Non-Myeloablative Conditioning and Bone Marrow Transplantation

NCT ID: NCT01850108

Last Updated: 2024-01-10

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-31
• Study Completion Date: 2024-12-31

Brief Summary

Allogeneic blood or marrow transplantation (alloBMT) is a curative therapy for a variety of hematologic disorders, including sickle cell disease and thalassemia. Even when it is clear that alloBMT can give to these patients an improvement in their disease, myeloablative transplants have important toxicities and mortalities associated. The lack of suitable donors continues to be a limit to access to transplantation. Substantial progress has been made recently in the development of pre-treatment regimens that facilitate the sustained engraftment of donor marrow with reduced toxicity. Most of these regimens incorporate highly immunosuppressive drugs, which allow the reduction or elimination of myeloablative agents or total body irradiation without endangering the sustained engraftment of HLA-identical allogeneic stem cells. Preliminary results of non-myeloablative allogeneic stem cell transplantation suggest that the procedure can be performed in patients who are ineligible for myeloablative alloBMT, and that sustained remissions of several hematologic malignancies can be obtained.

Conditions

Sickle Cell Disease; Hemoglobinopathies

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Non-Myeloablative Conditioning and Bone Marrow Transplantation

Group Type: EXPERIMENTAL

Thymoglobulin

Intervention Type: DRUG

Day 9 before BMT: 0.5mg/kg IV; Days 8 & 7 before BMT: 2mg/kg IV

Days 8 & 7 - 2mg/kg IV before BMT

Fludarabine

Intervention Type: DRUG

Days 6 and 2 before BMT: 30mg/m2/day IV

Cyclophosphamide (CTX)

Intervention Type: DRUG

Days 6 and 5 before BMT: 14.5mg/kg IV; Days 3 and 4 after BMT: 50mg/kg/day

Mesna

Intervention Type: DRUG

Days 3 \& 4 after BMT: 40 mg/kg IV

Sirolimus

Intervention Type: DRUG

Adjusted to maintain a serum trough level of 3-12 ng/mL, taken orally beginning on 5 days after BMT and taken to 1 year after BMT.

Mycophenolate mofetil (MMF)

Intervention Type: DRUG

15 mg/kg orally with maximum dose 3 mg/day beginning 5 days after BMT and taken to day 35 after BMT

Bone marrow transplantation

Intervention Type: PROCEDURE

Day 0 - Transplantation of hematopoietic cells derived from bone marrow of a donor to a recipient as treatment for hematologic disorders

Total body irradiation

Intervention Type: RADIATION

200 cGy on the day before BMT. Radiation delivered to the entire body of the recipient to eradicate bone marrow cells in the recipient to prepare the recipient to receive the transplanted

Interventions

Thymoglobulin

Day 9 before BMT: 0.5mg/kg IV; Days 8 & 7 before BMT: 2mg/kg IV

Days 8 & 7 - 2mg/kg IV before BMT

Intervention Type: DRUG

Fludarabine

Days 6 and 2 before BMT: 30mg/m2/day IV

Intervention Type: DRUG

Cyclophosphamide (CTX)

Days 6 and 5 before BMT: 14.5mg/kg IV; Days 3 and 4 after BMT: 50mg/kg/day

Intervention Type: DRUG

Mesna

Days 3 \& 4 after BMT: 40 mg/kg IV

Intervention Type: DRUG

Sirolimus

Adjusted to maintain a serum trough level of 3-12 ng/mL, taken orally beginning on 5 days after BMT and taken to 1 year after BMT.

Intervention Type: DRUG

Mycophenolate mofetil (MMF)

15 mg/kg orally with maximum dose 3 mg/day beginning 5 days after BMT and taken to day 35 after BMT

Intervention Type: DRUG

Bone marrow transplantation

Day 0 - Transplantation of hematopoietic cells derived from bone marrow of a donor to a recipient as treatment for hematologic disorders

Intervention Type: PROCEDURE

Total body irradiation

200 cGy on the day before BMT. Radiation delivered to the entire body of the recipient to eradicate bone marrow cells in the recipient to prepare the recipient to receive the transplanted

Intervention Type: RADIATION

Other Intervention Names

Fludara®; Cytoxan; rapamycin, Rapamune®

Eligibility Criteria

Inclusion Criteria

• Patients who are ineligible for BMT from an HLA-matched sibling donor can proceed to a haplo-BMT. Patients with an HLA-matched related donor will proceed to a matched BMT.
• Age 1-70 years
• Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
• Patients and donors must be able to sign consent forms. First degree relative should be willing to donate
• Patients must be geographically accessible and willing to participate in all stages of treatment.
• Eligible diagnoses: Patients with sickle cell anemia such as sickle cell anemia (Hb SS), Hb Sβ° thalassemia, Hb Sβ+thalassemia, Hb SC disease, Hb SE disease, Hb SD disease, Hemoglobin SO- Arab disease HbS with hereditary persistence of fetal hemoglobin. Other significant hemoglobinopathies.

