A Single Center, Open-label Study to Determine the Safety and Efficacy of a Dosing Regimen of Eculizumab Added to Conventional Treatment in the Prevention of Antibody-mediated Rejection (AMR) in Positive Crossmatch Living Donor Kidney Transplantation
Phase: PHASE1
Conditions: Kidney Transplant
Sponsor: Mark Stegall

 
 
A Single Center, Open-Label Study to 
Determine the Safety and Efficacy of a 
Dosing Regimen of Eculizumab Added to 
Conventional Treatment in the Prevention 
of Antibody-Mediated Rejection (AMR) in 
Positive Crossmatch Patients Undergoing 
Living Donor (LD) Kidney Transplantation 
NCT00670774 
03/09/2011 

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Title: 
A single center, open-label study to determine the safety and efficacy of a dosing 
regimen of eculizumab added to conventional treatment in the prevention of 
antibody-mediated rejection (AMR) in positive crossmatch living donor kidney 
transplantation (+XMatch LDKTx). 
 
Principal Investigator: 
Mark D. Stegall, MD 
 
Investigational Product, Dosage and Route of Administration: 
SolirisTM (eculizumab) 900 mg and 1200 mg, administered intravenously (IV) 
 
Study Duration:  
Up to 15 months, including 3 months follow-up after last dose of drug. 
 
Objectives: 
The primary objective of this study is to evaluate the safety and efficacy of 
eculizumab in preventing AMR in positive crossmatch patients undergoing 
+XMatch LDKTx. 
 
 
Background:  
Antibody against Class I and II Human Leukocyte Antigens (HLA) is an 
increasingly common finding in renal transplant candidates.1  When the anti-HLA 
antibody is directed against the kidney donor and is present at high levels at the 
time of transplant, the antibody binds to the renal allograft endothelium activating 
the complement cascade leading to graft thrombosis, termed hyperacute 
rejection.2  Anti-donor HLA antibody is measured using a crossmatch assay in 
which recipient serum is mixed with peripheral blood lymphocytes of the donor.  
A strongly positive crossmatch was long considered an absolute contraindication 
to kidney transplantation and most patients with anti-HLA antibody never were 
able to receive a kidney transplant.3  Unfortunately, these patients lives were 
shortened by chronic dialysis and their quality of life severely suffered. 
 
Over the past decade, significant progress has been made in overcoming early 
antibody-mediated renal allograft injury.  Our group here at Mayo Clinic, 
Rochester has been one of the leaders in this area of “desensitization”.2,4  Our 
protocols have primarily employed multiple pretransplant plasmaphereses (PP) in 
order to reduce anti-HLA antibody to “safe” levels at the time of transplant.  Our 
group has performed more than 200 such transplants in the past decade 
providing the possibility of transplant to previously untransplantable patients.  
With improvements in patient selection and management, the one-year graft 
survival has now reached almost 90%, however, several significant problems 
remain.   
 

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Despite our best efforts, transplantation in these patients is still complicated by a 
high rate of acute humoral rejection (AHR).2  AHR occurs later than hyperacute 
rejection (usually from 7-21 days after transplantation), but is otherwise similar to 
hyperacute rejection in that it involves activation of the complement cascade 
leading to severe allograft damage.  It occurs in greater than 40% of all 
transplants in which anti-HLA antibody is present at high levels (defined as a 
positive B cell flow crossmatch channel shift >200).   AHR can be quite difficult to 
control leading to early graft loss in approximately 10% of cases.  The long-term 
prognosis of successfully-treated AHR is poor with more than half of the patients 
losing their allograft in the next 3 years to accelerated endothelial cell damage 
termed transplant glomerulopathy.5  Thus, a major focus of our efforts is to 
develop new protocols to prevent AHR. 
 
Eculizumab: 
Eculizumab is a humanized IgG2/4K antibody produced by murine myeloma cell 
culture and purified by standard bioprocess technology. It is approved by the 
FDA for the treatment of Paroxysmal Nocturnal Hemoglobulinuria (PNH).   
Eculizumab binds specifically to the complement protein, C5, with high affinity, 
thereby inhibiting its cleavage to C5a and C5b and preventing the generation of 
the terminal complement complex, C5b-9.  PNH is a genetic disease in which 
patients generate abnormal RBCs that are deficient in terminal complement 
inhibitors, rendering these RBCs sensitive to terminal complement-mediated 
hemolysis.   
 
