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

Severe Aplastic Anemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02224872
• Other study ID #: J1424
• Secondary ID: IRB00031590
• Status: Completed
• Phase: Phase 2
• Start date: August 2014
• Est. completion date: December 2021

Study information

• Verified date: March 2023
• Source: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 18
• Est. completion date: December 2021
• Est. primary completion date: December 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 73 Years

Eligibility

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)

Related Conditions & MeSH terms

• Anemia
• Anemia, Aplastic
• Bone Marrow Failure Disorders
• Bone Marrow Failure Syndromes
• Hemoglobinuria, Paroxysmal
• Pancytopenia
• Severe Aplastic Anemia
• Syndrome

Intervention

Procedure:
• Bone marrow transplant
Day 0

Drug:
• Thymoglobulin
0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7
• Fludarabine
30 mg/M2 IV on days -6 to -2
• Cyclophosphamide
14.5 mg/kg IV on days -6, -5, 3, 4

Radiation:
• TBI
200 cGy on day -1

Drug:
• Mesna
40 mg/kg IV on days 3, 4
• 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
• Mycophenolic acid mofetil
15 mg/kg PO/IV TID beginning on day 5 through day 35

Locations

Country	Name	City	State
United States	The Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland
United States	Medical College of Wisconsin/Children's Hospital of Wisconsin	Milwaukee	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of Patients That Have Survived at One Year		1 year
Secondary	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
Secondary	Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant		1 year
Secondary	Number of Participants With Major Toxicities Related to Transplant		1 year
Secondary	Number of Patients That Expired Due to Transplant Related Mortality		1 year
Secondary	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
Secondary	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
Secondary	Participants With Chronic GVHD at One Year		1 year
Secondary	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
Secondary	Participants That Were GVHD Free, Relapse Free Survival (GRFS)		1 year