Principal Investigator: Yazan Abou-Ismail
Keywords: Thrombotic Microangiopathy , Hematopoietic Stem Cell Transplant Department: Hematology
IRB Number: 00143819
Specialty: Hematology/BMT
Sub Specialties:
Recruitment Status: Not yet recruiting

Contact Information

Sharada Dixit
Sharada.Dixit@hsc.utah.edu
801-587-7525

Brief Summary

Objectives:

Primary: To evaluate TMA response in adult and pediatric patients who developed TMA (according to the prespecified criteria) within 6 months of a HSCT procedure

Secondary: 

  • To evaluate TMA response at 52 weeks 
  • To evaluate individual components of TMA response 
  • To asses overall survival 
  • To assess non-relapse mortality

Endpoints: 

Primary: TMA response during the 26 week period after HSCT-TMA diagnosis defined as: 
− Hematologic response:
o Platelet count ≥ 50,000/mm3 without transfusion support
during the prior 7 days
o LDH < 1.5 × ULN
o Absence of schistocytes (if there were schistocytes present
at baseline)
− Renal response:
o Increase in eGFR ≥ 30% from baseline or discontinuation
of dialysis (for patients on dialysis at baseline)

Secondary:

  • TMA response during the 52-week period after HSCT-TMA
    diagnosis, defined as:
    − Hematologic response:
    o Platelet count ≥ 50,000/mm3 without transfusion support
    during the prior 7 days
    o LDH < 1.5 × ULN
    o Absence of schistocytes (if there were schistocytes present
    at baseline)
    − Renal response:
    o Increase in eGFR ≥ 30% from baseline or discontinuation
    of dialysis (for patients on dialysis at baseline)
  • Absolute values, change, and percent change in platelets from baseline to 26 weeks and to 52 weeks after HSCT-TMA diagnosis
  • Absolute values, change, and percent change in LDH values from baseline to 26 weeks and to 52 weeks after HSCT-TMA diagnosis
  • Absolute values, change, and percent change in eGFR from baseline to 26 weeks and to 52 weeks after HSCT-TMA diagnosis
  • Dialysis status at 26 weeks and 52 weeks after HSCT-TMA diagnosis
  • Change in CKD stage compared to baseline through 26 weeks and through 52 weeks after HSCT-TMA diagnosis
  • Overall survival at 26 weeks and 52 weeks after HSCT-TMA diagnosis
  • Non-relapse mortality (defined as patient’s death due to any cause during the study, with the exception of death due to underlying disease progression or relapse) at 26 weeks and 52 weeks after HSCT-TMA diagnosis

Note: For this study, “baseline” is defined as the time of HSCT-TMA diagnosis.
Abbreviations: CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HSCT = hematopoietic stem cell transplant; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy; ULN = upper limit of normal

 

Inclusion Criteria

Inclusion Criteria
Both living and deceased patients will be considered for study inclusion. Patients must meet all the following inclusion criteria to be eligible for inclusion in this study:
Age
1. Must have been ≥ 1 month of age at the time of HSCT-TMA diagnosis
Sex
2. Male or female
Weight
3. Body weight ≥ 5 kg at the time of HSCT-TMA diagnosis
Disease Characteristics
4. Documented TMA diagnosis within 6 months from the HSCT. For TMA diagnosis, all the following criteria are required:
• De novo thrombocytopenia or platelet transfusion refractoriness, where:
    - De novo thrombocytopenia is defined as a new decline in platelet count to ≤ 50,000/mm3
    - Transfusion refractoriness is defined as administration of platelet transfusions to maintain platelet count as assessed by the Investigator 
• De novo anemia (defined as a new decline in hemoglobin to ≤ 8 g/dL) or increase in
transfusion requirements (defined as the need to administer more frequent
transfusions in order to maintain hemoglobin ≥ 8 g/dL)
• Either one of the following markers of hemolysis: 
    - LDH > 1.5 × ULN 
    - Presence of schistocytes ≥ 2 high power field (HPF) in peripheral blood smear
5. Evidence of renal dysfunction assessed by either of the following:
a. Proteinuria on spot urinalysis defined as protein/creatinine ratio ≥ 0.5 mg/mg in adult patients and ≥ 2 mg/mg in pediatric patients
b. Abnormal creatinine ≥ ULN for adult patients and ≥ 97.5th percentile based on age at baseline for pediatric patients
6. Presence of hypertension defined as the presence of any 1 of the 3 conditions below:
a. For adult patients: systolic blood pressure ≥ 139 mm Hg or diastolic blood pressure
> 80 mm Hg.
For pediatric (< 18 years of age) patients: systolic blood pressure and/or diastolic
blood pressure ≥ 95th percentile based on age, sex, and height
b. Requirement for new antihypertensive medication after HSCT (for a patient not on
antihypertensive medication prior to HSCT)
c. For patients with underlying hypertensive disease, a change in their antihypertensive
regimen or new antihypertensive agents in addition to the antihypertensive
medication received prior to HSCT

Informed Consent
7. Patients or their legally authorized representative must provide informed consent (and assent as applicable) as described in Section 10.1.3 prior to data abstraction (per local regulations).

Exclusion Criteria

Exclusion Criteria
Patients will be excluded from the study if any of the following criteria is identified in the patient source documents/medical chart:
Medical Conditions (at the time of HSCT-TMA diagnosis):
1. History or presence of familial or acquired ‘a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13’ (ADAMTS13) deficiency (activity < 5%)
2. Shiga toxin-related hemolytic uremic syndrome (ST-HUS)
3. Positive direct Coombs test
4. Diagnosis of disseminated intravascular coagulation (DIC) according to the International Society of Thrombosis and Haemostasis (ISTH) scoring criteria outlined in Section 10.2
5. History or presence of bone marrow/graft failure
6. Diagnosis of veno-occlusive disease, regardless of severity, according to the European Society for Blood and Bone Marrow Transplantation (EBMT) criteria outlined in Section 10.3
7. Evidence of human immunodeficiency virus (HIV) infection
8. Presence of sepsis
9. Pregnant or breastfeeding during the TMA observational analysis period
Prior/Concomitant Therapy
10. Received a complement inhibitor (eg, eculizumab) post-HSCT through 12 months post TMA diagnosis
Other Exclusions
11. Participation in another investigational drug or investigational device study for the treatment of TMA within 30 days prior to HSCT-TMA diagnosis or during the 12 months following HSCT-TMA diagnosis