It is our hypothesis that blockade of terminal complement activation with 
eculizumab at the time of transplant in combination with our current protocols will 
reduce the incidence of AHR in patients with anti-donor HLA antibody. 
 
Patients included in this study will be those who have demonstrable anti-HLA 
antibody specific for their living donor.  This is defined as a positive B cell 
crossmatch with a channel shift of >200 and anti-donor specificities as 
determined using HLA coated microbeads.  These standard assays are 
performed by the Histocompatibility Laboratory here at Mayo Clinic, Rochester.   
 
Historical Control Group: 
A major limitation of studies in +Xmatch kidney transplants is that relatively few 
patients are transplanted each year.  For example, we only perform 
approximately 20 +Xmatch transplants/year and thus do not have large enough 
numbers to perform a randomized trial. 
 
We have retrospectively studied the incidence of AHR in our +Xmatch kidney 
transplants and this experience will serve as our historical control group (non-
eculizumab treated).  We currently stratify +Xmatch patients by their baseline 
anti-donor antibody levels as follows: 
 
 

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B cell flow crossmatch channel shift: 
Group 
Treatment 
>300 
high risk, perform pretransplant PP to safe levels (<300)  or 10 
PP (whichever endpoint is reached first)  
200-300 
moderate risk, no pretransplant PP, but close post –transplant 
monitoring 
<200 
low risk, not included in this study 
 
 
Almost all episodes of AHR occur in the first 28 days after transplant.  During this 
time frame, antibody levels in +Xmatch Kidney Transplant recipients usually 
follow one of two patterns:  1) anti-donor HLA levels remain low and AHR does 
not develop, or 2) anti-donor HLA antibody levels increase in the first few weeks 
and AHR develops.  AHR is always proven by kidney biopsy and is almost 
always accompanied by an increase in serum creatinine.  
 
In a recent published analysis of 60 +Xmatch KTx from 1/05 to 1/07, we found 
that the incidence of AHR was 39% (16/41) in patients with DSA levels >300 at 
baseline and 31% (9/29) in patients with DSA levels <300 at baseline.6  This 
study also demonstrated a good correlation between DSA levels post-transplant 
and histological findings on protocol renal allograft biopsies obtained at the same 
time point (see Figure below).  Specifically, when the B cell FXM channel shift 
was >359, AHR was noted on 92% (923/25) of  biopsies.  AHR was not found on 
any biopsies with a B cell FXM <300.  Thus, this study forms the basis for the 
historical control group for the current study.    
 
B Cell Flow Crossmatch
0
100
200
300
400
500
600
700
Channel Shift
No Rejection
C4d deposition
Moderate Rejection
Severe Rejection
 
 
Figure:  Association of donor specific alloantibody level to histologic 
evidence of acute humoral rejection in +Xmatch KTx 
 

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Statistical Analysis: 
The primary endpoint of this study is the incidence of AHR in the first 28 days 
after +XMatch KTx.   
 
We plan to enroll 40 patients in the trial.  The overall expected AHR rate in these 
forty patients is 40% (16 patients should develop AHR).  20 patients are powered 
to detect a 50% reduction in AHR with a p value <0.05, one-sided t test (actual 
number of AHR patients =4). 
 
We also will examine the AHR in patients with B cell flow crossmatch channel 
shifts > 400. This should be an additional method to determine the efficacy of 
eculizumab.  Historically, we have shown that almost all patients with channel 
shifts >400 have AHR, but hypothesize that eculizumab should prevent AHR at 
this level.  
 
 
 
 
Patient Population: 
o 40 patients on eculizumab plus conventional therapy  
o Patients recruited for this study will be recipients of a LD kidney transplant 
from two identified risk groups: 
 Group A-High Risk: Patients have a positive crossmatch (+XM) to the 
donor allograft (defined as a positive T-cell flow cytometry [FCXM] of 
greater than or equal to 300 prior to desensitization, or as a positive B-
cell FCXM of  greater than or equal to 300 prior to desensitization with 
demonstrable Class II DSA on solid-phase assays), or 
 Group B-Moderate Risk: Patients have a positive B cell FCXM in the 
range of 200 – 299 
o All transplant recipients must undergo desensitization with multiple 
pretransplant plasmapheresis treatments prior to transplantation to either 
achieve a FCXM of <300 or until the patient has undergone 10 PP.  
o All patients must have all appropriate vaccinations administered at least two 
weeks prior to the time that desensitization is begun consistent with local 
practice 
 
