Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants

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

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.

Study Overview

• Status: Completed
• Conditions: Thrombotic Microangiopathy; Disorder Related to Bone Marrow Transplantation
• Intervention / Treatment: Drug: eculizumab

Detailed 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.

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • New York Presbyterian Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adults (age 18-65) undergoing an allogeneic hematopoietic stem cell transplant

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Transplant, no TMA; Adult patients who undergo an allogeneic hematopoietic stem cell transplant but do not meet the criteria for a thrombotic microangiopathy in the one year follow up period. No interventions anticipated.
Transplant, +TMA; Adult patients who undergo an allogeneic hematopoietic stem cell transplant and meet the criteria for a thrombotic microangiopathy in the one year follow up period. Possible interventions include observation, treatment of an underlying infection or GvHD, use of plasma exchange, or use of anti-complement therapy (eculizumab or other anti-complement drug). Eculizumab is used as a 900mg intravenous infusion over 35 minutes, given weekly for 4 weeks, then 1200mg every other week. Patients must be vaccinated against meningococcus 2 weeks before starting drug or, if that is not feasible because of the physician's assessment of the severity of the TMA, given prophylactic antibiotics for the 2 week period before immunization has taken hold.	Drug: eculizumab; Other Names: Soliris

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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

Collaborators and Investigators

• Sponsor: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Jeffrey Laurence, MD, Weill Medical College of Cornell University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): March 28, 2018
• Study Completion (Actual): March 28, 2018

Study Registration Dates

• First Submitted: October 15, 2015
• First Submitted That Met QC Criteria: November 12, 2015
• First Posted (Estimate): November 13, 2015

Study Record Updates

• Last Update Posted (Actual): March 30, 2018
• Last Update Submitted That Met QC Criteria: March 28, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Hematologic Diseases; Thrombocytopenia; Blood Platelet Disorders; Vascular Diseases; Thrombotic Microangiopathies; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 1403014892

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No plan to share IPD.