Defibrotide TMA Prophylaxis Pilot Trial

This is an open-label, single arm pilot study of defibrotide given as prophylaxis to patients
receiving a conditioned stem cell transplant for the purpose of preventing post-transplant
microangiopathy. The University of California San Francisco Blood and Marrow Transplant
program reviewed all cases of non-relapse related death from 2012 through 2015 and identified
a complication of endothelial injury known as transplant associated thrombotic
microangiopathy (TMA) as the most common cause of transplant related mortality in its patient
population. TMA is a multi-system disease in which widespread endothelial injury leads to
microangiopathic hemolytic anemia, intravascular platelet activation and formation of thrombi
within the microcirculation. Diagnosis of TMA can be difficult as systemic signs and symptoms
of TMA are often similar to other common transplant complications, such as medication induced
hypertension and cytopenias. The reported prevalence of TMA is varied likely due to
diagnostic uncertainty and transplant center expertise, but large retrospective studies have
reported it as 10-39%, with the majority of cases occurring in the first 100 days after
transplant. Of the patients who develop TMA, approximately half of them will develop severe
disease. Outcomes are poor with a reported 30-50% mortality rate and as high as 80% in
patients with severe disease. Furthermore, survivors of TMA may have significant morbidity
(e.g. renal failure and need for long-term dialysis, heart failure, and significantly
prolonged hospital admission). There is no gold standard of treatment for TMA. Supportive
care includes renal support, discontinuation of calcineurin inhibitors, and treatment of
infections. Treatment options include plasma exchange, complement cascade blockade, and
defibrotide. Early treatment is crucial to decrease morbidity and mortality.

Despite the early recognition and treatment of TMA, poor outcomes occur when patients are
treated with complement blockade alone. This suggests that complement activation may trigger
a complex cascade of parallel inflammatory mediators that lead to end organ damage
independent of the complement pathway. The goal is to prevent TMA whenever possible via
augmentation of endothelial repair. Defibrotide is an anticoagulant and fibrinolytic agent
that has been shown to be an effective treatment in other endothelial disorders such as
hepatic veno-occlusive disease. It is a polydeoxyribonucleotide salt that blocks plasminogen
activator inhibitor-1 (PAI-1) and attenuates the effect of tumor necrosis factor. It also
increases prostaglandin E2 and prostacyclin levels which alters the platelet activity
adhesion and aggregation and relaxes the smooth muscle of blood vessel walls. All of this
likely protects the endothelium from damage. It has been shown that patients with TMA who
were treated with defibrotide had a 77% response rate.

The use of defibrotide in the context of veno occlusive disease (VOD) treatment and
prevention has been studied extensively, including a landmark report showing that defibrotide
given to children during stem cell transplant conditioning is safe and effective in the
prevention of veno-occlusive disease. Also, defibrotide showed a 67-77% response rate when
used as treatment in patients who developed TMA. However, there has not been a prospective
study to show that such prophylaxis is effective in the prevention of TMA in pediatric
patients undergoing hematopoetic stem cell transplant (HCT).

Patients will receive Defibrotide 6.25mg/kg via two hour intravenous infusions given every 6
hours. Defibrotide will start the day before conditioning is initiated, and will last for 28
to 35 days. During defibrotide administration, participants will have assessments of
administration feasibility, hypersensitivity reaction, and bleeding. All hematopoietic stem
cell transplant standard of care evaluations will be conducted, including routine clinical
evaluations and laboratory assessments.

Patients will be followed for 6 months post-HSCT, or until death, whichever occurs first. All
patients will be evaluated for toxicity from the time of their first treatment with the study
drug. The study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and
modified criteria for hematologic adverse events. Patients removed from study for
unacceptable treatment related adverse event(s) will be followed until resolution or
stabilization of all treatment-related adverse events to Grade 2 or lower.

Biomarkers indicative of endothelial damage and TMA activity will be drawn to assess
subclinical TMA activity as well as risk for subsequent development of TMA while on
defibrotide. These include plasma free hemoglobin, suppression of tumorigenicity,
angiopoietin 2, and plasminogen activator inhibitor - 1. Study labs will be assessed at 4
time points prior to Day +21, and at diagnosis of TMA.

Inclusion Criteria

1. Age 0-30 years of age

2. Life expectancy > 6 months

3. Eastern Cooperative Oncology Group or Karnofsky Performance Status >40

4. Meets minimum organ function requirements per institutional standard of care guiding
clearance for autologous or allogeneic stem cell transplantation.

5. Patients must meet TMA High-Risk criteria 5A or 5B below:

5A. Patients undergoing tandem autologous transplant with thiotepa in one or more of the
conditioning regimens

OR:

5B. . Patients with at least 3 of the following characteristics:

1. >10 years of age

2. Non-Caucasian race/ Hispanic ethnicity

3. Undergoing haploidentical transplant

4. Minor ABO blood group mismatch

Exclusion Criteria:

1. Age >30 years

2. Life expectancy < 6 months

3. Known bleeding diathesis or bleeding risk deemed by the treating physician to be a
contraindication to administration of anticoagulants.

4. Known hypersensitivity reaction to defibrotide

5. Any patient not meeting TMA High-Risk criteria

6. Pregnant women are excluded from this study because they will be receiving teratogenic
therapy as part of the stem cell transplant.