Identification and Treatment of Thrombotic Microangiopathies in Allogeneic Stem Cell Transplants
| Status: | Completed |
|---|---|
| Conditions: | Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/17/2018 |
| Start Date: | September 2014 |
| End Date: | March 28, 2018 |
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.
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.
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.
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.
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
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