Study Design: 
There are three Phases in this study: 
 
Enrollment Phase 
Screening Period:  Informed consent signed; inclusion/exclusion criteria obtained 
and evaluated.  Patient will be vaccinated against Neisseria meningitides, 
Pneumococcus or Hemophilus influenzae.  Patients will be desensitized 
according to the standard of care (local Desensitization Protocol). 
 
Treatment Phase (Table 1) 

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o Patients will be given 1200 mg of eculizumab intravenously over 30 minutes, 
one hour prior to surgery.  
o Patients will be given 900 mg of eculizumab on Day 1 post-transplant. 
o Patients will not undergo post-transplant plasmapheresis unless they 
demonstrate AHR on biopsy. 
o Patients will then be given 900 mg of eculizumab weekly through four weeks 
post-transplant 
o At week 4, patients will be assessed for B cell FCXM.  Patients with B cell 
FCXM less than 200 will stop eculizumab treatment.  Patients with B cell 
FXCM greater than or equal to 200 will continue eculizumab treatment every 
14 days from week 5 through week 9.  The dose will be increased and dosing 
will now be every 2 weeks instead of weekly. Similar “discontinuation 
assessments” will be performed at week 9, 26 and 52.  If the BFXM is <200, 
then the eculizuamb will be stopped.  If the BFXM >200, then the eculizumab 
will be continued as outlined below. 
o In addition, eculizumab 600 mg will be administered immediately after each 
plasmapheresis (PP) and immediately after any fresh frozen plasma (FFP) 
that is given post-transplant during the treatment period 
o Between 5 and 8 doses of eculizumab will be administered over the course of 
the study (plus additional doses based on individual PP and/or FFP 
requirements) 
o Blood for serum levels of eculizumab will be drawn prior to each dose and 
one hour after each infusion to determine the pharmacokinetic-
pharmacodynamic (PK-PD) relationship. Blood serum levels will also be 
drawn prior and post plasmapheresis. 
 
 
 
Table 1:  Eculizumab Dosing Schedule 
Day/Week 
Eculizumab Dose 
Day 0 (1 hr pre-transplant) 
1200mg 
Day 1 
900mg 
Week 1 
900mg 
Week 2 
900mg 
Week 3 
900mg 
Week 4 
(1st discontinuation assessment) 
900mg 
 
-If FCXM >200, continue 
Eculizumab as follows 
Week 5 
1200mg 
Week 7 
1200mg 
Week 9 
(2nd discontinuation assessment) 
1200mg 
Week 26 
(3rd discontinuation assessment) 
1200mg every 2 weeks 
Week 39 
1200mg every 2 weeks 

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(4th discontinuation assessment) 
Week 52 
(Last discontinuation assessment) 
Discontinue drug 
 
 
Follow-up Phase: 
Following the completion of dosing, patients will return for follow-up visits at 3 
and 6 months post-transplant to obtain biopsies and collect follow-up data. 
Patients who continue the drug for 12 months will receive their final assessment 
at 15 months. 
 
Biopsy Protocol:  All patients will undergo protocol renal allograft biopsy at 30 
minutes, days 4, 7, 14 and months 1, 3, and 6 and 12 to rule out AMR.  We also 
will perform biopsies for increased serum creatinine >0.2 mg/dl over baseline not 
attributable to other causes (increased serum tacrolimus level, urine leak, urinary 
obstruction, etc).   Biopsies will be processed for light microscopy, electron 
microscopy and C4d immediately in order to rule out AMR.  Biopsies will be 
banked and stained for membrane attack complex in batches. 
 
