Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for Thrombotic Thrombocytopenic Purpura (TTP)
Evaluating the Effectiveness of Adding Rituximab to Standard Treatment for Thrombotic Thrombocytopenic Purpura (TTP)
Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that causes blood clots to form
 in blood vessels. The main treatment for TTP is plasma exchange, in which affected patients
 receive transfusions of plasma, the liquid part of blood, from healthy donors. This study
 will examine the effectiveness of an antibody, rituximab, in combination with plasma
 exchange, at improving the immune response in people with TTP and decreasing the recurrence
 of TTP.
TTP is a disorder that causes blood clots to form in the small blood vessels throughout the
 body. If the clots in fact block the blood vessels, blood flow is restricted to various
 organs, including the brain, kidneys, and heart. This can lead to neurological problems,
 stroke, abnormal kidney function, and heart problems. Because a large number of platelets are
 used in the blood clotting process, people with TTP have a reduced number of platelets
 circulating in their blood. They also have fewer red blood cells circulating in their blood
 because the red blood cells break down prematurely as blood squeezes past a blood clot.

 The primary treatment for TTP is plasmapheresis, also called plasma exchange, which is a
 procedure that circulates a person's blood through a machine that first removes the damaged
 plasma and then adds healthy donor plasma into the blood. Next, patients receive a blood
 transfusion with the new blood. Corticosteroids, a type of medication that reduces the amount
 of antibodies a person's body makes, are also commonly used in conjunction with plasma
 exchange to treat TTP. Plasma exchange is usually effective, with platelet and red blood cell
 counts returning to normal after the procedure is complete. However, some people do
 experience a relapse of TTP and will require repeat plasma exchanges. Rituximab, an antibody
 currently used to treat lymphoma and rheumatoid arthritis, may improve immune system response
 and decrease the number of days needed to undergo the plasma exchange procedure. The purpose
 of this study is to evaluate the effectiveness of rituximab in combination with plasma
 exchange at improving an early treatment response in people with TTP and decreasing the
 likelihood of a relapse of TTP.

 This 3-year study will enroll people who have recently been diagnosed with TTP or recently
 experienced a relapse and have not yet had six plasma exchanges during the current episode of
 TTP. Participants will be randomly assigned to receive either plasma exchanges and
 corticosteroids or plasma exchanges, corticosteroids, and rituximab. Blood will be collected
 from participants at baseline and each day they undergo the plasma exchange procedure. All
 participants will receive a plasma exchange every day until their platelet counts are normal
 and signs of tissue damage have improved. Participants will receive corticosteroid medication
 every day until plasma exchange is stopped, at which time the dosage will be gradually
 tapered until 7 weeks after the last plasma exchange. Participants receiving rituximab will
 receive the first dose intravenously within 7 days of the first plasma exchange; they will
 continue to receive rituximab once a week for 4 weeks. After the plasma exchanges are
 completed, all participants will have routine follow-up care with their doctors to make sure
 there is no TTP relapse. In the 1 year after study entry, additional blood collections will
 occur at varying times. Study researchers will monitor participants' health in the 3 years
 after study entry by following up with their doctors or through periodic phone calls. A
 portion of blood will be collected and stored for future TTP research purposes; this is
 optional.
Inclusion Criteria:

 -  Differential or admission diagnosis of TTP-like syndrome, defined as the following:

 1. Platelet count of less than 80,000/µL for newly diagnosed patients and less than
 120,000/µL for relapsed patients

 2. Microangiopathic hemolytic anemia (MHA) with red blood cell fragmentation

 3. Lactate dehydrogenase (LDH) level greater than two times the upper limit of
 normal for newly diagnosed patients and greater than the upper limit of normal
 for relapsed patients

 -  Receiving or will receive treatment for TTP with plasma exchange

 -  Has not started the sixth plasma exchange in the current TTP episode

 Exclusion Criteria:

 -  Treated for TTP in the 2 months before study entry

 -  Previously enrolled in this study

 -  Severe active infection indicated by sepsis (requirement for pressors with or without
 positive blood cultures) or clinical evidence of enteric infection with E. coli 0157
 or related organism

 -  Currently under treatment for cancer or has a current diagnosis of cancer (other than
 localized skin carcinoma)

 -  Microangiopathic hemolytic anemia due to a mechanical heart valve

 -  Severe high blood pressure, as defined by systolic blood pressure of greater than 180
 and diastolic blood pressure of greater than 120, or papilledema

 -  Has ever had an organ or stem cell transplant

 -  Has received calcineurin inhibitors (e.g., sirolimus, tacrolimus, cyclosporin A) in
 the 6 months before TTP diagnosis

 -  Diagnosis of disseminated intravascular coagulation (DIC), defined as the following:

 1. International normalized ratio (INR) level greater than 2.0 (unrelated to
 anticoagulation, unresponsive to vitamin K administration) OR

 2. Fibrinogen less than 100 mg/dL

 -  Pregnant

 -  Requires ventilator assistance or intravenous pressors for treatment of TTP. If no
 longer required prior to study entry, patient is eligible for the study.

 -  Known congenital TTP or family history of TTP

 -  Established diagnosis of lupus, and/or actively treated for lupus in the 60 days
 before study entry. In addition, people with two or more of the following systemic
 lupus erythematosus (SLE) clinical criteria in the 60 days before study entry will be
 excluded:

 1. Characteristic skin rash, either malar or photosensitive

 2. Symmetric polyarthritis

 3. Serositis, either pleurisy or pericarditis

 -  Previously received rituximab

 -  Has taken the following drugs known to be associated with TTP-like syndrome in the 3
 months before study entry: clopidogrel (Plavix), ticlopidine (Ticlid), or quinine

 -  Will receive more than 1.5 plasma volumes per day after study entry

 -  HIV history or positive serology

 -  History of hepatitis B or positive serology for HBsAg or Anti-hepatitis B core antigen
 (Anti-HBc)

 -  History of hepatitis C

 -  Known persistent or unexplained platelet count below 150,000/µL in the 3 months before
 current TTP episode

 -  Known hypersensitivities or allergies to murine and/or humanized antibodies

 -  Currently participating in trials of investigational therapies or devices (other than
 investigational central catheters)

 -  Has ever had a diagnosis of ventricular tachycardia

 -  Acute transmural heart attack during the current hospital admission