Page 340 - Hematology_ Basic Principles and Practice ( PDFDrive )

282 Part III Immunologic Basis of Hematology

N. meningitidis infections 200,201 but not to other infections. In con- emergence of resistant strains. It is possible to monitor antibody titers
trast, inherited mutations in C3 result in a broader spectrum of and the CDC is now recommending a booster of the a, c, w, y
infections as well as autoimmunity. Eculizumab is derived from the conjugate vaccine at 2 months for those with complement
sequence of an immunoglobulin from a mouse hybridoma, generated deficiency.
by immunizing mice with purified human C5, followed by screening Patients with PNH may fail to respond to eculizumab because of
of thousands of clones. The antibody secreted by the selected clone, (1) underlying aplastic anemia; (2) rapid drug clearance, as manifested
m5G1.1mAb, could inhibit complement activation at a 0.5:1 ratio by a nonsuppressed CH50 level, or a low eculizumab level on day 14
(as expected given the bivalency of IgG) in a standard hemolytic of the treatment cycle; (3) the Arg885His polymorphism in the C5
assay. 202–204 The CDRs were cloned and grafted onto the respective gene, as seen in about 3% of the Japanese population, such that the
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human light and heavy chain sequences. An IgG2/IgG4 hybrid was drug does not recognize the C5 protein at all ; or (4) extravascular
chosen for the constant regions, because IgG2 binds Fc receptors hemolysis, caused by opsonization of C3d-coated red cells in the
minimally, and IgG4 activates complement minimally, given that reticuloendothelial system.
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these were two functions not desired for this particular drug. The The latter as described by Risitano et al is most interesting,
humanized antibody retains the affinity of the mouse antibody, with reflecting a mechanism that has been “unmasked” by eculizumab.
a dissociation constant (K d ) of 120 pM. It has a half-life in humans Despite blockade at the C5 level, the PNH red cell is still lacking
of approximately 11 days, and it has been suggested that a minimum CD55, which normally functions to inhibit the classical and alterna-
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trough level of 35 µg/mL is required for sustained inhibition of tive C3 and C5 convertases. The PNH red cell is also lacking
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terminal complement in humans. Although there is currently only CD59, which may inhibit not only the MAC formation, but also the
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one laboratory that offers serum drug level testing, testing for CH50, deposition of C3d on the red cell in the setting of loss of CD55.
which is inhibited by eculizumab, is widely available and predicts Indeed, in some patients on eculizumab, C3d deposition on the red
clinical responses. 207 cell can be demonstrated by the direct antiglobulin test or by flow
Early development of eculizumab focused on testing the drug (and cytometry; such cells would have been lysed by the MAC in untreated
in some cases a related single chain variant) in patients with rheu- patients. Opsonization by C3d can account for persistently elevated
matoid arthritis, lupus, coronary bypass, myocardial infarction, and reticulocyte counts, the requirement for occasional transfusions, and
membranous nephritis. 208–211 The strategy of therapeutically inhibit- progressive iron overload in some patients on eculizumab. Polymor-
ing terminal complement in PNH was validated by a pilot study, a phisms in the CR1 gene, which affect levels of expression of this
randomized study, and an open label study of eculizumab, where complement-regulating gene, may predict which patients have a
dramatic reductions in the serum hemolytic activity, lactate dehy- partial versus complete response to eculizumab. 223
drogenase, visible hemoglobinuria, and transfusion requirements—as Atypical hemolytic uremic syndrome (aHUS) (see Chapter 134),
well as improvements in male erectile dysfunction and esophageal a different complement-mediated disorder, is the other FDA-approved
spasms—were shown after a series of loading doses of 600 mg weekly indication for eculizumab. aHUS is characterized by thrombocyto-
for 4 weeks followed then by 900 mg, repeated every 2 weeks. 212–214 penia, hemolysis, an elevated lactate dehydrogenase (LDH), micro-
While these studies were dramatic enough for drug approval in 2007, angiopathy, and dysfunction of many organs, but particularly the
the question could have arisen as to whether correction of anemia and kidneys. Other entities with similar presentations that need to be
amelioration of transfusion requirements was an outcome important distinguished include thrombotic thrombocytopenia purpura (TTP),
enough to justify the risk of meningococcal infection, a potentially malignant hypertension, Shiga toxin–producing E. coli (STEC),
fatal outcome, whose incidence was not known at the time. However, calcineurin inhibitors (and other medications), lupus, and the
that same year, it was reported that the use of eculizumab dramatically antiphospholipid antibody syndrome, the latter two being potential
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decreased the rate of thromboses, which are often recurrent, triggers for aHUS itself. The disease is recognized by schistocytes on
and which represent the most important predictor of mortality. the peripheral smear, an elevated LDH, and a disintegrin and metal-
Survival curves in treated patients are now similar to age-matched loproteinase with thrombospondin motifs 13 (ADAMTS 13) level
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controls. Whereas pregnancies had been fraught with thrombotic (drawn before empiric pheresis) that is not significantly decreased,
complications, there is now evidence that not only is eculizumab safe and a variable and often subadequate response to plasmapheresis.
