Nonmyeloablative Donor Stem Cell Transplant in Treating Patients with Congenital Anemias including Sickle Cell Disease and Thalassemia
- Sickle cell disease - patients with sickle cell disease at high risk for disease related morbidity or mortality, defined by having irreversible end-organ damage (A, B, C, D, or E) or potentially reversible complication(s) not ameliorated by hydroxyurea (F): * A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral magnetic resonance imaging (MRI) or an abnormal trans-cranial Doppler examination (>= 200 m/s); or * B. Sickle cell related renal insufficiency defined by a creatinine level >= 1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy or nephrotic syndrome or creatinine clearance < 50 mL/min or requiring peritoneal or hemodialysis; or * C. Pulmonary hypertension as defined by tricuspid regurgitant jet velocity (TRV) of >= 2.5 m/s at least 3 weeks after a vaso-occlusive crisis; or * D. Recurrent tricorporal priapism defined as at least two episodes of an erection lasting >= 4 hours involving the corpora cavernosa and corpus spongiosa; or * E. Sickle hepatopathy defined as either ferritin > 1000 mcg/L or direct bilirubin > 0.4 mg/dL at baseline; or
- F. Any one of the below complications * Vaso-occlusive crises; eligible for hydroxyurea*: at least 3 hospital admissions in the last year; eligible for hematopoietic stem cell transplantation (HSCT): more than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea* * Acute chest syndrome (ACS); eligible for hydroxyurea*: 2 prior ACS while > 3 years of age and adequately treated for asthma; eligible for HSCT: any ACS while on hydroxyurea* * Osteonecrosis of 2 or more joints; eligible for hydroxyurea*: and significantly affecting their quality of life by Karnofsky score 50-60; eligible for HSCT: and on hydroxyurea* where total hemoglobin increase less than 1 g/dL or fetal hemoglobin increases < 2.5 times the baseline level * Red cell alloimmunization; eligible for hydroxyurea*: transfusion-dependent; eligible for HSCT: total hemoglobin increase < 1 g/dL while on hydroxyurea* * Note: hydroxyurea at maximum tolerated dose
- Thalassemia - patients with thalassemia who have grade 2 or 3 iron overload, determined by the presence of 2 or more of the following: * Portal fibrosis by liver biopsy * Inadequate chelation history (defined as failure to maintain adequate compliance with chelation with desferroxamine initiated within 18 months of the first transfusion and administered subcutaneously for 8-10 hours at least 5 days each week) * Hepatomegaly of greater than 2 cm below the costochondral margin
- 6/6 human leukocyte antigen (HLA) matched family donor available
- Ability to comprehend and willing to sign an informed consent, assent obtained from minors
- Negative serum beta-human chorionic gonadotropin (HCG)
- DONOR: 6/6 HLA identical family donor
- DONOR: Weight > 20 kg (in so far that the weight difference between recipient and donor does not exceed a reasonable likelihood of being able to obtain an adequate cell dose from the donor within two aphereses)
- DONOR: Fit to receive G-CSF (filgrastim) and give peripheral blood stem cells (normal blood counts, normotensive, and no history of stroke)
- DONOR: Ability to comprehend and willing to sign an informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of 3 or more or Lanksy performance status of < 40
- Diffusion capacity of carbon monoxide (DLCO) < 50% predicted (corrected for hemoglobin and alveolar volume)
- Baseline oxygen saturation of < 85% or partial pressure of oxygen in arterial blood (PaO2) < 70
- Left ventricular ejection fraction: < 40% estimated by echocardiogram (ECHO)
- Transaminases > 5x upper limit of normal for age
- Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen
- Major anticipated illness or organ failure incompatible with survival from peripheral blood stem cell (PBSC) transplant
- Pregnant or lactating * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
- Major ABO mismatch
- DONOR: Pregnant or lactating * Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately * A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: ** Has not undergone a hysterectomy or bilateral oophorectomy; or ** Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
- DONOR: Human immunodeficiency virus (HIV) positive
- DONOR: Hemoglobin S >= 50%, or beta thalassemia intermediate
I. To evaluate the safety, efficacy, and toxicity of a low intensity nonmyeloablative preparative regimen followed by an allogeneic granulocyte colony-stimulating factor (filgrastim, G-CSF) mobilized peripheral blood stem cell transplant in a population of patients with severe congenital anemias including sickle cell disease and thalassemia at increased risk for complications with or ineligible for standard myeloablative allogeneic (allo)-transplantation.
I. To examine the level of chimerism required to maintain both graft survival as well as hematologic normalcy.
II. To determine the incidence and severity of acute and chronic graft versus host disease (GVHD) using a novel nonmyeloablative conditioning regimen.
III. To determine the rate of graft rejection using a novel nonmyeloablative conditioning regimen.
IV. To determine disease-free survival, overall survival, relapse, transplant-related mortality, and death from all causes using a novel nonmyeloablative conditioning regimen.
Donors receive filgrastim subcutaneously (SC) or intravenously (IV) for up to 6 days with leukapheresis collections of peripheral blood progenitor cells (PBPC) on day 5 (and day 6 if required).
Patients receive alemtuzumab IV over 2 hours on days -7 to -3 and then undergo total body irradiation (TBI) on day -2. Patients also receive sirolimus orally (PO) starting on day -1 for at least 1 year, after which it tapers by 10% each month. Patients undergo nonmyeloablative allogeneic hematopoietic stem cell transplant and receive donor PBPC IV over 30 minutes to 2 hours on day 0.
After completion of study treatment, patients are followed up periodically for 100 days, every 6 months for 2 years, and then annually for 3 years.
Trial Phase Phase II
Trial Type Treatment
UT Southwestern / Simmons Cancer Center-Dallas
- Primary ID 012013-015
- Secondary IDs NCI-2014-02134
- Clinicaltrials.gov ID NCT02038478