The following criteria must be met for the diagnosis of AMR: 
Serological Criteria: 
Evidence of circulating DSA by channel shift (T-cell or B-cell of greater than 300) 
Plus 
Immunological Criteria: 
Positive C4d staining in peri-tubular capillaries (PTC) 
Plus 
Histological Criteria (has one or more of the following): 
o Neutrophil infiltration in the PTC 
o Arteriole fibrinoid necrosis 
o Acute tubular injury pattern 
o Mesangiolysis 
o Glomerular microthrombi 
o Evidence of endothelial damage based on electron microscopy 
 
 
 
Efficacy Assessments: 
Major endpoints for this study are: 
 
1. The incidence of AMR during the first 4 weeks and the first 9 weeks post 
transplant.  Diagnosis of AMR will be based histological findings using Banff 
’05 criteria.7 
 
2. In patients who have serum creatinine increased by 0.2 mg/dL or greater 
above nadir, a second endpoint will be the number of days of serum 
creatinine is >0.2 mg/dL above nadir through 9 weeks. 

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3. Once AMR criteria are met initially – a third endpoint will be the duration and 
severity of biopsy characteristics consistent with AMR through three months.  
Duration is measured as number of days with biopsy Grade 2 or greater; 
severity is measured by number of days at Grade 3 vs. Grade 2. 
 
4. Once AMR criteria are met initially - serum creatinine (renal function) at one, 
three, and six months.   
 
NOTE: Biopsies will be performed after AMR is diagnosed in the following 
manner: 
 
After the initial biopsy, PPs are done daily for 3 days, followed by another biopsy.  
If the second biopsy also demonstrates AMR, the process is repeated until there 
is resolution of the AMR.  For patients with recalcitrant AMR (persists beyond 2 
weeks), splenectomy will be considered. 
 
 
Other endpoints include: 
1.  
Incidence of AMR at 30 minutes, 4 days, 7 days, 14 days, 1 month, 3 and 
6 months post-transplant 
2.  
Presence of C5b-9 in all biopsies at any time point in the first 12 months 
after transplant 
3.  
The incidence of AMR in patients with B-cell FXM >350 at any time point 
in the first 12  months after transplant.  In the control group, 92% of these 
patients showed AMR 
4.  
In patients with B-cell FXM >350 at any time point in the first 12 months 
after transplant, the percentage of patients demonstrating an increase in 
serum creatinine > 0.2 mg/dL from nadir determined within the first week 
post-transplant throughout the duration of the 3 month dosing period 
5.  
Incidence of delayed graft function (DGF) post-transplant (defined as the 
requirement of dialysis within the first week post transplant) 
6.  
Incidence of dialysis post-transplant through 9 weeks (number of days) 
7.  
Number of PP post-transplant through 9 weeks 
8.  
Percentage of patients requiring splenectomy 
9. 
 Effect on renal function 
o Creatinine clearance (calculated) 
o Iothalamate clearance (at 1 month and 2 months post-transplant) 
 
10. 
Graft survival at 3, 6, 9, and 12 months 
11. 
Incidence of transplant glomerulopathy within 12 months of transplant 
12. 
Change in serum creatinine from just prior to transplant to the nadir 
13. 
Serum creatinine at 1, 3, 6, 9 and 12 months post-transplant 
14. 
Percentage of patients developing acute cellular rejection (ACR) at 1 and 
2, 3 and 6 months 
15. 
Histologic evidence of damage by electron microscopy even in the 
absence of light microscopic damage 

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16.      Number of patients whose FXM remained elevated (>200) through 12 
months of treatment.  
17. 
Number of patients whose FXM decreased sufficiently (<200) to warrant 
discontinuation of the drug prior to the 12 month mandatory drug 
discontinuation.  
Follow-up (post-treatment) biopsies will be performed at 3 and 6 months post-
transplant in all patients and at 3 months after the last dose of eculizumab in 
those that continue drug after 6 months to look for histological evidence of 
complement-mediated damage and cell infiltration. 
 
Safety Assessments: 
Adverse events will be collected and recorded at each patient visit. 
 
