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Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT03077542
Recruitment Status : Recruiting
First Posted : March 13, 2017
Last Update Posted : September 19, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Brief Summary:

Background:

Peripheral blood stem cell transplantation procedures are used for people with sickle cell disease. Researchers want to improve the success and reduce the complications for these procedures. This might allow more people to have a transplant.

Objective:

To see if a new transplant regime is effective, safe and well tolerated in people with sickle cell disease.

Eligibility:

Adults at least 18 years old with sickle cell disease and certain complications.

A relative who is a half tissue match.

Design:

Participants will be screened with medical history, physical exam, and blood tests. Recipients will also have:

  • Heart, lung, and mental health tests
  • Chest x-rays
  • Bone marrow taken from the pelvic bone
  • Eyes and teeth checked

Recipients will have a large central line inserted into a vein for up to 6 months.

Donors will have their veins tested and have an IV inserted for 1 day or on rare occasions 2 days.

Donors will get a drug to activate bone marrow. It will be injected for about 6 days.

Donors will have at least 1 five-hour procedure where bone marrow stem cells will be collected. Blood will be taken from a vein in one arm or in rare cases from a groin vein and put through a machine. Some blood will be saved and the rest will be returned. Stem cells will be taken from the saved blood in a lab and frozen until ready to give to the recipient.

Recipients will have:

  • Stems cells collected and frozen
  • Hygiene lessons
  • Bone density scans
  • Low-dose radiation
  • Drugs for their immune system
  • Donor cells infused through their central line
  • Transfusions

After about 30 days, recipients will leave the hospital. They must stay near NIH for 3 months after the transplant and have frequent visits. After returning home, they will have 8 visits over 5 years, then be contacted yearly.


Condition or disease Intervention/treatment Phase
Sickle Cell Disease Procedure: haploidentical stem cell transplant Drug: sirolimus Drug: campath Drug: pentostatin Drug: cyclophosphamide Phase 1 Phase 2

Detailed Description:

Nonmyeloablative allogeneic peripheral blood stem cell (PBSC) transplants are currently being investigated in phase I/II trials assessing engraftment, efficacy, and toxicity at a number of transplant centers. Our ongoing protocol for patients with severe congenital anemias, particularly sickle cell disease (SCD), and an HLA-matched sibling donor has had excellent preliminary results. None of the patients who engrafted had sickle-related events or any evidence of graft versus host disease (GVHD). There was no significant toxicity associated with the conditioning regimen. An additional protocol is ongoing for patients with high risk of graft rejection which employs pentostatin and oral cyclophosphamide (PC) pre-transplant to further deplete recipient lymphocytes in an attempt to decrease the rate of graft rejection. Four of 4 patients transplanted remain free of SCD.

Our main limitation has been a lack of HLA-matched sibling donors in the majority of patients. We performed a study in which patients with severe SCD who lacked a suitable donor underwent a search for a matched unrelated donor or umbilical cord donor. The vast majority of patients were not found to have an appropriate alternative donor. We therefore seek to develop a safe nonmyeloablative regimen to be applied to the haploidentical setting so that family members can serve as donors and greatly expand the donor pool.

We developed a nonmyeloablative haploidentical PBSC transplant protocol which included 3 cohorts, with stopping rules built in for regimen failure, defined as graft rejection or severe GVHD. All included 400 cGy total body irradiation (TBI), alemtuzumab, and sirolimus. The first cohort included no cyclophosphamide. The 2nd included one dose of cyclophosphamide given at 50mg/kg on day 3 post-transplant, and the 3rd included 100mg/kg cyclophosphamide given in divided doses on days 3 and 4 post-transplant. The engraftment rate and percentage of patients who remained free of SCD improved with each successive cohort. However, the graft rejection rate in the 3rd cohort remained high at 50%. To attempt to reduce the rate of graft rejection in the haploidentical setting, this protocol will add PC to the conditioning regimen.

In this protocol, we propose PBSC transplantation in patients with SCD considered at high risk for complications from or ineligible for standard bone marrow transplantation, with allogeneic peripheral blood stem cells from a haploidentical donor using a novel immunosuppressive regimen without myeloablation in an attempt to further decrease the transplant-related morbidity/mortality. The low intensity nonmyeloablative conditioning regimen will consist of a relatively low radiation dose for therapeutic radiation, Alemtuzumab (Campath ), Sirolimus (Rapamune ), Cyclophosphamide (Cytoxan ), and pentostatin (Nipent ) as a strategy to provide adequate immunosuppression to allow sufficient engraftment for clinical remission with a lower risk of GVHD development. T-cell replete, donor-derived, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSC will be used to establish hematopoietic and lymphoid reconstitution.

