Transplanting stem cells to treat severe blood disorders

Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes Using G-CSF Mobilized CD34+ Selected Hematopoietic Precursor Cells Co-Infused With a Reduced Dose of Non-Mobilized Donor T-Cells

This study is testing a new way to use stem cells for treating severe blood disorders to see if it can reduce complications and improve outcomes for patients with conditions like severe aplastic anemia.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 4 Years to 80 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: chemotherapy, methotrexate, cyclophosphamide, fludarabine
• Locations: 2 sites (Baltimore, Maryland and 1 other locations)
• Trial ID: NCT01174108 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates a novel approach to allogeneic hematopoietic stem cell transplantation for patients with severe aplastic anemia and other bone marrow failure syndromes. The study aims to reduce complications associated with traditional stem cell transplants by using G-CSF mobilized CD34+ selected hematopoietic precursor cells co-infused with a reduced dose of non-mobilized donor T-cells. The methodology involves conditioning with cyclophosphamide, fludarabine, and anti-thymocyte globulin, followed by the infusion of a CD34+ cell-rich graft. Researchers are assessing the effectiveness of this approach in preventing graft rejection and minimizing complications such as chronic graft versus host disease.

Who should consider this trial

Good fit: Ideal candidates include patients diagnosed with severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, or myelodysplastic syndrome who have a high risk of graft rejection.

Not a fit: Patients with conditions not related to severe blood disorders or those who are not candidates for stem cell transplantation may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to safer and more effective stem cell transplants for patients with severe blood disorders.

How similar studies have performed: Other studies have shown promise with similar approaches, but this specific methodology is novel and has not been extensively tested.

Eligibility criteria

* INCLUSION CRITERIA:
* Recipient:

  * Patients diagnosed with one of the following hematologic diseases which are associated with reasonable longevity, shown to be curable by allogeneic BMT but where concern for a high procedural mortality with conventional BMT may delay or prevent such treatment:

    * 1\) Paroxysmal nocturnal hemoglobinuria (PNH) associated with life-threatening thrombosis, and/or cytopenia, and/or transfusion dependence and/or recurrent and debilitating hemolytic crisis
    * 2\) Severe aplastic anemia (SAA) or pure red cell aplasia (PRCA \[acquired or congenital\]) with bone marrow cellularity \<30% (excluding lymphocytes) associated with RBC or platelet transfusion dependence and/or neutropenia (absolute neutrophil count \<=1000 cells/uL or for patients receiving granulocyte transfusions, absolute neutrophil count \<=1000 cells/ uL before beginning granulocyte transfusions). in newly diagnosed patients and/or in patients who have failed immunosuppressive therapy.
    * 3\) Refractory anemia (RA) or RARS MDS patients who have associated transfusion dependence and/or neutropenia.
  * Ages 4 to 80 (both inclusive), and weight \>15 kg
  * Availability of HLA identical or single HLA locus mismatched family donor or 10/10 matched unrelated donor at the allelic level (HLA alleles A, B, C, DR, and DQ).
  * 9/10 donors where all the HLA sequences have the same antigen/peptide binding domains in key exons to the patient. This can result in identical protein sequences between patient and donor. Allele mismatches in p and g groups can be considered acceptable due to the exact matching which exists in the binding domains.
  * Telomere Length Testing
  * Germline/Inherited gene panel in patients where a suspicion for a familial bone marrow failure syndrome (BMFS) exist, hTERC and hTERT, GATA2 mutation testing will be performed on protocol 04-H-0012 or performed elsewhere prior to enrolling on 04-H-0012.

EXCLUSION CRITERIA:

\- Recipient: any of the following

* Major anticipated illness or organ failure incompatible with survival from PBSC transplant
* Diffusion capacity of carbon monoxide (DLCO) \<40% predicted (patients under the age of 10 may be excluded from this criterion if they have difficulty performing the test correctly and thus are unable to have their DLCO assessed) using DL Adj and DL/VA/Adj.
* Left ventricular ejection fraction \<40% (evaluated by ECHO)
* Serum creatinine greater than 2.5mg/dl or creatinine clearance less than 50 ml/min by 24 hr urine collection
* Serum bilirubin greater than 4 mg/dl, transaminases greater than 5 times the upper limit of normal
* Pregnant or lactating
* Fanconi s anemia (test to be performed at a CLIA-certified laboratory)
* ECOG performance status of 3 or more (See NIH Bone \& Marrow Transplant Consortium Supportive Care Guidelines for HSCT Recipients or Institutional Guidelines for bone and marrow transplants)
* Other malignant diseases liable to relapse or progress within 5 years, with the exception of a separate hematologic malignancy where allogeneic stem cell transplant has been shown to be potentially curative.
* Presence of an active infection not adequately responding to appropriate therapy.
* Inability to comprehend the investigational nature of the study and provide informed consent. The procedure will be explained to subjects age 8 -17 years with formal consent being obtained from parents or legal guardian.

INCLUSION CRITERIA:

-Related Donor:

* Related donor deemed suitable and eligible, and willing to donate, per clinical evaluations who are additionally willing to donate blood samples for research. Related donors will be evaluated in accordance with existing Standard Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but study participation is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study
* Age greater than or equal to 4 and less than or equal to 80 years old

EXCLUSION CRITERIA:

-Related Donor: None

INCLUSION CRITERIA \& EXCLUSION CRITERIA: Unrelated Donor

\- The NMDP unrelated donor inclusion criteria will be used as outlined in document (http://bethematch.org/WorkArea/DownloadAsset.aspx?id=1960). Donor eligibility will be completed per NMDP standards and in accordance with most recent and stringent FDA guidelines.

Where this trial is running

Baltimore, Maryland and 1 other locations

• University of Maryland, Baltimore (UMB) — Baltimore, Maryland, United States (Completed)
• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Richard W Childs, M.D. — National Heart, Lung, and Blood Institute (NHLBI)
• Study coordinator: Melissa M Spencer, R.N.

Conditions Severe Aplastic Anemia; MDS; Myelodysplastic Syndrome; Pure Red Cell Aplasia; Paroxysmal Nocturnal Hemoglobinuria; Miltenyi CD34 Reagent System