Inclusion Criteria:  
1.  
18 years of age 
2.  
Has end stage renal disease (ESRD) and is to receive a kidney transplant 
from a LD to whom he/she has either: 
a. 
a positive crossmatch requiring pretransplant desensitization 
(defined as a positive T-cell FCXM of greater than or equal to 300 
prior to desensitization, or as a positive B-cell FCXM of > 300 prior 
to desensitization with demonstrable Class II DSA on solid-phase 
assays) or  
b. 
a positive crossmatch not requiring desensitization (defined as 
FCXM between 200 and 299) 
3.  
Willing to comply with the protocol 
4.  
Females of child-bearing potential must have a negative pregnancy test 
(serum β-HCG) and sexually active females must agree to use a reliable 
and medically approved method of contraception 
5.  
Willing and able to give written informed consent 
6.  
Vaccinated against Neisseria meningitides (quadrivalent vaccine), 
Pneumococcus or H. influenzae at least two weeks prior to beginning 
desensitization 
 
Exclusion criteria:  
1.  
Unstable cardiovascular condition 
2.  
Previous splenectomy 
3.  
Active bacterial or other infection which is clinically significant in the 
opinion of the investigator 
4.  
Known or suspected hereditary complement deficiency 
5.  
Participation in any other investigational drug study or was exposed to an 
investigational drug or device within 30 days of randomization 
6.  
Pregnant, breast-feeding, or intending to conceive during the course of the 
study, including the three month follow-up period after drug 
discontinuation 
7.  
Known hypersensitivity to the treatment drug or any of its excipients 
8. 
History of illicit drug use or alcohol abuse within the previous year 

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9.  
History of meningococcal disease 
10.  
Medical condition that, in the opinion of the investigator, might interfere 
with the patient’s participation in the study, pose an added risk for the 
patient, or confound the assessment of the patient (e.g. severe 
cardiovascular or pulmonary disease) 
11.  
Previously been enrolled in this trial 
 
 
Safety Information in Patients with PNH: 
Eculizumab generally is well-tolerated by patients with PNH.   Safety data is 
provided from 3 parent trials in which 195 patients with PNH were treated with 
eculizumab for a median of 22 months and had infection related adverse events 
and serious adverse events (SAEs) similar to placebo treated controls in the first 
6 months.8-10 
 
Eculizumab blocks terminal complement therefore patients may have increased 
susceptibility to infections, especially with encapsulated bacteria.  There appears 
to be an increased incidence of bacterial meningitis with eculizumab treatment.  
All patients were vaccinated against Neisseria meningitides and during 382 
patient years of treatment, there were 2 cases of meningococcal septicemia 
(0.52 per 100 patient years) which were promptly treated and recovered without 
sequelae.  The current recommendation is to administer meningococcal vaccine 
at least 2 weeks prior to receiving the first dose of eculizumab and this 
recommendation will be followed in our trial.  Patients will be monitored for early 
signs of meningococcal infections (headache, neck stiffness, fever, mental status 
changes) and will be treated with antibiotics if necessary.8-10 
 
As with all protein products, eculizumab administration may result in infusion 
reactions including anaphylaxis or other hypersensitivity reactions.  In previous 
clinical trials, no patients experienced transfusion reactions that required 
discontinuation of drug.  However, if signs of a drug reaction occur, the infusion 
will be stopped and appropriate medical therapy will be administered.8-10 
 
Adverse Reactions:   
The most frequently reported adverse reactions (>10% overall and greater than 
placebo) are: headache, nasopharyngitis, back pain and nausea. 
 
Contraindications: 
1.   Patients not currently vaccinated against Neisseria meningitides 
2. Pregnancy 
3. Nursing mothers 
4. Age <18 years 
 
The safety of eculizumab in pediatric populations, in pregnancy and in nursing 
mothers has not been determined. 
 

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Eculizumab in Transplant Patients: 
Two kidney transplant recipients have received eculizumab for the treatment of 
acute humoral rejection (AHR).  One of the patients was here at Mayo (under an 
FDA-approved compassionate use protocol in 2006) and one at Johns Hopkins.  
Neither developed infection nor any other side effect related to eculizumab 
despite receiving multiple other immunosuppressive agents.  The patient here at 
Mayo still has a functioning graft two years after treatment. 
 
In addition, 6 patients have received eculizumab in the current trial with no 
infections or complications that can be directly linked to the drug.  Importantly, 3 
of the 6 patients have developed high levels of DSA that should have resulted in 
AHR, but none of the 3 had AHR on biopsy and all grafts are functioning 
normally. 
 
Safety Monitoring Protocol for Eculizumab:   
As stated previously, abundant data suggests that eculizumab is safe when given 
as monotherapy.  However, we will be giving the drug as part of a multi-drug 
immunosuppressive therapy.  Only two patients have received eculizumab in a 
situation that is similar, but not identical, to that of the study. 
 
