Study of Reduced Toxicity Myeloablative Conditioning Regimen for Wiskott-Aldrich Syndrome (WAS)

Phase I/II Study of Reduced Toxicity Myeloablative Conditioning Regimen for Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS) is a rare X-linked congenital immune-deficiency syndrome and hematopoietic stem cell transplantation (HSCT) has become a curative modality. But the transplant with the conventional conditioning resulted in high incidence of treatment related toxicities and non-myeloablative conditioning resulted in high incidence of engraftment failure. Recently, fludarabine based reduced toxicity myeloablative conditioning regimen was developed for adult myeloid malignancies with promising result of good engraftment and low treatment related toxicities. To increase the engraftment potential without serious complication, reduced toxicity myeloablative conditioning regimen composed of fludarabine, busulfan, and thymoglobulin is designed for Wiskott-Aldrich syndrome.

Study Overview

• Status: Completed
• Conditions: Wiskott-Aldrich Syndrome
• Intervention / Treatment: Drug: Fludarabine, Busulfan, Thymoglobulin

Detailed Description

Wiskott-Aldrich syndrome (WAS) is an rare X-linked congenital immune-deficiency syndrome characterized by the triad of recurrent infection, eczema and thrombocytopenia with small size of platelet (Puck JM, 2006). Clinical studies revealed high rate of autoimmune disorder and malignancy in WAS (Ochs HD, 2006). The identification of the molecular defect in 1994 (Derry JM, 1994) has broadened the clinical spectrum of the syndrome to include chronic or intermittent X-linked thrombocytopenia (XLT), a relatively mild form of WAS and X-lined neutropenia caused by an arrest of myelopoiesis (Ochs HD, 2006).

The incidence of WAS in Korea was very low and only 6 patients diagnosed between 2001 and 2005 (Kim JG, 2006).

Conventional treatments for WAS such as prophylactic antibiotics and immune globin for infection and platelet transfusion for bleeding were not so successful (Thrasher AJ, 2000). Bone marrow transplantation (BMT) from an HLA-matched related donor is an effective treatment (Filipovich AH, 2001) and patients without appropriate related donor could receive alternative stem cell source such as matched unrelated donor or cord blood. But the transplant with the alternative donor needed more intensive conditioning to overcome the hematologic and immunologic barrier with increased treatment related toxicity. Further progress depends in particular on the development of alternative preparative conditioning regimens which allow stable engraftment of donor precursor cells with minimal systemic toxic side effects (Friedrich W, 2004).

Recently, we reported successful unrelated bone marrow transplantation in a boy with WAS with reduced toxicity myeloablative conditioning regimen to increase the engraftment potential without serious complication (Kang, 2008), and extended to multicenter phase I/II pilot study with this reduced toxicity myeloablative conditioning regimen in the HSCT for WAS.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Korea, Republic of
  • Chongno-gu
    • Seoul, Chongno-gu, Korea, Republic of, 110-744
      • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of Wiskott-Aldrich syndrome with gene analysis.
2. Indicated for hematopoietic stem cell transplantation.
3. Age: no limitation.
4. Performance status: ECOG 0-2.

5. Patients must be free of significant functional deficits in major organs, but the following eligibility criteria may be modified in individual cases:

   • Heart: a shortening fraction > 30%, ejection fraction > 45%.
   • Liver: total bilirubin < 2 × upper limit of normal; ALT < 3 × upper limit of normal.
   • Kidney: creatinine <2 × normal or a creatinine clearance (GFR) > 60 ml/min/1.73m2.
6. Patients must lack any active viral infections or active fungal infection.
7. Appropriate hematopoietic stem cell donor is available.
8. Patients (or one of parents if patients age < 19) should sign informed consent.

Exclusion Criteria:

1. Pregnant or nursing women.
2. Malignant (except acute myeloid leukemia) or nonmalignant illness that is uncontrolled or whose control may be jeopardized by complications of study therapy.
3. Psychiatric disorder that would preclude compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fludarabine	Drug: Fludarabine, Busulfan, Thymoglobulin; fludarabine (40 mg/m2 once daily i.v. on days -8, -7, -6, -5, -4 & -3) busulfan (0.8 mg/kg every 6 hours i.v. on days -6, -5, -4, & -3) thymoglobulin (2.5 mg/kg once daily i.v. on days -8, -7, -6 for cord blood and on days -4, -3, -2 for bone marrow or mobilized peripheral blood)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To evaluate the engraftment potential of fludarabine, busulfan plus thymoglobulin conditioning regimen for HSCT in WAS.	Feb. 2007 to Jan. 2012
To evaluate the incidence and severity of toxicity and treatment related mortality.	Feb. 2007 to Jan. 2012

Secondary Outcome Measures

Outcome Measure	Time Frame
To evaluate overall and event free survival rate.	Feb. 2007 to Jan. 2012
To evaluate acute and chronic graft versus host disease (GVHD).	Feb. 2007 to Jan. 2012
To evaluate immunologic recovery after HSCT.	Feb. 2007 to Jan. 2012

Collaborators and Investigators

• Sponsor: The Korean Society of Pediatric Hematology Oncology
• Investigators: Principal Investigator: Hyo Seop Ahn, Ph. D, The Korean Society of Pediatric Hematology Oncology

Study record dates

Study Major Dates

• Study Start: February 1, 2007
• Primary Completion (Actual): March 1, 2012
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: April 21, 2009
• First Submitted That Met QC Criteria: April 21, 2009
• First Posted (Estimate): April 22, 2009

Study Record Updates

• Last Update Posted (Estimate): July 14, 2014
• Last Update Submitted That Met QC Criteria: July 11, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Keywords: HSCT; Wiskott-Aldrich syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Disease; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Leukopenia; Leukocyte Disorders; Primary Immunodeficiency Diseases; Lymphopenia; Syndrome; Wiskott-Aldrich Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Fludarabine; Busulfan; Thymoglobulin
• Other Study ID Numbers: KSPHO-S0701