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Immune Suppression Treatment for People With Sickle Cell Disease or Beta-Thalassemia Who are Going to Receive an Allogeneic Hematopoietic Cell Transplantation (HCT)
Trial Status: active
This phase II trial tests how well immune suppression drugs given before standard conditioning therapy and allogeneic hematopoietic cell transplantation (HCT) works in preventing serious side effects, including graft failure and graft versus host disease (GvHD) in transplant patients with sickle cell disease and beta-thalassemia. Sickle cell disease and beta-thalassemia are blood diseases caused by a genetic change (mutation) in hemoglobin, the protein in red blood cells that carries oxygen throughout the body. In people with sickle cell disease, the red blood cells take on an abnormal “sickle” shape that blocks blood flow and causes pain or damage to organs in the body. In people with beta-thalassemia, the body cannot make enough of a protein called beta-globin. This reduces the production of hemoglobin and means the body does not get enough oxygen. HCT involves receiving healthy blood-forming cells (stem cells) from a donor to replace the diseased or damaged cells in the bone marrow. Before HCT, people normally receive standard conditioning therapy to suppress (restrain) their immune system and prepare their body for HCT. Two serious side effects of HCT are graft failure and GvHD. In graft failure, the transplanted stem cells did not grow successfully inside the body. GvHD occurs when the donor’s T cells (white blood cells that are part of the immune system) attack the cells of the recipient’s body. Chemotherapy drugs, such as fludarabine, cyclophosphamide, bortezomib, rituximab, rabbit antithymocyte globulin, and busulfan work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Treatment with fludarabine and dexamethasone and/or cyclophosphamide, bortezomib and rituximab, drugs that lower the activity of the body's immune system (immune suppression), before standard conditioning therapy with rabbit antithymocyte globulin and busulfan followed by HCT may help prevent serious side effects, including graft failure and GvHD, in patients with sickle cell disease or beta-thalassemia.
Inclusion Criteria
Age > 12 and < 35 years. Patients of age 2–12 and 35–50 years will be included after 8 patients reach day 100 without TRM and if >= 4 of the first 8 patients reach day 100 without graft failure or grade III–IV acute GvHD
Suitable haploidentical donor
Performance score >= 70% by Karnofsky Performance Scale or 0 to 1 by Eastern Cooperative Oncology Group (ECOG) (age > 16 years), or Lansky Play-Performance Scale >= 70% (age =< 16 years)
For patients >= 18 years of age:
* Estimated glomerular filtration rate (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 m^2 as calculated by the Schwartz formula
Conjugated (direct) bilirubin less than 2 x upper limit of normal
Alanine aminotransferase (ALT) or aspartate aminotransferase (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 pulmonary function tests (PFT), oxygen saturation > 92% on room air by pulse oximetry
For SCD patients: HbSS, hemoglobin HbSC, HbS/beta^0 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/second (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 transcranial doppler (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 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 central nervous system (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 iron (Fe)/g liver dry weight
Human immunodeficiency virus (HIV) positive
Active hepatitis B or C
Other uncontrolled infections
Body mass index (BMI) > 40
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 cell product, including a known history of allergic reactions to dimethyl sulfoxide (DMSO)
Additional locations may be listed on ClinicalTrials.gov for NCT05736419.
I. To estimate treatment-related mortality (TRM) or primary graft failure at 1-year post-HCT.
SEONDARY OBJECTIVES:
I. To estimate the cumulative incidence of treatment-related mortality at 1 and 2 years post-HCT.
II. To estimate overall survival and event-free survival at 100 days, 1 year, and 2 years post-HCT.
III. To estimate cumulative incidence of grade II–IV and grade III–IV acute GvHD at 180 days post-HCT.
IV. To estimate cumulative incidence of chronic GvHD at 1-year post-HCT.
V. To estimate cumulative incidence of primary and secondary graft failure at 100 days, 1 year, and 2 years post-HCT.
VI. To characterize donor chimerism at 28 days, 100 days, 180 days, 1 year, and 2 years post-HCT.
VII. To estimate graft-failure/GvHD-free survival at 1 year and 2 years post-HCT.
VIII. To evaluate immune reconstitution and cumulative incidence of infectious complications up to 2 years post-HCT.
IX. To evaluate hematologic outcomes (hemoglobin, reticulocyte count, bilirubin, lactate dehydrogenase, hemoglobin electrophoresis, and red blood cell [RBC] transfusion frequency) up to 2 years post-HCT.
X. In patients with sickle cell disease (SCD), to evaluate incidence of vaso-occlusive episodes, acute chest syndromes, and stroke up to 2 years post-HCT.
XI. To evaluate quality of life by the Patient Reported Outcomes Measurement Information System (PROMIS) score post-HCT.
EXPLORATORY OBJECTIVE:
I. To evaluate pharmacokinetics of rabbit antithymocyte globulin (rATG) and fludarabine in pre-transplant immune suppression (PTIS)-based HCT.
OUTLINE:
Patients receive fludarabine intravenously (IV) on days -68 to -64 of cycle 1 and days -40 to -36 of cycle 2 and dexamethasone IV on days -68 to -64 and days -40 to -36 for two cycles prior to HCT. Patients may receive cyclophosphamide IV on days -46, -45, and -44 instead of fludarabine in cycle 2 per physician discretion. Patients may also receive bortezomib IV on days -71, -68, -65, -61, -43, -40, -37, and -33 and rituximab IV on days -71, -58, -43, and -30 and/or plasmapheresis based on mean fluorescence intensity (MFI). Patients then receive rATG IV starting on day -12 and continuing daily for 2–3 total doses and fludarabine IV and busulfan IV on days -6 to -3 standard conditioning therapy followed by HCT on day 0.
Patients also undergo bone marrow (BM) aspirate/biopsy, magnetic resonance imaging (MRI), computed tomography (CT) during screening.
After completion of study treatment, patients are followed up to 2 years.
Trial PhasePhase II
Trial Typeprevention
Lead OrganizationMemorial Sloan Kettering Cancer Center