for the fetus, but it also may be instrumental in reducing maternal Compared with TTP, the degree of thrombocytopenia is not as severe,
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mortality. The effect of eculizumab on thrombosis points to a role there are fewer schistocytes, but the degree of renal insufficiency is
for complement (e.g., activation of CD59-deficient platelets derived often much more severe. aHUS is genetically complex, in that it can
from the PNH clone) among the proposed mechanisms to explain result from inherited mutations in the genes encoding the inhibitory
hypercoagulability in PNH. complement factors H, I, membrane cofactor protein (CD46) or
Neisseria infections, as seen in patients with inherited deficiencies thrombomodulin—or gain of function mutations in the effector
of terminal complement, have indeed been seen in patients treated complement factors B or C3. Autoantibodies against factor H can
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with eculizumab, sometimes despite immunization ; the risk may produce a similar syndrome, and in a substantial proportion, no
be ~1% per year. All patients on eculizumab can now be vaccinated mutation is ever found. The inheritance is typically dominant with
with a new quadrivalent meningococcal B vaccine (Trumenba or incomplete penetrance. 224
Bexsero) in addition to one of the quadrivalent a,c,w,y vaccines (e.g., The FDA granted approval to eculizumab for the treatment of
Menactra, Menomune, Menveo). All patients must be instructed to aHUS based on two single arm studies reporting rapid improvement
report to an emergency room for blood cultures and immediate in thrombocytopenia, typically by day 7, and a more gradual
empiric treatment with antibiotics (e.g., ceftriaxone) in the event of improvement in the renal function, in many cases, allowing for dis-
any fever over 100.0°F or 37.7°C. Patients should also carry with continuation of dialysis. 225,226 As in PNH, where eculizumab only
them a letter from their physician explaining their condition (or wear masks an underlying defect, relapses have been seen upon drug dis-
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an alert bracelet) and should carry on their persons at all times an continuation. Since recurrences after renal transplantation are
antibiotic that covers meningococcal infection, such as azithromycin common in aHUS, initiation and maintenance of eculizumab before
or ciprofloxacin. Interestingly, meningococcal infections in hypo- and after transplant may be critical for maintaining graft function.
complementemic patients are a bit less fulminant than in normal Since undertreatment would be more serious here than in PNH, the
hosts, and generally do not result in central nervous system (CNS) recommended dose in aHUS is higher.
infections but rather septicemia, such that lumbar punctures are There is a growing literature on successful “off label” use of ecu-
rarely required for patients on eculizumab—and should never delay lizumab, for example, for catastrophic antiphospholipid antibody
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empiric treatment with antibiotics. As for adults who have been syndrome, cold agglutinin disease, HUS due to Shiga toxin–
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splenectomized, practices vary such that in the United Kingdom, all associated E. coli, antibody-mediated renal graft rejection and
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patients on eculizumab are treated prophylactically with penicillin, dense deposit disease, calcineurin inhibitor-induced thrombotic
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whereas in the United States, there is more of a concern for the microangiopathy, Devic neuromyelitis optica, myasthenia