Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells

NCT02512679 | Terminated Phase 2 Results DMC

• 1 other identifier: CCI-06-00177
• Study Type: interventional
• Target: 20
• Locations: 0 countries
• Sites: N/A

Brief Summary

Many genetic diseases of lymphohematopoietic cells (such as sickle cell anemia, thalassemia, Diamond-Blackfan anemia, Combined Immune Deficiency (CID), Wiskott-Aldrich syndrome, chronic granulomatous disease, X-linked lymphoproliferative disease, and metabolic diseases affecting hematopoiesis) are sublethal diseases caused by mutations that adversely affect the development or function of different types of blood cells. Although pathophysiologically diverse, these genetic diseases share a similar clinical course of significant progressive morbidity, overall poor quality of life, and ultimate death from complications of the disease or its palliative treatment. Supportive care for these diseases includes chronic transfusion, iron chelation, and surgery (splenectomy or cholecystectomy) for the hemoglobinopathies; prophylactic antibiotics, intravenous immunoglobulin, and immunomodulator therapies for the immune deficiencies; and enzyme replacement injections and dietary restriction for some of the metabolic diseases. The suboptimal results of such supportive care measures have led to efforts to implement more aggressive therapeutic interventions to cure these lymphohematopoietic diseases. The most logical strategies for cure of these diseases have been either replacement of the patient's own hematopoietic stem cells (HSC) with those derived from a normal donor allogeneic bone marrow transplant (BMT) or hematopoietic stem cell transplant (HSCT), or to genetically modify the patient's own stem cells to replace the defective gene (gene therapy).

Conditions

Stem Cell Transplantation; Bone Marrow Transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation; Genetic Diseases; Thalassemia; Pediatrics; Diamond-Blackfan Anemia; Combined Immune Deficiency; Wiskott-Aldrich Syndrome; Chronic Granulomatous Disease; X-linked Lymphoproliferative Disease; Metabolic Diseases

Keywords

Hematopoietic Stem Cell Transplantation Pediatrics,; stem cell transplantation; bone marrow transplantation; Peripheral Blood Stem Cell Transplantation; Allogeneic Transplantation; pediatrics; Combined Immune Deficiency; Chronic Granulomatous disease

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Neutrophil Engraftment (=/>500 Cells/uL) and Platelet Engraftment (>20K Cell/uL) at 30 Days

  Absolute Neutrophil Count (ANC) =/\>500;(recovery of white cell count - self sustain platelet above 20,000 per cubic milimeter (20K) - evaluation by Chimerism Study (STR or FISH) at day +30

  30 days

• Number of Participants With Disease Recurrence at 1 Year Post-transplant

  assess rate of disease recurrence ("late relapse") due to autologous recovery of recipient hematopoiesis at one year post-HSCT.

  1 year

• Number of Participants Who Developed Severe Mucositis, Veno-occlusive Disease (VOD), Toxicity of the Kidney, Liver, or Gastrointestinal (GI) Tract up to 1 Year Post-transplant

  Assessment of conditioning regimen related toxicity was evaluated and documented with daily assessment during hospitalization and post-transplant follow-up up to one year. None of the subjects developed VOD necessitating any therapeutic intervention, severe mucositis, or toxicity of the Kidney, Liver or Gastrointestinal.

  1 year

Secondary Outcomes (2)

• Number of Participants Who Developed Graft-Versus-Host-Disease (GVHD) as Determined by the Glucksberg Scale

  1 yr

• Number of Participants Who Were Disease Progression-Free and Death-Free at 1 Year Post-transplant

  1 yr

Study Arms (4)

Cyclophosphamide Dose Level 1

OTHER

Cyclophosphamide given by Intravenous (IV) at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. Drug to be given in combination of Busulfan, Campath and Fludarabine

Drug: Cyclophosphamide Dose Level 1

Cyclophosphamide Dose Level 2

OTHER

Cyclophosphamide given by intravenous (IV) at a total dose of 70 mg/kg (divided in two doses) given once a day for two days in combination with Busulfan, Campath and Fludarabine.

Drug: Cyclophosphamide Dose Level 2

Cyclophosphamide Dose Level 3

OTHER

Cyclophosphamide given by intravenous (IV) at total does of 35 mg/kg as a one time dose in combination with Busulfan, Fludarabine and Campath

Drug: Cyclophosphamide Dose Level 3

Cyclophosphamide Dose Level 4

OTHER

No cyclophosphamide given with Busulfan, Fludarabine and Campath

Drug: Cyclophosphamide Dose Level 4

Interventions

Cyclophosphamide Dose Level 1 DRUG

given by IV at a total dose of 105 mg/kg, to be divided into three doses of one 35 mg/kg dose per day, for 3 days on the first level. After ten patients the de-escalation will begin if the stopping rule is not met.

Also known as: Cytoxan

Cyclophosphamide Dose Level 1

Cyclophosphamide Dose Level 2 DRUG

Level 2 will be 70mg/kg in 2 divided given once a day for 2 days;

Also known as: Cytoxan

Cyclophosphamide Dose Level 2

Cyclophosphamide Dose Level 3 DRUG

Level 3 will be 35mg/kg as a one-time dose.

