TO THE EDITOR: Corticosteroids have been widely used in patients with paroxysmal nocturnal
hemoglobinuria (PNH), based on the notion that administration may ameliorate hemolysis.
However, there is no strong evidence of clinical benefit in the inhibition of complement-mediated
hemolysis associated with corticosteroids. The short-term use of prednisolone (Pd)
may be beneficial in some situations, but long-term use is generally not recommended
because of concerns regarding complications [1
2]. Eculizumab is a humanized monoclonal antibody that blocks terminal complement
by binding to C5. This antibody is a standard therapeutic modality for PNH and has
altered the natural history of the disease [3
4]. A subpopulation of patients placed on eculizumab, however, still require red blood
cell (RBC) transfusion , and standard salvage therapies for these patients have
yet to be determined. We retrospectively analyzed the therapeutic effects of low-dose
Pd in patients with PNH who show inadequate responses to eculizumab treatment.
Seven patients were treated with eculizumab between February 2012 and April 2016 at
Chungnam National University Hospital. All patients were men and the median duration
of the disease was 19.1 years (range, 5.1–24.5 yr). At the time of analysis, all patients
were still taking eculizumab, and the median duration of eculizumab treatment was
36.3 months (range, 6.9–39.1 mo). After 6 months of eculizumab treatment, all patients
showed improvement of anemia and hemolysis. Four (57.1%) patients showed an optimal
response, one (14.2%) showed a major response and 2 (28.5%) showed a partial response,
according to a modification of a previously reported stratification [6
7]. During the first 12 months of eculizumab treatment, 4 patients no longer required
RBC transfusion; however, 3 patients continued to require transfusion, although the
transfusion requirements were reduced. Low-dose Pd (5 mg/day) was additionally administered
to these 3 patients.
Of the 3 patients requiring transfusion, patient 1 was previously diagnosed with aplastic
anemia (AA) and patient 2 had concurrent chronic kidney disease. At the time of initiation
of low-dose Pd therapy, the hemoglobin (Hb) levels were 8.9, 8.9, and 8.3 g/dL, respectively,
and the lactate dehydrogenase (LDH) levels were 418, 655, and 1,069 IU/L, respectively,
in these 3 patients. The direct Coombs test was positive in all 3 patients, and the
CH50 levels after 6 months of eculizumab treatment were 4.4 U/mL, <2.0 U/mL, and 20.9
U/mL, respectively (<2.0 U/mL, 10.3 U/mL, 5.4 U/mL, and 5.2 U/mL, respectively, in
patients with optimal response). Low-dose Pd (5 mg/day) was administered to these
3 patients, and the Hb levels gradually increased over 12 months. The LDH levels were
maintained or modestly decreased. Patient 3 experienced 2 infection episodes (upper
respiratory infection with fever and tenosynovitis of the right wrist). Decreases
in the Hb level and increases in the LDH level were observed during each event. During
the 12 months of additional low-dose Pd therapy, the requirements for RBC transfusion
in these 3 patients were modestly decreased. While a total of 26 packs of RBC transfusion
were needed before Pd therapy, only 10 packs were needed after 12 months, indicating
that low-dose Pd induced a favorable effect of about 60% reduction in RBC transfusion
requirements (Table 1). There were no severe adverse events related to low-dose Pd
therapy. Patient 1 experienced a mild upper respiratory infection after 1 month of
Pd, and this spontaneously resolved. As mentioned above, patient 3 experienced 2 mild
infections that were manageable with oral antibiotics.
In the present analysis, 3 of 7 patients required RBC transfusion, even after long-term
eculizumab treatment. Inadequate hematologic benefit in some patients may be related
to complement protein C3. Because eculizumab inhibits the terminal complement cascade
and has no effect on proximal components, C3 and its fragments accumulate on RBCs
in PNH patients. This phenomenon leads to destruction of RBCs in the spleen and liver.
As a result, extravascular hemolysis is increased and might result in dependence on
RBC transfusion . Considering such a mechanism, corticosteroids and splenectomy
may be a treatment option for patients demonstrating enhanced extravascular hemolysis
following eculizumab therapy [7
8]. Bone marrow function affects erythropoiesis and thus the outcome of eculizumab
treatment. A red cell production index (RPI) >2.5 in anemia suggests sufficient erythropoiesis.
In a previous report, patients with low RPI did not respond well to eculizumab .
Interestingly, Peffault de Latour et al. reported that CH50 activity is a simple biomarker
related to intravascular hemolysis and circulating free eculizumab levels. In this
study, low CH50 activity (CH50 ≤10% of normal) was significantly associated with low
LDH levels. Furthermore, low circulating free eculizumab correlated with CH50 >10%
and the need for transfusions .
In the present analysis, patient 3 showed a low (1.1) RPI and a very high (1,069 IU/L)
LDH level at the time of initiation of Pd therapy. Furthermore, the patient showed
a slightly higher level of CH50 compared with other patients. Considering these findings,
this patient might have had components of both ineffective erythropoiesis and extravascular
hemolysis. After 12 months of Pd therapy, the level of CH50 decreased from 20.9 to
6.7 U/mL, and both the need for RBC transfusion and the LDH level also decreased.
Patient No. 1 had AA prior to the diagnosis of PNH, and thus defective bone marrow
function might have led, at least in part, to the inadequate response to eculizumab.
Patient 2 showed a serum erythropoietin (EPO) level of 56.8 mIU/mL (reference range,
3.7–31.5 mIU/mL), just above the normal range, suggesting the presence of an inadequate
EPO response to anemia since EPO levels tend to be very high in PNH patients .
Taken together, factors other than enhanced extravascular hemolysis appeared to have
a role in these 3 patients.
These results indicates that low-dose Pd might be helpful in patients who continue
to be dependent on RBC transfusion despite long-term eculizumab, although its mechanisms
of action remain unclear. There has been little information on the use of corticosteroid
therapy to control extravascular hemolysis occurring after eculizumab treatment. Furthermore,
the results of the small series conducted to date have not been consistent. Berzuini
et al.  reported that prednisolone at an initial dose of 75 mg per day led to
satisfactory results in one patient. In contrast, Risitano et al.  reported unsatisfactory
results in 14 patients. Notably, long-term use of high-dose corticosteroid is always
accompanied by concerns related to its well-known complications. That is the reason
why we used low-dose Pd in this study. The results of the current study suggest that
low-dose Pd might be helpful in patients who remain dependent on RBC transfusion despite
long-term eculizumab treatment.
In summary, we suggest that low-dose Pd reduces red cell transfusion requirements
in some PNH patients with inadequate response to eculizumab. However, the long-term
efficacy and adverse effects of the low-dose Pd treatment need to be determined.