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

Primary Purpose

Severe Aplastic Anemia, Bone Marrow Failure Syndromes

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Bone marrow transplant

Thymoglobulin

Fludarabine

Cyclophosphamide

TBI

Mesna

Tacrolimus

Mycophenolic acid mofetil

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring bone marrow transplant, thymoglobulin, cyclophosphamide, fludarabine, tacrolimus, Mycophenolic Acid Mofetil, chemotherapy, GVHD, haploidentical

Eligibility Criteria

undefined - 73 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

The Sidney Kimmel Comprehensive Cancer Center
Medical College of Wisconsin/Children's Hospital of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bone marrow transplant

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Number of Patients That Have Survived at One 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.

Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant

Number of Participants With Major Toxicities Related to Transplant

Number of Patients That Expired Due to Transplant Related Mortality

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.

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

Participants With Chronic GVHD at One 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.

Participants That Were GVHD Free, Relapse Free Survival (GRFS)

Full Information

NCT ID

NCT02224872

First Posted

August 18, 2014

Last Updated

March 8, 2023

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

1. Study Identification

Unique Protocol Identification Number

NCT02224872

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Completed

Study Start Date

August 2014 (undefined)

Primary Completion Date

December 2021 (Actual)

Study Completion Date

December 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Aplastic Anemia, Bone Marrow Failure Syndromes

Keywords

bone marrow transplant, thymoglobulin, cyclophosphamide, fludarabine, tacrolimus, Mycophenolic Acid Mofetil, chemotherapy, GVHD, haploidentical

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Bone marrow transplant

Arm Type

Experimental

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Bone marrow transplant

Intervention Description

Day 0

Intervention Type

Drug

Intervention Name(s)

Thymoglobulin

Intervention Description

0.5 mg/kg IV on Day -9 2 mg/kg IV on Days -8, -7

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Intervention Description

30 mg/M2 IV on days -6 to -2

Intervention Type

Drug

Intervention Name(s)

Cyclophosphamide

Other Intervention Name(s)

CTX

Intervention Description

14.5 mg/kg IV on days -6, -5, 3, 4

Intervention Type

Radiation

Intervention Name(s)

TBI

Intervention Description

200 cGy on day -1

Intervention Type

Drug

Intervention Name(s)

Mesna

Intervention Description

40 mg/kg IV on days 3, 4

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Mycophenolic acid mofetil

Other Intervention Name(s)

MMF

Intervention Description

15 mg/kg PO/IV TID beginning on day 5 through day 35

Primary Outcome Measure Information:

Title

Is This Type of Transplantation for Severe Aplastic Anemia Feasible and Safe?

Description

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Number of Patients That Have Survived at One Year

Time Frame

1 year

Title

Number of Patients That Have Acheived Full Donor Chimerism by Day 60 After Transplant

Description

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.

Time Frame

60 days

Title

Number of Patients That Expired Due to Non-relapsed-related Mortality Following Transplant

Time Frame

1 year

Title

Number of Participants With Major Toxicities Related to Transplant

Time Frame

1 year

Title

Number of Patients That Expired Due to Transplant Related Mortality

Time Frame

1 year

Title

Number of Patients With Primary or Secondary Graft Failure Following Transplant

Description

Time Frame

1 year

Title

Number of Participants With Grade II-IV or Grade III-IV Acute GVHD

Description

Participants were graded during clinical visits based on evidence and extent of skin rash, liver involvement, and GI tract involvement

Time Frame

1 year

Title

Participants With Chronic GVHD at One Year

Time Frame

1 year

Title

Length of Time Required for Patients to Recover ANC and Platelet Counts After Transplant

Description

Time Frame

1 year

Title

Participants That Were GVHD Free, Relapse Free Survival (GRFS)

Time Frame

1 year

10. Eligibility

Sex

All

Maximum Age & Unit of Time

73 Years

Accepts Healthy Volunteers

Eligibility Criteria

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: Left ventricular ejection fraction > or = to 35%, or shortening fraction > 25% (For pediatric patients, a normal ejection fraction is required) Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST ≤ 5 x ULN 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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Amy DeZern, MD

Organizational Affiliation

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Official's Role

Principal Investigator

Facility Information:

Facility Name

The Sidney Kimmel Comprehensive Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Medical College of Wisconsin/Children's Hospital of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

32343796

Citation

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.

Results Reference

derived

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

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