Also known as: Cytoxan

Cyclophosphamide Dose Level 3

Cyclophosphamide Dose Level 4 DRUG

Level 4 will be no cytoxan.

Also known as: Cytoxan

Cyclophosphamide Dose Level 4

Eligibility Criteria

• Age: 3 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients with lethal or sublethal genetic lymphohematological disease (such as Hemaphagocytic lymphohistiocytosis (HLH) / Familial Erythrophagocytic Lymphohistiocytosis (FEL), Hurler's Syndrome, Hunter's Syndrome, Kostmann's Syndrome, Blackfan-Diamond Anemia, Chronic granulomatous Disease (CGD), Red Cell Aplasia, CID, Sickle Cell Anemia, Thalassemia, Adreno-leukodystrophy, metachromatic leukodystrophy, Wiskott-Aldrich Syndrome, X-Linked Lymphoproliferative Disease (XLD), Metabolic diseases affecting hematopoiesis, but not limited to), who are candidates for allogeneic transplantation for their disease and have a histocompatible sibling or related donor, ages 0 to 21 years, will be candidates for this study protocol. The suitable related donor is a 10/10 or 9/10 allele Human Leukocyte Antigen (HLA) match with the patient. All patients who have previously had serious life- threatening events due to disease process may be included in the study. Patients must have adequate physical function and vital organ function to tolerate transplant procedure, as measured by:
• Cardiac: Shortening fraction \>26% or left ventricular ejection fraction at rest must be \> 40%.
• Hepatic: Bilirubin, Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) \< 3x upper limit of normal (as per local laboratory) for age (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome).
• Renal: Serum creatinine \< 2x upper limit of normal for age or if serum creatinine elevated beyond normal range patient must have creatinine Clearance or Glomerular filtration rate (GFR) \>50% lower limit of normal for age.
• Pulmonary: Forced expiratory volume (FEV)1, Forced Vital Capacity (FVC), and Diffusing Lung Capacity for Carbon Monoxide (DLCO) (corrected for Hgb) \> 50% predicted. For patients where pulse oximetry is performed, O2 saturation \> 92%
• Evaluation of iron status in patients who have received more than 12 red cell transfusions. Measurements of serum ferritin levels and MRI of the liver and heart tissue will evaluate the iron stores. If high iron load is identified in these organs further evaluation will be done to determine the suitability as transplant recipient. Should these studies indicate that chelation is necessary the following should apply: That the treating hematologist will provide the specific chelation type and timing. Evaluation of organ iron load will be part of the HSCT work-up and if high iron load is identified then the BMT team will work with the hematologist attending in developing a plan for the patient.

You may not qualify if:

• Karnofsky performance status \< 70%, or Lansky \< 40% for patients \< 16 years old.
• Uncontrolled bacterial, viral, or fungal infections (currently taking medication yet clinical symptoms progress).
• Seropositivity for the human immunodeficiency virus (HIV).
• Acute active hepatitis.
• Diagnosis of end-organ dysfunction that precludes the ability to tolerate the transplant procedure.
• Patients with a diagnosis of Fanconi Anemia are excluded.

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead
• Lucile Packard Children's Hospital: collaborator

Related Publications (1)

• Mahadeo KM, Weinberg KI, Abdel-Azim H, Miklos DB, Killen R, Kohn D, Crooks GM, Shah AJ, Kharbanda S, Agarwal R, Kapoor N. A reduced-toxicity regimen is associated with durable engraftment and clinical cure of nonmalignant genetic diseases among children undergoing blood and marrow transplantation with an HLA-matched related donor. Biol Blood Marrow Transplant. 2015 Mar;21(3):440-4. doi: 10.1016/j.bbmt.2014.11.005. Epub 2014 Nov 13.

  PMID: 25459642 RESULT

Related Links

• Reduced-toxicity regimen for related HSCT transplants

MeSH Terms

Conditions

Genetic Diseases, Inborn; Thalassemia; Anemia, Diamond-Blackfan; Wiskott-Aldrich Syndrome; Granulomatous Disease, Chronic; Lymphoproliferative Disorders; Metabolic Diseases

Interventions

Cyclophosphamide

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Anemia, Hypoplastic, Congenital; Anemia, Aplastic; Red-Cell Aplasia, Pure; Congenital Bone Marrow Failure Syndromes; Bone Marrow Failure Disorders; Bone Marrow Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Lymphopenia; Leukopenia; Cytopenia; Hemorrhagic Disorders; Leukocyte Disorders; Genetic Diseases, X-Linked; Primary Immunodeficiency Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Phagocyte Bactericidal Dysfunction; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Lymphatic Diseases; Immunoproliferative Disorders; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Limitations and Caveats

De-escalation was not ensued. All enrolled subjects engrafted without toxicity for dose level one.

Results Point of Contact

• Title: Neena Kapoor, M.D.
• Organization: Children's Hospital Los Angeles

nkapoor@chla.usc.edu

343-361-2434

Study Officials

• Neena Kapoor, M.D.

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 21, 2015
• First Posted: July 31, 2015
• Study Start: February 1, 2007
• Primary Completion: September 1, 2013
• Study Completion: February 1, 2014
• Last Updated: February 27, 2017
• Results First Posted: June 17, 2016

Record last verified: 2017-01

Data Sharing

• IPD Sharing: Will share