non-myeloablative conditioning and bone marrow transplantation

Conditions: Sickle Cell Disease; Hemoglobinopathies

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.


Eligibility criteria:
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.