Transplantation of Partially Mismatched Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia

A Phase II Trial of Non-Myeloablative Conditioning and Transplantation of Partially HLA-Mismatched/Haploidentical Related or Matched Unrelated Bone Marrow for Patients With Refractory Severe Aplastic Anemia and Other Bone Marrow Failure Syndromes

Our primary objective is to determine if it is feasible for SAA patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide with partially HLA-mismatched donors.

Study Overview

• Status: Completed
• Conditions: Bone Marrow Failure Syndromes; Severe Aplastic Anemia
• Intervention / Treatment: Procedure: Bone marrow transplant; Drug: Thymoglobulin; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: TBI; Drug: Mesna; Drug: Tacrolimus; Drug: Mycophenolic acid mofetil

Detailed Description

This research is being done to find out if bone marrow transplantation (BMT) followed by chemotherapy will help people with aplastic anemia who have failed other treatments.

You have a severe, life threatening disease (severe aplastic anemia) in your bone marrow. Your disease has come back or not responded after receiving one or more immunosuppressive treatments. High dose chemotherapy followed by bone marrow transplantation (BMT) has been used to treat blood diseases like yours but complications from Graft vs. Host disease (GVHD) and graft failure have limited the survival for those people.

A small study done at Johns Hopkins has shown that in subjects with other diseases (blood cancers) some immunosuppressive drugs given after the BMT have decreased how often subjects had complications of GVHD and engraftment failure.

People with aplastic anemia who have refractory disease (not responding to standard treatment) may join.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Sidney Kimmel Comprehensive Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin/Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 73 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with relapsed or refractory SAA or very SAA defined:

  • Bone marrow (< 25% cellular)

  • Peripheral cytopenias (at least 2 of 3)

    • ANC < 500 per ml
    • Platelets < 20,000 per ml
    • Absolute retic < 60,000 or corrected retic < 1%
  • Very severe: as above, but ANC < 200
  • Disease may be designated as acquired or inherited if previous counts known (these other bone marrow failure disorders that are characterized by aplastic anemia may go by additional names such as dyskeratosis congenita or PNH)
  • Failed at least one course of immunosuppressive therapy (if presumed acquired disease). Patients with inherited disease will be characterized as refractory and do not require immunosuppressive first.
• Age 0- upper age limit as determined by current institutional standards
• Good performance status (ECOG 0 or 1; Karnofsky and Lansky 70-100)
• Patients and donors must be able to sign consent forms (or if a minor the parent will sign). Donors should be willing to donate.
• Patients must be geographically accessible and willing to participate in all stages of treatment.

• Adequate end-organ function as measured by:

  1. Left ventricular ejection fraction > or = to 35%, or shortening fraction > 25% (For pediatric patients, a normal ejection fraction is required)
  2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST ≤ 5 x ULN
  3. FEV1 and FVC > or = to 40% of predicted; or in pediatric patients, if unable to perform pulmonary function tests due to young age, oxygen saturation >92% on room air

Exclusion Criteria:

• Patients will not be excluded on the basis of sex, racial or ethnic background.
• Prior transfusions from selected donor (as this could have cause recipient alloimmunization against the donor)
• Women of childbearing potential who currently are pregnant (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.
• Uncontrolled viral, bacterial, or fungal infections (HIV infection permitted if viral load undetectable)

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: Bone marrow transplant; Thymoglobulin on days -9 to -7 Fludarabine on days -6 to -2 Cyclophosphamide on days -6, -5, 3, 4 TBI on day -1 BMT on day 0 Mesna on days 3, 4 Tacrolimus on days 5-365 Mycophenolic acid mofetil on days 5-35

Procedure: Bone marrow transplant; Day 0; Drug: Thymoglobulin; 0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7; Drug: Fludarabine; 30 mg/M2 IV on days -6 to -2; Drug: Cyclophosphamide; 14.5 mg/kg IV on days -6, -5, 3, 4; Other Names: CTX; Radiation: TBI; 200 cGy on day -1; Drug: Mesna; 40 mg/kg IV on days 3, 4; Drug: Tacrolimus; For patients 18 years or older, tacrolimus will be given per institutional standards; may be increased or later changed to a PO BID schedule. Treatment to continue until Day 365 or longer if GVHD present; Drug: Mycophenolic acid mofetil; 15 mg/kg PO/IV TID beginning on day 5 through day 35; Other Names: MMF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe?	Feasibility will be met with the following conditions: the patient has the transplant, is assessed for the safety endpoint, and survives one year. The safety monitoring plan is included to monitor graft failure (day 60), grade 2-4 acute graft versus host disease (day100), 6 month mortality (day 180), and chronic graft versus host disease (day 180).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients That Have Survived at One Year		1 year
Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant	Donor chimerism will be measured in the peripheral blood around day 30 and day 60. Patients with >5% donor chimerism around day 60 will be considered as having engrafted.	60 days
Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant		1 year
Number of Participants With Major Toxicities Related to Transplant		1 year
Number of Patients That Expired Due to Transplant Related Mortality		1 year
Number of Patients With Primary or Secondary Graft Failure Following Transplant	Graft failure: < 5% donor chimerism in blood and/or bone marrow on ~Day 30 or after and on all subsequent measurements. Primary graft failure: < 5% donor chimerism in blood and/or bone marrow by ~ Day 56 Secondary graft failure: achievement of > 5% donor chimerism, followed by sustained <5% donor chimerism in blood and/or bone marrow.	1 year
Number of Participants With Grade II-IV or Grade III-IV Acute GVHD	Participants were graded during clinical visits based on evidence and extent of skin rash, liver involvement, and GI tract involvement	1 year
Participants With Chronic GVHD at One Year		1 year
Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant	CBC drawn daily with a WBC differential once the total WBC is greater than 100 until ANC > 500 for three days or two consecutive measurements over a three day period; then CBC drawn weekly with differential.	1 year
Participants That Were GVHD Free, Relapse Free Survival (GRFS)		1 year

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Investigators: Principal Investigator: Amy DeZern, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• DeZern AE, Zahurak ML, Symons HJ, Cooke KR, Rosner GL, Gladstone DE, Huff CA, Swinnen LJ, Imus P, Borrello I, Wagner-Johnston N, Ambinder RF, Luznik L, Bolanos-Meade J, Fuchs EJ, Jones RJ, Brodsky RA. Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide. Blood Adv. 2020 Apr 28;4(8):1770-1779. doi: 10.1182/bloodadvances.2020001729.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): December 1, 2021
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: August 18, 2014
• First Submitted That Met QC Criteria: August 21, 2014
• First Posted (Estimate): August 25, 2014

Study Record Updates

• Last Update Posted (Estimate): March 10, 2023
• Last Update Submitted That Met QC Criteria: March 8, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: chemotherapy; cyclophosphamide; GVHD; tacrolimus; fludarabine; haploidentical; bone marrow transplant; thymoglobulin; Mycophenolic Acid Mofetil
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Bone Marrow Diseases; Hematologic Diseases; Anemia, Hemolytic; Myelodysplastic Syndromes; Syndrome; Anemia; Anemia, Aplastic; Bone Marrow Failure Disorders; Pancytopenia; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Cyclophosphamide; Fludarabine; Tacrolimus; Mycophenolic Acid; Thymoglobulin
• Other Study ID Numbers: J1424; IRB00031590 (Other Identifier: JHMIRB)