NMA Haplo or MUD BMT for Newly Diagnosed Severe Aplastic Anemia

A Phase II Trial of Non-Myeloablative (NMA) Conditioning and Transplantation of Partially HLA-Mismatched/Haploidentical Related or Matched Unrelated Donor (MUD) Bone Marrow for Newly Diagnosed Patients With Severe Aplastic Anemia

Our primary objective is to determine if it is feasible for previously untreated severe aplastic anemia (SAA) patients to be transplanted using non-myeloablative conditioning and post transplantation cyclophosphamide.

Study Overview

• Status: Completed
• Conditions: Aplastic Anemia; Immunosuppression; Severe Aplastic Anemia; Bone Marrow Failure
• Intervention / Treatment: Drug: Thymoglobulin; Drug: Fludarabine; Drug: Cyclophosphamide; Radiation: Total body irradiation; Drug: Tacrolimus; Drug: Mycophenolate mofetil

Detailed Description

This is a clinical trial of upfront bone marrow transplantation for patients with SAA who do not have a fully human leukocyte antigen (HLA) matched donor. The trial uses a conditioning regimen which has been successful in the refractory and relapsed setting to maximize engraftment and post transplant therapy to minimize graft versus host disease (GVHD). This would be used here in patients who have not yet undergone immunosuppressive therapy for their SAA or are thought to be unlikely to respond to immunosuppressive therapy for SAA.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of inherited or acquired severe aplastic anemia (SAA)

• One of the following available donors:

  1. HLA-haploidentical relative
  2. If recipient is >= 40 years old, may use HLA-matched related donor
  3. For recipients with inherited bone marrow failure syndromes (IBMFS) with clear evidence of same disorder in potential related donors, may use 10/10 matched unrelated donor
• Recipient and/or legal guardian must sign protocol informed consent
• Donor must be willing to donate bone marrow
• Left ventricular ejection fraction (LVEF) >= 40%. For recipients < 13 years old, shortening fraction >= 26% may be used instead.
• Bilirubin < 3 x upper limit of normal (ULN) for age, unless patient has Gilbert's disease
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 5 x ULN for age
• For patients >= 13 years old: estimated creatinine clearance > 50 mL/min using Cockcroft-Gault formula and actual body weight
• For patients >= 1 but < 13 years old: glomerular filtration rate (GFR) estimated by updated Schwartz formula >= 90 mL/min/1.73 m^2. If estimated GFR is < 90 mL/min/1.73 m^2, 24-hour measured creatinine clearance must be > 50 mL/min/1.73 m^2.
• For patients >= 8 years old, diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) > 40%; forced expiratory volume at one second (FEV1) > 50%; forced vital capacity (FVC) > 50%
• For patients < 8 years old or unable to undergo pulmonary function testing: no evidence of dyspnea at rest; no need for supplemental oxygen; oxygen saturation > 92% on room air
• Karnofsky/Lansky status (depending on age) >= 70%
• Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time. If unwilling, they must agree to complete abstinence.

Exclusion Criteria:

• Previous administration of immunosuppressive therapy for SAA.
• Fanconi anemia. At minimum, this diagnosis must be excluded by diepoxybutane (DEB) or equivalent testing on peripheral blood or marrow in patients < 30 years old.
• Clonal cytogenetic abnormalities consistent with pre-myelodysplastic syndrome (pre-MDS) or MDS on bone marrow examination
• Presence of anti-donor antibodies
• Prior allogeneic stem cell transplant
• Prior solid organ transplant
• Uncontrolled bacterial, viral, or fungal infection
• HIV seropositivity
• Active hepatitis B or C infection determined by serology and/or nucleic acid testing (NAT)
• Pregnancy or active breastfeeding
• Prior malignancies except: resected basal carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent > 5 years previously. Other prior cancers will not be allowed unless approved by the PI.

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; Non-myeloablative bone marrow transplant with a Thymoglobulin (ATG), fludarabine (Flu), cyclophosphamide (Cy), total body irradiation (TBI) preparative regimen and post-transplant Cy, mycophenolate mofetil (MMF), and tacrolimus as GVHD prophylaxis.

Drug: Thymoglobulin; Day -9: 0.5 mg/kg Days -8 and -7: 2 mg/kg daily; Other Names: ATG; Anti-thymocyte globulin; Drug: Fludarabine; Days -6 through -2: 30 mg/m^2 IV daily; Other Names: Fludara; Drug: Cyclophosphamide; Days -6 and -5: 14.5 mg/kg IV daily Days 3 and 4: 50 mg/kg IV daily; Other Names: Cytoxan; CTX; Cy; Radiation: Total body irradiation; Day -1: 200 centigray (cGy) in a single fraction; Other Names: TBI; Drug: Tacrolimus; Start on Day 5 through Day 365; Other Names: Prograf; FK506; FK-506; Drug: Mycophenolate mofetil; Days 5 through 35: 15 mg/kg PO three times daily (max 3 g/day); Other Names: CellCept; MMF

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival and Engraftment at One Year	Number of enrolled participants who receive BMT, achieve engraftment, and are alive at one year post bone marrow transplant (BMT).	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival at One Year	Number of participants alive at one year after BMT.	1 year
Probability of Neutrophil Recovery as Assessed by the Number of Participants Who Have Recovered Neutrophil Counts	Probability of neutrophil recovery will be assessed by the number of participants who have recovered neutrophil counts at 1 year (>500 ANC).	1 year
Probability of Platelet Recovery as Assessed by Number of Participants Who Have Recovered Platelet Counts	Probability of platelet recovery will be assessed by the number of participants who have recovered platelet counts at 1 year.	1 year
Number of Participants Who Experience Primary Graft Failure	Number of participants who experience primary graft failure by one year after BMT.	1 year
Number of Participants Who Experience Secondary Graft Failure	Number of participants who experience secondary graft failure by one year after BMT.	1 year
Number of Participants Who Experience Grades II-IV Acute GVHD	Number of participants who experience grade II, III, or IV acute GVHD by Day 100.	Day 100
Number of Participants Who Experience Grades III-IV Acute GVHD	Number of participants who experience grade III or IV acute GVHD by Day 100.	Day 100
Number of Participants Who Experience Chronic GVHD	Number of participants who experience chronic GVHD by two years after BMT.	2 years
Number of Participants With Full Donor Chimerism	Number of participants with full donor chimerism at Day 60.	Day 60
GVHD-free Relapse-free Survival (GRFS)	Number of participants alive, without relapse, and without GVHD at 1 year.	1 year
Transplant-related Mortality	Number of participants deceased for reasons related to BMT at 1 year.	1 year

Collaborators and Investigators

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

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 (Actual): September 1, 2016
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 1, 2021

Study Registration Dates

• First Submitted: July 12, 2016
• First Submitted That Met QC Criteria: July 13, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Actual): July 12, 2022
• Last Update Submitted That Met QC Criteria: June 16, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: immunosuppression; bone marrow; cyclophosphamide; tacrolimus; fludarabine; allogeneic; ATG; bone marrow transplant; nonmyeloablative; non-myeloablative; thymoglobulin
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Anemia; Anemia, Aplastic; Bone Marrow Failure Disorders; Pancytopenia; 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; Antilymphocyte Serum
• Other Study ID Numbers: J1688; IRB00107139 (Other Identifier: JHMIRB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No