Page 603 - Williams Hematology ( PDFDrive )

578 Part VI: The Erythrocyte Chapter 40: Paroxysmal Nocturnal Hemoglobinuria 579

41
of cases. There is no evidence that treatment with immunosuppressive (see Fig. 40–1). The MAC consists of complement components C5b,
therapy influences clonal expansion either positively or negatively. C6, C7, C8, and multiple molecules of C9. Eculizumab (Soliris) is a
The basis of the relationship between PNH and aplastic anemia is humanized monoclonal antibody that binds to complement C5, pre-
speculative. The vast majority of patients with PNH have some evidence venting its activation to C5b and thereby inhibiting MAC formation
49
of marrow failure (e.g., thrombocytopenia, leukopenia, or both) during (see Fig. 40–1). In 2007, eculizumab was approved by both the FDA
the course of their disease. 26,42,43 Therefore, marrow injury may play a and the European Union Commission (now the European Medicines
central role in the development of PNH by providing the conditions Agency) for treatment of the hemolysis of PNH. Treatment with ecu-
that favor the growth/survival of PIGA-mutant, GPI-AP–deficient stem lizumab reduces transfusion requirements, ameliorates the anemia of
cells. Finding a population of GPI-AP–deficient erythrocytes in patients PNH, and markedly improves quality of life by resolving the debili-
with aplastic anemia is clinically relevant, as these patients have a par- tating constitutional symptoms (fatigue, lethargy, asthenia) associated
50
ticularly high probability of responding to immunosuppressive therapy, with chronic complement-mediated intravascular hemolysis. Follow-
and the onset of the response appears to be more rapid compared to ing treatment, serum LDH concentration returns to normal, but mild
patients with aplastic anemia without a population of GPI-AP–deficient to moderate anemia and reticulocytosis usually persist, likely the result
erythrocytes. 31,33,44 of ongoing extravascular hemolysis mediated by opsonization of PNH
The presence of PNH cells has also been observed in patients with erythrocytes by activated complement C3, as eculizumab does not block
MDS. 30,33,39,45 Notably, the association between PNH and MDS appears the activity of the APC C3 convertase (see Fig. 40–1). 51,52 In some cases,
to be confined to low-risk categories of MDS, particularly the refrac- extravascular hemolysis is sufficiently severe so as to require therapy. 53
tory anemia (RA) variant. 30,33,39 Using high-sensitivity flow cytometry in Thromboembolic events are the major cause of morbidity and
which equal to or greater than 0.003 percent GPI-AP–deficient RBCs or mortality in PNH, and eculizumab appears to ameliorate the throm-
28
PMNs was classified as abnormal, Wang and colleagues reported that 21 bophilia of PNH, although the studies that support that conclusion had
of 119 (18 percent) patients with RA MDS had a population of PNH cells, suboptimal design. 54
whereas GPI-AP–deficient cells were not detected in patients with RA Eculizumab is given by intravenous infusion on a biweekly sched-
with ringed sideroblast (RARS), RA with excess of blasts (RAEB), or RA ule following an initial loading period consisting of five weekly treat-
with excess of blasts in transformation (RAEB-t). Compared to patients ments. In general, the drug is well tolerated; however, patients with
with RA without a population of PNH cells (RA-PNH−), patients with congenital deficiency of complement C5 have an increased risk of
RA with a population of PNH cells (RA-PNH+) had a distinct clinical infection with Neisseria species. For this reason, patients treated with
profile characterized by the following features: (1) less-pronounced mor- eculizumab (which blocks the function of C5; see Fig. 40–1) are at risk
phologic abnormalities of blood cells; (2) more severe thrombocytope- for meningococcal septicemia. All patients must be inoculated with a
nia; (3) lower rates of karyotypic abnormalities; (4) higher incidence meningococcal vaccine 2 weeks before starting therapy, but the vaccine
of HLA-DR15; (5) lower rate of progression to acute leukemia; and (6) is not 100 percent protective. Whether prophylactic antibiotic therapy
higher probability of response to cyclosporine therapy. aimed at preventing meningococcal infection is justified for a patient
That a population of PNH cells is associated only with low-risk receiving eculizumab remains to be determined. Despite the fact that
MDS was confirmed in a North American study of 137 patients classified the percentage of GPI-AP–deficient erythrocytes increases during
by World Health Organization (WHO) criteria. 39,46 The study found treatment with eculizumab, there have been no reports of catastrophic
55
a population of PNH cells in 1 of 5 (20 percent) patients with 5q− hemolytic crises in the relatively few PNH patients who have discontin-
syndrome, in 6 of 17 (35 percent) patients with RA, and in 2 of 37 (5 ued treatment with eculizumab. 54,56
percent) patients with refractory cytopenias with multilineage dysplasia Eculizumab is expensive (approximately $400,000/year in the
(RCMD), whereas no patient with RARS (0 of 9), RCMD-ringed side- United States), and it has no effect on either the underlying stem cell
roblasts (0 of 6), RAEB (0 of 26), MDS unspecified (0 of 10), myelodys- abnormality or the associated marrow failure. Consequently, treatment
plastic/myeloproliferative disease (0 of 10), primary myelofibrosis (0 of must continue indefinitely and leukopenia, thrombocytopenia, and
5), chronic myelomonocytic leukemia (0 of 5), or acute myeloid leukemia reticulocytopenia, if present, persist.
(0 of 6) had a detectable population of GPI-AP–deficient blood cells. 39
When combined with evidence of polyclonal hematopoiesis (based
on the pattern of X-chromosome inactivation in female patients), the OTHER TREATMENT FOR PAROXYSMAL
presence of a population of PNH cells in patients with MDS predicts a NOCTURNAL HEMOGLOBINURIA
relatively benign clinical course and a high probability of response to Other than eculizumab, there is no specific treatment for PNH, and
30
immunosuppressive therapy in patients. A relatively good response to for patients who are not being treated with eculizumab, management
immunosuppressive therapy for patients with MDS and aplastic anemia is largely supportive (reviewed in Ref. 28). Although hemolysis is ame-
was also predicted by expression of HLA-DR15 in studies of both North liorated in some patients by treatment with glucocorticoids or andro-
American and Japanese patients. 47,48 Together, these observations pro- gens, the use of steroids in the management of patients with PNH is
vide compelling indirect evidence that aplastic anemia and a subgroup controversial. The main value of glucocorticoids may be in attenuating
28
of low-risk MDS are immune-mediated diseases and that the immune acute hemolytic exacerbations. Under these circumstances, brief pulses
pathophysiologic process provides the selection pressure that favors the of prednisone may reduce the severity and duration of the crisis. The
outgrowth of PIGA mutant, GPI-AP–deficient stem cells. value of glucocorticoids in treating chronic hemolysis is limited by tox-
icity, and the harm that can accrue from long-term use cannot be over-
THERAPY emphasized. An every-other-day schedule may attenuate some of the
57
adverse effects of chronic glucocorticoid use, but patients may note
ECULIZUMAB worsening of symptoms on the off day.
Androgen therapy, either alone or in combination with gluco-
The complement-mediated intravascular hemolysis of PNH can be corticoids, has been used successfully to treat the anemia of PNH. 57,58
inhibited by blocking formation of the terminal complement pathway As with glucocorticoids, the mechanism by which androgenic steroids
generated MAC, the cytolytic component of the complement system ameliorate the anemia of PNH is not fully understood, although the

Kaushansky_chapter 40_p0571-0582.indd 578 9/17/15 6:23 PM