Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants

NCT02604420 | Completed

• 1 other identifier: 1403014892
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Thrombotic Microangiopathy; Disorder Related to Bone Marrow Transplantation

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Number of participants with allogeneic stem cell transplant-linked TMA persisting after control of infection, GvHD and altering medications responsive to intervention

  2 years

Study Arms (2)

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

Interventions

eculizumab DRUG

Also known as: Soliris

Transplant, +TMA

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• participants scheduled to undergo an allogeneic stem cell transplant
• willing to consent to genetic testing

You may not qualify if:

• 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

Sponsors & Collaborators

• Weill Medical College of Cornell University: lead

Study Sites (1)

New York Presbyterian Hospital

New York, New York, 10021, United States

Location

Related 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.

  PMID: 25654478 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Peripheral blood mononuclear cells Plasma Bone marrow core biopsies

MeSH Terms

Conditions

Thrombotic Microangiopathies

Interventions

eculizumab

Condition Hierarchy (Ancestors)

Thrombocytopenia; Blood Platelet Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Cytopenia

Study Officials

• Jeffrey Laurence, MD

  Weill Medical College of Cornell University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 15, 2015
• First Posted: November 13, 2015
• Study Start: September 1, 2014
• Primary Completion: March 28, 2018
• Study Completion: March 28, 2018
• Last Updated: March 30, 2018

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)