Alpha Beta T-cells and CD19 B-cells Depleted Stem Cell Transplant in Treating Patients with Non-Malignant Blood and Immune Disorders

Status: Active

Description

This phase II trial studies how well alpha beta T-cells and CD19 B-cells depleted stem cell transplant works in treating patients with blood and immune disorders. Donor stem cell transplants contain kinds of white blood cells called T-cells and B-cells along with all the blood-forming cells that make up a healthy immune system. Sometimes donor stem cells are referred to as the "graft" and the patient receiving the "graft" is called the "host." Graft versus host disease (GVHD) and posttransplant lymphoproliferative disease (PTLD) are side effects that can occur after transplantation. Removing alpha-beta T cells and CD19 B-cells from donor cells may help diminish these complications.

Eligibility Criteria

Inclusion Criteria

  • Lethal disorders of hematopoiesis correctable by transplant for which alpha/beta T-cell and CD-19 depleted allogeneic hematopoietic stem cell transplantation is indicated including: * Hemoglobinopathies: ** Sickle cell disease (HbSS, HbSC, HbSB0 thalassemia, HbSB+, HbSD, HbSE) with at least one of the following criteria (Walters et al): *** Cerebrovascular accident lasting longer than 24 hours. *** Impaired neuropsychological function with abnormal brain magnetic resonance imaging/magnetic resonance angiography (MRI/MRA). *** Recurrent hospitalizations (> 2 episodes/year over several years) or exchange transfusions for acute chest syndrome. *** Recurrent priapism. *** Stage I or II sickle chronic lung disease. *** Sickle cell nephropathy (moderate to severe proteinuria or glomerular filtration rate 30-50% of predicted normal value for age). *** Bilateral proliferative retinopathy with major visual impairment in at least one eye. *** Osteonecrosis of multiple joints. *** Red cell alloimmunization during chronic transfusion therapy. ** Thalassemia major with at least one of the following criteria: *** Age < 16 years. *** Available human leukocyte antigen (HLA)-identical sibling. *** Red blood cell transfusion dependency. *** Lucarelli class 1 or 2 risk status (i.e. with only 0-2 of the following factors: hepatomegaly, portal fibrosis, or poor response to chelation therapy). *** Recurrence of disease after previous stem cell transplant. * Bone marrow failure syndromes: ** Aplastic anemia refractory to immunosuppressive therapy. ** Diamond Blackfan anemia refractory to conventional therapy. ** Shwachman-Diamond syndrome. ** Severe congenital neutropenia. ** Congenital amegakaryocytic thrombocytopenia. ** Thrombocytopenia absent radii syndrome. ** Other marrow failure disorders not otherwise specified. * Autoimmune cytopenias refractory to all conventional treatments ** Autoimmune hemolytic anemia. ** Immune thrombocytopenia. ** Evan's syndrome. ** Pure red cell aplasia. * Histiocytic disorders: ** Hemophagocytic lymphohistiocytosis. ** High risk, recurrent or refractory Langerhans cell histiocytosis. ** Secondary hemophagocytic lymphohistiocytosis (HLH).
  • Asymptomatic cardiac function or if symptomatic then left ventricular ejection fraction (LVEF) at rest must be > 50% and must improve with exercise.
  • < 3 x upper limit of normal (ULN) aspartate aminotransferase (AST), unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant for. Patients with higher bilirubin levels due to causes other than active liver disease are also eligible with principal investigator (PI) approval e.g. patients with paroxysmal nocturnal hemoglobinuria (PNH), Gilbert's disease or other hemolytic
  • < 1.5 mg/dl total serum bilirubin, unless there is congenital benign hyperbilirubinemia or if the hyperbilirubinemia is directly caused by the disease in which the patient is receiving a transplant for. Patients with higher bilirubin levels due to causes other than active liver disease are also eligible with PI approval e.g. patients with PNH, Gilbert's disease or other hemolytic disorders.
  • Asymptomatic pulmonary function or if symptomatic, diffusing capacity of the lungs for carbon monoxide (DLCO) > 50% of predicted (corrected for hemoglobin).
  • Serum creatinine < 1.5 x normal for age. If serum creatinine is outside the normal range, then creatinine clearance (CrCl) > 70 mL/min/1.73m^2 (calculated or estimated) or glomerular filtration rate (GFR) (mL/min/1.72m^2) > 30% of predicted normal for age.
  • Each patient must be willing to participate as a research subject and must sign an informed consent form.
  • DONOR: Each donor must meet criteria outlined by institutional guidelines and be medically eligible to donate according to the National Marrow Donor Program (NMDP) (or equivalent donor search organization) criteria including testing for antibodies to Human T-Lymphotrophic Virus Types I & II (Anti-human T-lymphotropic virus [HTLV]-I/II) and screening for West Nile Virus, Creutzfeldt–Jakob disease and Zika.
  • DONOR: Pediatric donors should weigh >= 25.0 kg, have adequate peripheral venous catheter access for leukapheresis or must agree to placement of a central catheter.
  • DONOR: Donor should be healthy and agree to receive granulocyte-colony stimulating factor (G-CSF) followed by donation of peripheral blood stem cells.
  • DONOR: Donors must agree to anesthesia and marrow donation (in cases of inadequate peripheral blood stem cells [PBSC] collection).
  • DONOR: Related or unrelated donors who are 7/8 or 8/8 HLA-antigen matched for haplotypes A, B, C, DRB1 OR
  • DONOR: Related donors who are 4-6/8 HLA-antigen matched.

