Clinical trial NCT02833805: NMA Haplo or MUD BMT for Newly Diagnosed Severe Aplastic Anemia
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Severe Aplastic Anemia
Aplastic Anemia
Bone Marrow Failure
Immunosuppression
Keywords: immunosuppression
nonmyeloablative
non-myeloablative
allogeneic
tacrolimus
bone marrow
bone marrow transplant
cyclophosphamide
thymoglobulin
ATG
fludarabine
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
First posted: 2016-07-14
Enrollment: 21
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Overall Survival and Engraftment at One Year
timeFrame: 1 year
Secondary outcomes:
measure: Overall Survival at One Year
timeFrame: 1 year
measure: Probability of Neutrophil Recovery as Assessed by the Number of Participants Who Have Recovered Neutrophil Counts
timeFrame: 1 year
measure: Probability of Platelet Recovery as Assessed by Number of Participants Who Have Recovered Platelet Counts
timeFrame: 1 year
measure: Number of Participants Who Experience Primary Graft Failure
timeFrame: 1 year
measure: Number of Participants Who Experience Secondary Graft Failure
timeFrame: 1 year
measure: Number of Participants Who Experience Grades II-IV Acute GVHD
timeFrame: Day 100
measure: Number of Participants Who Experience Grades III-IV Acute GVHD
timeFrame: Day 100
measure: Number of Participants Who Experience Chronic GVHD
timeFrame: 2 years
measure: Number of Participants With Full Donor Chimerism
timeFrame: Day 60
measure: GVHD-free Relapse-free Survival (GRFS)
timeFrame: 1 year
measure: Transplant-related Mortality
timeFrame: 1 year
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Amy E DeZern, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.