Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants

Thrombotic Microangiopathy Clinical Trial

Official title:

Identification of the Pathogenesis of Thrombotic Microangiopathy in the Allo Stem Cell Transplant Setting in Adults

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02604420
• Other study ID #: 1403014892
• Status: Completed
• First received: October 15, 2015
• Last updated: March 28, 2018
• Start date: September 2014
• Est. completion date: March 28, 2018

Study information

• Verified date: March 2018
• Source: Weill Medical College of Cornell University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Mortality in the major thrombotic microangiopathies (TMAs), TTP and aHUS, exceeds 90% unless rapidly diagnosed and appropriately treated. TMAs complicate 10-20% of allogeneic bone marrow hematopoietic stem cell transplants (alloHSCT), conveying inferior survival. Multiple etiologies have been proposed for these transplant-associated TMAs (TA-TMAs), but once infection, graft vs. host disease (GvHD), and drug effects have been ruled out, most are treated as TTP-like disorders using plasma exchange (PEx). But PEx has no impact on mortality in this setting. Clear definition of the pathophysiology of the TA-TMAs is required to guide effective treatment. Investigators hypothesize that an aHUS-type TMA, related to dysregulation of the alternative complement pathway, is involved and will be characterized by elevated plasma levels of C5b-9 and detectable C5b-9 deposition in bone marrow sinusoidal vessels. Investigators further hypothesize that treatment with inhibitors of terminal complement components will reverse the TMA in vivo, and block endothelial cell damage in our in vitro model systems. The data investigators generate from this observational study of TA-TMAs should enable prediction of their development prior to overt clinical manifestations, and guide appropriate therapy.

Description:

Investigators plan to enroll 120 adult patients who are undergoing an allogeneic hematopoietic stem cell transplant and follow them serially for one year. Investigators will harvest and store at -80oC plasma and PBMCs, and collect bone marrow core biopsy specimens on all individuals at baseline, days 28, 100, 190, 365 post-transplant, and at time of relapse of primary disease relapse or TMA development. These time points, bone marrow procedures, and blood draws are part of the ordinary and customary followup of any allogeneic HSCT patient at our institution. With these patient samples investigators will:

1. Determine the incidence of all TMAs fitting the criteria of a Coombs negative hemolytic anemia, thrombocytopenia (25% decrease from baseline) and elevated (2x baseline) LDH, with schistocytes and organ system involvement (typically increased creatinine or new microscopic hematuria or proteinuria)

2. Determine the incidence of an aHUS-like TMA, i.e., a TMA characterized by ADAMTS13 activity in plasma >5% with clinical and laboratory findings which persists after stopping their calcineurin or mTOR inhibitor for one half life (3-7 days, depending on the drug), and ruling out or treating an underlying systemic infection or GvHD.

3. Determine complement component activation, proinflammatory cytokine profile, and baseline complement mutations. This will include ELISA-based measures of plasma C5a, C5b-9, MASP-1-3, tumor necrosis factor(TNF)-α, and interferon-γ, and pre-transplant complement mutational analysis .

4. Assay participants plasma for the ability to induce injury in primary human microvascular endothelial cells (MVEC), and the ability of an anti-C5 monoclonal antibody (mAb) (Alexion, eculizumab (Soliris)) and anti-MASP2 (Omeros, OMS721) mAb, to block these changes in the investigators' established model.

5. Define the degree of C5b-9 deposition in sinusoidal CD34+ endothelial cells by immunohistochemistry, (IHC) examining marrow core biopsies collected at each patient visit and at time of TMA development.

6. Correlate changes in plasma biomarkers, marrow sinusoidal C5b-9 deposition, and the in vitro plasma-MVEC injury model with treatment interventions and treatment outcomes, chosen by the transplant attending of record in this observational cohort.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: March 28, 2018
• Est. primary completion date: March 28, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• participants scheduled to undergo an allogeneic stem cell transplant

• willing to consent to genetic testing

Exclusion Criteria:

• pregnant women

• nursing mothers

• women of child-bearing potential who are unwilling to use medically accepted methods of contraception

• patients with known contraindications to use of eculizumab

• patients who cannot tolerate plasma exchange

Related Conditions & MeSH terms

• Disorder Related to Bone Marrow Transplantation
• Thrombotic Microangiopathies
• Thrombotic Microangiopathy
• Vascular Diseases

Intervention

Drug:
• eculizumab

Locations

Country	Name	City	State
United States	New York Presbyterian Hospital	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Weill Medical College of Cornell University

Country where clinical trial is conducted

United States, 

References & Publications (1)

Chapin J, Shore T, Forsberg P, Desman G, Van Besien K, Laurence J. Hematopoietic transplant-associated thrombotic microangiopathy: case report and review of diagnosis and treatments. Clin Adv Hematol Oncol. 2014 Sep;12(9):565-73. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of participants with thrombotic microangiopathy occurring in the allogeneic stem cell transplant setting	Per protocol a thrombotic microangiopathy is defined as development of: increase in number of schistocytes per high power microscopic field from baseline; increase in baseline level of anemia, measured by hemoglobin decline, which must be Coombs negative; unexplained doubling from baseline of serum LDH	2 years
Primary	Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications	Investigators will determine the number of participants with TMAs that persist after: stopping calcineurin and mTOR inhibitor use for one half-life (3-7 days, depending on drug); treating an underlying infection, if identified; suppressing new GvHD, if present	2 years
Secondary	Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications responsive to intervention	This is an observational study. No interventions are specified, by standards of practice could include supportive care, plasma exchange, use of eculizumab (Soliris)	2 years