Exclusion Criteria

  • Inherited deoxyribonucleic acid (DNA) repair deficiency: * Fanconi anemia. * Dyskeratosis congenita. These are presently undergoing transplantation based on a multi-center protocol.
  • Inherited metabolic disorders: * Hurler syndrome. * Sly syndrome (mucopolysaccharidosis type VII [MPSVIII]). * Alpha-Mannosidosis. * X-linked adrenoleukodystrophy (X-ALD). * Osteopetrosis.
  • Stage III-IV sickle chronic lung disease.
  • Patients with thalassemia major with Pesaro risk score > II.
  • Female patients who are pregnant or breast-feeding.
  • Active viral, bacterial or fungal infection.
  • Patient seropositive for HIV-I/II; HTLV-I/II.
  • Karnofsky (adult)/Lansky (pediatric) < 70%.
  • DONOR: Donors who are seropositive for human immunodeficiency virus (HIV)-I/II or HTLV-I/II and female patients who are pregnant or breastfeeding will not be eligible for this study.

Locations & Contacts

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Maria I. Cancio
Phone: 212-639-2446

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess two-year overall survival.

SECONDARY OBJECTIVES:

I. To assess neutrophil engraftment following T- and B-cell depleted grafts in patients with nonmalignant hematologic disorders using a chemotherapy-only cytoreduction.

II. To assess the rate of grade III-IV acute and chronic graft versus host disease (GvHD) following this novel T- and B-cell depleted approach.

III. To assess graft composition CD34, T-alpha/beta, T-gamma delta, B, and natural killer (NK) cells post T-cell and B-cell depletion.

IV. To assess the immune reconstitution following alpha/beta T-cell depleted stem cell transplant as measured at approximately 1, 2, 3, 6, and 12 months.

V. To assess the rate and specifics of the immune reconstitution post transplant compared to those achieved in CD34 positively selected grafts as part of protocol 10-050.

VI. To assess the CD34+ cell dose using this negative selection method with T-cell receptor (TCR) alpha beta T-cell and CD19 B-cell depletion method and compare to the cell dose achieved using a positive selection method in CD34 positive grafts as part of protocol 10-050.

VII. To assess the incidence of post-transplant infectious complications, including cytomegalovirus (CMV), Epstein-Barr virus (EBV), adenovirus and human herpesvirus 6 (HHV6) (viremia, organ involvement and infection).

VIII . To assess the incidence of transplant-related mortality and of disease free survival post transplant.

OUTLINE: Patients are assigned to 1 of 2 regimens.

REGIMEN I: Patients receive rabbit anti-thymocyte globulin (ATG) intravenously (IV) over 12 hours on days -12 to -10, clofarabine IV daily over 2 hours on days -9 to -5, thiotepa IV daily over 4 hours on days -4 and -3, melphalan IV daily over 30 minutes on days -3 and -2, , and rituximab IV on day -1 in the absence of disease progression or unacceptable toxicity. Participants also receive tacrolimus IV over 24 hours or orally (PO) or mycophenolate mofetil IV over 8 hours beginning on day -2. Patients then receive allogeneic TCR alpha/beta-positive T-lymphocyte-depleted peripheral blood stem cells IV over 15 minutes using the ClinicMACS system on day 0 and granulocyte-colony stimulating factor (G-CSF) beginning on day 7.

REGIMEN II: Patients receive rabbit ATG on days -11 to -9, melphalan IV daily over 30 minutes on days -8 and -7, fludarabine IV daily over 30 minutes on days -6 to -2, thiotepa IV daily over 4 hours on days -6 and -5, tacrolimus IV over 24 hours or mycophenolate mofetil IV over 8 hours on day -2, and rituximab IV on day -1 in the absence of disease progression or unacceptable toxicity. Patients then receive allogeneic TCR alpha/beta-positive T-lymphocyte-depleted peripheral blood stem cells IV over 15 minutes using the ClinicMACS system on day 0 and G-CSF beginning on day 7.

After completion of study treatment, patients are followed up for 6 months, then at 9, 12, and 24 months, and then yearly.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Maria I. Cancio

Trial IDs

Primary ID 17-596
Secondary IDs NCI-2018-01909
Clinicaltrials.gov ID NCT03615144