The primary perceived risk for patients in this study will be infection.  Patients will 
be followed closely while treated with eculizumab.  The patient’s will receive the 
drug both as an inpatient and as an outpatient.  They will be monitored at least 
every other day during the first month of the study and will remain in Rochester 
when receiving the drug.  As part of our routine post-transplant care, the patient 
will be examined by a nephrologist or physician assistant who is a member of the 
study team.  They will be examined for clinical signs of infection.  In addition, they 
will have vital signs (temperature), screening for opportunistic infection (CMV and 
Polyoma virus copies) and CBC as per our protocol. 
 
 
Data Safety Monitoring Protocol: 
Given the small size of the study (40 patients) and the relative short accrual 
period (likely to be 2 years), we plan to employ a data safety monitoring protocol 
with specific stopping rules instead of a Data Safety Monitoring Board. 
 
The stopping rules include: 
1. 
Any infection with Neisseria meningitides, Pneumococcus or H. influenzae 
at any time 
2. 
Any patient death for any cause 
3. 
Systemic bacterial infection in two patients (including urosepsis or line 
sepsis) 
4. 
Severe reaction to eculizumab infusion 
 
If these occur, we will stop enrollment, notify the IRB and reassess the study.  
 

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References: 
1. UNOS.  2006. United Network for Organ Sharing. 5 Apr. 2006. 
http://www.unos.org 
2. Stegall MD, Gloor JM, Winters JL, Moore SB, DeGoey SR.  A comparison 
of plasmapheresis vs. high-dose IVIG desensitization in renal allograft 
recipients with high levels of donor specific alloantibody.  Am J Transplant. 
6:346-51 (2006).  
3. Gebel HM, Bray RA, Nickerson P. Pre-transplant assessment of donor-
reactive HLA-specific antibodies in renal transplantation: Contraindication 
vs. risk. Am J Transplant. 3: 1488 (2003). 
4. Gloor JM, DeGoey SR, Pineda AA, Moore SB, Prieto M, Nyberg SL, 
Larson TS, Griffin MD, Textor SC, Velosa JA, Schwab TR, Fix LA, Stegall 
MD. Overcoming a positive crossmatch in living donor kidney 
transplantation. Am J Transplant. 3:1017-23 (2003). 
5. Gloor JM, Cosio FC, Rea D, Wadei HM, Winters JL, Moore SB, DeGoey 
SR, Lager DL, Grande JP, Stegall MD.  Histologic findings in renal 
allografts one-year after positive crossmatch or ABO incompatible kidney 
transplantation.  Am J Transplant. 6:1841-47 (2006). 
6. Burns JM, Cornell LD, Perry DK, et al.  Alloantibody levels and acute 
humoral rejection early after positive crossmatch kidney transplantation.  
Am J Transplant  2008; 8:2684-2694. 
7. Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, Campbell 
PM, Cascalho M, Collins AB, Demetris AJ, Drachenberg CB, Gibson IW, 
Grimm PC, Haas M, Lerut E, Liapis H, Mannon RB, Marcus PB, Mengel 
M, Mihatsch MJ, Nankivell BJ, Nickeleit V, Papadimitriou JC, Platt JL, 
Randhawa P, Roberts I, Salinas-Madriga L, Salomon DR, Seron D, Sheaff 
M, Weening JJ. Banff '05 Meeting Report: differential diagnosis of chronic 
allograft injury and elimination of chronic allograft nephropathy ('CAN'). 
Am J Transplant. 7:518-26 (2007). 
8. Hillmen P, Young NS, Schubert J, et al. The complement inhibitor 
eculizumab in paroxysmal nocturnal hemoglobulinuria. N Engl J Med. 
355:1233-43 (2006). 
9. Hillmen P, Hall C, Marsh JC, et al. Effect of eculizumab on hemolysis and 
transfusion requirements in patients with paroxysmal nocturnal 
hemoglobulinuria. N Engl J Med. 350:552-59 (2004). 
10. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, 
Schubert J, Valls AG, Coyle L, de Castro C, Fu CL, Maciejewski JP, 
Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase III study of 
the complement inhibitor eculizumab for the treatment of patients with 
paroxysmal nocturnal hemoglobulinuria. Blood. 2007 Nov 30; [Epub ahead 
of print].