Non-Myeloablative Conditioning and Bone Marrow Transplantation

• Thymoglobulin (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 (Drug), also known as Fludara®: Days 6 and 2 before BMT: 30mg/m2/day IV
• Cyclophosphamide (CTX) (Drug), also known as Cytoxan: Days 6 and 5 before BMT: 14.5mg/kg IV; Days 3 and 4 after BMT: 50mg/kg/day
• Mesna (Drug): Days 3 \& 4 after BMT: 40 mg/kg IV
• Sirolimus (Drug), also known as rapamycin, Rapamune®: 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) (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 (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 (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

Primary outcomes

• Transplant-related Mortality (TRM) [at 1 year after BMT]: Defined as death in the absence of recurrent sickle cell disease or hemoglobinopathy

Secondary outcomes

• Number of Patients Who Developed Grade I-IV Acute Graft-vs.-Host Disease [2 years]: GVHD Severity was graded using the established National Institutes of Health's consensus criteria \[36\].
• Number of Patients With Donor Hematopoietic Chimerism in Peripheral Blood <95% at 6 Months After Mini-haploBMT [Up to approximately 180 after mini-haploBMT]: Partially human leukocyte antigen (HLA)-mismatched bone marrow from first-degree relatives. Defined in percentages of donor cells in patient's peripheral blood, measured in 4 ways. * Mixed donor chimerism: > 0% but < 95% * Complete donor chimerism > 95% Any amount of donor chimerism after day 60 will be considered as having engrafted
• Number of Participants With Hematologic and Non-hematologic Toxicities Following minihaploBMT [Day 60 after BMT]: Hematologic toxicity: -Absolute neutrophil count (ANC): consecutive values of < 500/µL on 3 different days after chemotherapy post-BMT Platelet count: consecutive values of < 20,000 µL on 3 different days after chemotherapy post-BMT Non-hematologic toxicities: -Toxicities necessitating hospitalization Toxicities grade 4 or above Meets the criteria of the following SAE: * Relapse of underlying disease * Grade 3 ocular toxicity not related to ocular GVHD * Grade 3 related non-hematologic toxicity

Sex: All, ages: 1 Year to 70 Years, accepts healthy volunteers

RECIPIENT 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

RECIPIENT 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.

Participant flow

Outcome results

• Transplant-related Mortality (TRM) (Primary), Count of participants, Participants: Non-Myeloablative Conditioning and Bone Marrow Transplantation 0
• Number of Patients Who Developed Grade I-IV Acute Graft-vs.-Host Disease (Secondary), Count of participants, Participants: Non-Myeloablative Conditioning and Bone Marrow Transplantation 2
• Number of Patients With Donor Hematopoietic Chimerism in Peripheral Blood <95% at 6 Months After Mini-haploBMT (Secondary), Count of participants, Participants: Non-Myeloablative Conditioning and Bone Marrow Transplantation 1
• Number of Participants With Hematologic and Non-hematologic Toxicities Following minihaploBMT (Secondary), Count of participants, Participants: Non-Myeloablative Conditioning and Bone Marrow Transplantation 1

Adverse events

Time frame: Day 100 after transplant

Serious adverse events by term

• Results publication: Alasbali R, Alzahrani M, Wilkerson K, Akhom P, Alotaibi F, Alahmari B, de la Fuente J, DeBaun MR, Rasheed W, Samarkandi H, El Fakih R, Saleh M, Elhassan T, Alzahrani H, Aljurf M, Almohareb F, Kassim AA, AlAhmari A. Excellent outcomes using a novel reduced intensity conditioning with thiotepa and post-transplant cyclophosphamide for HLA-matched related donor transplant in adolescents and adults with sickle cell disease. Bone Marrow Transplant. 2026 Jul;61(7):847-851. doi: 10.1038/s41409-026-02876-3. Epub 2026 Apr 28. PMID 42049986
• Results publication: 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. PMID 38493482
• Results publication: 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. PMID 37883803

• Study Protocol and Statistical Analysis Plan (PDF, 2017-12-04)

• Adetola A Kassim, MD, Principal investigator, Vanderbilt-Ingram Cancer Center