Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants
Condition: Thrombotic Microangiopathy; Disorder Related to Bone Marrow Transplantation
MeSH terms: Vascular Diseases; Thrombotic Microangiopathies
Study type: Observational

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.
    

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.
    

Intervention name(s): eculizumab
Intervention type(s): Drug
Other intervention name(s): Soliris
Intervention MeSH terms: Eculizumab
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Adults (age 18-65) undergoing an allogeneic hematopoietic stem cell transplant
      
Biospecimen description: 
      Peripheral blood mononuclear cells Plasma Bone marrow core biopsies