receive another drug, called cyclophosphamide, instead of fludarabine. In addition, depending on the results of participants' routine blood tests, participants may receive the drugs bortezomib and rituximab, which also help with immune suppression.
Interventions
DRUGFludarabine
PK-guided fludarabine dosing will be used for each of the 2 cycles, using the InsightRx DoseMeRx platform.
DRUGCyclophosphamide
Cyclophosphamide will be administered Post-Transplant
DRUGTacrolimus
Tacrolimus will be administered beginning on day +5
DRUGMycophenolate Mofetil
Mycophenolate mofetil (MMF) will be administered three times daily starting on day +5.
BIOLOGICALRabbit ATG
The dose and schedule of ATG will be determined according to the nomogram in Appendix A
DRUGDexamethasone
Standard Regimen: Dexamethasone on days -68 to -64 and days -40 to -36.
DRUGBortezomib
Bortezomib on days -71, -68, -65, -61, -43, -40, -37, and -33
DRUGRituximab
Rituximab on days -71, -58, -43, and -30.
Sponsors
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 2 and ≤ 50 years * Suitable haploidentical donor. * Performance score ≥ 70% by Karnofsky Performance Scale or 0 to 1 by ECOG (age \> 16 years), or Lansky Play-Performance Scale ≥ 70% (age ≤ 16 years). * Adequate major organ system function as demonstrated by: * For patients ≥ 18 years of age: * eGFR ≥ 50 mL/min by Cockcroft-Gault formula * For patients \< 18 years of age: * Serum creatinine clearance: glomerular filtration rate \[GFR\]) must be \>50 mL/min/1.73 m2 as calculated by the Schwartz formula * Conjugated (direct) bilirubin less than 3x upper limit of normal. * ALT or AST ≤ 3 times institutional upper limit of normal. * Left ventricular ejection fraction ≥ 50%. * Diffusing capacity for carbon monoxide (DLCO) ≥ 50% predicted, corrected for hemoglobin. For children \< 7 years of age who are unable to perform PFT, oxygen saturation \> 92% on room air by pulse oximetry. * For SCD patients: HbSS, HbSC, HbS/β° with one or more of the following complications: * Acute chest syndrome: 2 or more episodes in the 2 years preceding enrollment * Vaso-occlusive episodes: 3 or more episodes in the 2 years preceding enrollment * Recurrent priapism: 2 or more episodes in the 2 years preceding enrollment * History of osteomyelitis or osteonecrosis * Cerebrovascular disease: * Imaging evidence of prior overt or silent stroke * History of a neurologic event resulting in focal neurologic deficits lasting \> 24 hours * Abnormal transcranial Doppler: Timed average maximum mean velocity ≥ 200 cm/sec in terminal portion of the carotid or proximal portion of the middle cerebral artery or \> 185 cm/sec plus evidence of intracranial vasculopathy if imaging TCD is used * Pulmonary hypertension: Confirmed by right heart catheterization with mean pulmonary arterial pressure ≥ 25 mmHg or mean pulmonary vascular resistance \> 2 Wood units * Red blood cell alloimmunization (\> 3 alloantibodies) * For thalassemia patients: Any genotype, with all of the following: * Onset of red blood cell transfusion dependence during the first 3 years of life * RBC transfusion history \> 225 mL/kg/year or \> 15 lifetime RBC transfusions * Pre-transfusion hemoglobin ≤ 7 g/dL * Hepatosplenomegaly * Patient or the patient's legal representative, parent(s) or guardian should be able to provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years. * For sexually active men and women of childbearing potential, must agree to use a form of contraception considered effective and medically acceptable by the Investigator.
Exclusion criteria
* Prior myeloablative allogeneic HCT. * Overt stroke or CNS instrumentation (e.g. for Moyamoya disease) within 6 months of enrollment. * Liver cirrhosis. Mild fibrosis will be permitted, i.e. fine reticulin or grade 1 of 4, with bridging fibrosis. * Hepatic iron content ≥ 3 mg Fe/g liver dry weight, if applicable * Active hepatitis B or C. * Other uncontrolled infections. * Other malignancy/cancer diagnosis unless in remission after definitive therapy for a minimum of 2 years. Exceptions: Ductal carcinoma in situ, basal cell carcinoma, cervical intraepithelial neoplasia. * Positive pregnancy test in a woman with child-bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization. * Inability to comply with medical therapy or follow-up. * Known history of allergic reactions to any constituents of the stem cell product, including a known history of allergic reactions to DMSO.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment related mortality/TRM or primary graft failure | 1 year | The primary outcome is to estimate treatment-related mortality (TRM) or primary graft failure at 1 year post-HCT. |
Countries
United States
Contacts
CONTACTMaria Cancio, MD
CONTACTJaap Jan Boelens, MD, PhD
PRINCIPAL_INVESTIGATORMaria Cancio, MD
Memorial Sloan Kettering Cancer Center
Outcome results
None listed