The primary endpoint of this study is the percentage of patients at 100 days post-transplant who have not rejected their grafts, and who are without severe GVHD (defined as grade 3 and higher acute GVHD and moderate to severe chronic GVHD). Other endpoints include degree of donor-host chimerism necessary for long-term graft survival and disease amelioration, incidence of acute and chronic GVHD, incidence of graft rejection, transplant-related morbidity, as well as disease-free and overall survival.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Nonmyeloablative Haploidentical Peripheral Blood Mobilized Hematopoietic Precursor Cell Transplantation for Sickle Cell Disease
Actual Study Start Date : April 6, 2017
Estimated Primary Completion Date : September 30, 2025
Estimated Study Completion Date : August 31, 2026


Arm Intervention/treatment
Experimental: recipient
recipient
Procedure: haploidentical stem cell transplant
haploidentical stem cell transplant

Drug: sirolimus
conditioning regimen

Drug: campath
conditioning regimen

Drug: pentostatin
conditioning regimen

Drug: cyclophosphamide
conditioning regimen




Primary Outcome Measures :
  1. The percentage of patients at 100 days (+/- 1 week) post-transplantwith sustained donor type hemoglobin on hemoglobin electrophoresis (HbS less than 50% when donors have sickle cell trait and <10% when donors have normal hemoglobin), who d... [ Time Frame: 100 days post transplant ]

Secondary Outcome Measures :
  1. The level of chimerism required to maintain both graft survival as well as hematologic normalcy. [ Time Frame: 100 days post transplant ]


Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA-RECIPIENTS:

Patients with any type of sickle cell disease who are at high risk for disease-related morbidity or mortality, defined by having severe end-organ damage (A, B, or C) or potentially modifiable complication(s) not ameliorated by hydroxyurea (D):

A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct or hemorrhage on cerebral MRI or cerebral arteriopathy requiring chronic transfusion therapy; OR

B. Tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.5 m/s30,31 at baseline (without vaso-occlusive crisis) and/or pulmonary hypertension; OR Sickle hepatopathy defined as either ferritin >1000 mcg/L and platelet count < 250,000/uL (without vaso-occlusive crisis) OR direct bilirubin > 0.4 mg/dL and platelet count <250,000/uL (without vaso-occlusive crisis)^3

C. Sickle hepatopathy defined as EITHER ferritin >1000mcg/L OR direct bilirubin >0.4 mg/dL AND platelet count <250,000/uL at baseline (without vaso-occlusive crisis^3)

D. Any one of the below complications:

  • Complication-Vaso-occlusive crises; Eligible for hydroxyurea*-At least 3 hospital admissions in the last year 5; Eligible for HSCT-More than 1 hospital admission per year while on maximal tolerated dose of hydroxyurea* 2
  • Complication-Acute chest syndrome; Eligible for hydroxyurea*-2 prior ACS; Eligible for HSCT-any ACS while on hydroxyurea* 82.

    • hydroxyurea at maximum tolerated dose for at least 6 months

Non-disease specific:

A. Age greater than or equal to 18 years

B. Haploidentical relative donor available

C. Ability to comprehend and willing to sign an informed consent

D. Negative serum beta-HCG

E. Ejection fraction greater than or equal to 35%

F. Glomerular filtration rate >60 mL/min/1.73m^2 by cystatin C-based or othalamate-based or other equivalent GFR testing

EXCLUSION CRITERIA-RECIPIENT:

Any of the following would exclude the subject from participating

  1. Available 6/6 HLA-matched sibling donor
  2. ECOG performance status of 3 or more
  3. 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.
  4. Patients with fever or suspected minor infection should await resolution of symptoms before starting the conditioning regimen.
  5. Major anticipated illness or organ failure incompatible with survival from PBSC transplant
  6. Pregnant or lactating
  7. Anti-donor HLA antibodies
  8. Patients seronegative for EBV who have EBV seropositive donors

INCLUSION CRITERIA-DONOR:

  1. Haploidentical relative donor
  2. Weight > 20 kg (insofar 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)
  3. Fit to receive filgrastim (G-CSF) and to give peripheral blood stem cells (blood counts and blood pressure within DTM standards)
  4. No history of congestive heart failure or unstable angina, and no history of stroke
  5. Ability to comprehend and willing to sign an informed consent; assent obtained from minors

EXCLUSION CRITERIA-DONOR:

Any of the following would exclude the donor from participating

  1. Pregnant or breastfeedingl
  2. HIV positive
  3. Hemoglobin S > 50%

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03077542


Contacts
Contact: Courtney D Fitzhugh, M.D. (301) 402-6496 courtney.fitzhugh@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010    prpl@cc.nih.gov   
Sponsors and Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Principal Investigator: Courtney D Fitzhugh, M.D. National Heart, Lung, and Blood Institute (NHLBI)

Additional Information:
Responsible Party: National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier: NCT03077542     History of Changes
Other Study ID Numbers: 170069
17-H-0069
First Posted: March 13, 2017    Key Record Dates
Last Update Posted: September 19, 2018
Last Verified: September 13, 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) ):
Peripheral Blood Stem Cells
Host-Donor Chimerism
Graft Versus Host Disease
Haploidentical
Donor Apheresis

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Cyclophosphamide
Sirolimus
Pentostatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Adenosine Deaminase Inhibitors
Enzyme Inhibitors