Plus one of the following:

• Attenuation of progressive disease (adults):
• Severe and debilitating vaso-occlusive pain despite hydroxyurea or regular blood transfusion therapy.
• Stroke and silent infarct; stroke or central nervous system event lasting more than 24 hours; MRI changes indicative of brain parenchyma damage and MRA evidence of cerebrovascular disease.
• Recurrent acute chest syndrome requiring exchange hospitalization.
• Chronic lung disease as defined by progressive restrictive disease irrespective of oxygen requirements.
• Chronic kidney disease, CKD stage II - IV
• Transfusion dépendent thalassemia

Exclusion Criteria

• Poor performance status (ECOG>1).
• Poor cardiac function: left ventricular ejection fraction<35%.
• Poor pulmonary function: FEV1 and FVC<40% predicted.
• Pulmonary hypertension moderate to severe by echocardiographic standards.
• Poor liver function: direct bilirubin >3.1 mg/dl
• HIV-positive
• Minor (donor anti-recipient) ABO incompatibility if an ABO compatible donor is available.
• Prior transfusions from donor or recipient if caused alloimmunization vs. donor cells.
• Women of childbearing potential who currently are pregnant (Beta-HCG+) or who are not practicing adequate contraception.
• Patients who have any debilitating medical or psychiatric illness that would preclude their giving informed consent or their receiving optimal treatment and follow-up. However, patients with history of stroke and significant cognitive deficit,that would preclude giving informed consent or assent will not be excluded, if they have a family member or significant other with Power of Attorney to also consent of their behalf.

CRITERIA FOR DONOR ELIGIBILITY:

• Weight ≥ 20kg and age ≥ 18 years or per institutional guidelines
• Donors must meet the selection criteria as defined by the Foundation for the Accreditation of Hematopoietic Cell Therapy (FAHCT) and will be screened per the American Association of Blood Banks (AABB). (AABB guidelines and the recipients will be informed of any deviations.)
• HLA-haploidentical first-degree relatives of the patient. Participants must be HLA typed at high resolution using DNA based typing at HLA-A, -B, -C and DRB1 and have available: An HLA haploidentical first degree relative donor (parents, siblings or half siblings, or children) with 2, 3, or 4 (out of 8) HLA-mismatches who is willing and able to donate bone marrow. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.

When more than one donor is available, the donor with the lowest number of HLA allele mismatches will be chosen, unless there is HLA cross-match incompatibility or a medical reason to select otherwise, in which case donor selection is the responsibility of the PI, in consultation with the immunogenetics laboratory. In cases where there is more than one donor with the least degree of mismatch, donors will be selected based on the most favorable combination of:

• HLA compatibility in cross-match testing and
• ABO compatibility
• Donor age <40 years
• Avoid female donors for male recipients and
• Avoid CMV mismatched donor-recipient transplants:

HLA cross-matching (in order of priority):

• Mutually compatible (no cross-matching antibodies)
• Recipient non-cross-reactive with donor, donor cross-reactive with recipient
• Mutually cross-reactive

ABO compatibility (in order of priority):

• Compatible
• Major incompatibility
• Minor incompatibility
• Major and minor incompatibility
• Donors will be selected to minimize HLA mismatch in the Host-versus-graft direction.
• Donors fulfilling the following criteria are ineligible for registration onto this study:
• All donors will be screened by hemoglobin electrophoresis; donors with a clinically significant hemoglobinopathy are ineligible. Sickle trait is acceptable.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Vanderbilt-Ingram Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Adetola A. Kassim

Professor of Medicine; Clinical Director, Sickle Cell Anemia Program; Medical Oncologist

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Adetola A Kassim, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt-Ingram Cancer Center

Locations

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

Saint-Louis Hospital

Paris, , France

St Mary's Hospital

London, , United Kingdom

Countries

United States; France; United Kingdom

References

Kassim AA, de la Fuente J, Nur E, Wilkerson KL, Alahmari AD, Seber A, Bonfim C, Simoes BP, Alzahrani M, Eckrich MJ, Horn B, Hanna R, Dhedin N, Rangarajan HG, Gouveia RV, Almohareb F, Aljurf M, Essa M, Alahmari B, Gatwood K, Connelly JA, Dovern E, Rodeghier M, DeBaun MR. An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease. Blood. 2024 Jun 20;143(25):2654-2665. doi: 10.1182/blood.2023023301.

Reference Type: DERIVED

PMID: 38493482 (View on PubMed)

Aumann MA, Richerson W, Song AK, Davis LT, Pruthi S, Davis S, Patel NJ, Custer C, Kassim AA, DeBaun MR, Donahue MJ, Jordan LC. Cerebral hemodynamic changes after haploidentical hematopoietic stem cell transplant in adults with sickle cell disease. Blood Adv. 2024 Feb 13;8(3):608-619. doi: 10.1182/bloodadvances.2023010717.

Reference Type: DERIVED

PMID: 37883803 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.vicc.org/ct/

Vanderbilt-Ingram Cancer Center, Find a Clinical Trial

Other Identifiers

VICCNCCTT12108

Identifier Type: -

Identifier Source: org_study_id