Page 773 - Hematology_ Basic Principles and Practice ( PDFDrive )

660 Part V Red Blood Cells

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patients received additional therapies. Eight patients achieved CR interaction with other drugs. Cyclophosphamide may have long-term
and three PR, but six patients still had moderate signs of hemolysis mutagenic effects. Other immunosuppressive drugs such as cyclospo-
and therefore did not formally fulfill the criteria for a CR. Thus, the rine or mycophenolate mofetil (MMF) have shown high response
true response rates for steroid-refractory WAIHAs seem to be consid- rates in very small series.
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erably high, but still not completely clear. The efficacy and toxicity Repeated cycles of high-dose cyclophosphamide (50 mg/kg/day
of rituximab monotherapy was previously tested in several additional for 4 days) remain an option in selected, highly refractory patients.
retrospective studies in a mixed population of refractory primary or In a pilot study, six out of nine patients received a CR with a median
secondary AIHA. Response usually occurs within 3 weeks. Patients duration of 15 months or more. Alemtuzumab has also been effective
taking steroids before initiation of rituximab should continue on at a dose of 10 mg/day for 10 days. Promising results were recently
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steroids until response to the CD20 antibody. In the D’Arena et al published for a combination of low-dose rituximab (100 mg on days
study, at a mean follow-up of 604 days, all patients were still in CR 1, 8, 15, and 22) with alemtuzumab (10 mg on days 1–3). The results
or PR. The longest remission duration was 2884 days. Because of the of autologous stem cell transplantation were disappointing, but
small patient number, data on long-term efficacy of rituximab should allogeneic transplantation may be used as a last-resort treatment in
be regarded with caution. Predictors of long-term response are patients with Evans syndrome.
achievement of a CR, conversion to a negative DAT result, and previ- In general, second-line treatment should be selected taking into
ous splenectomy. Retreatment with rituximab is feasible and may be account severity of AIHA, age, comorbidity, and patient preference.
necessary after 1–3 years. Rituximab has been given to children Because of the low curative potential of all treatment options, patient
without apparent safety problems. safety remains the major concern.
The caveats of rituximab therapy are that the drug is not licensed
for the indication and that infectious complications are rare but
sometimes life threatening, particularly with repeat or maintenance Treatment of Secondary Warm Autoimmune
treatment. There is a small long-term risk of progressive multifo- Hemolytic Anemia
cal leukoencephalopathy. Nevertheless, rituximab is the preferred
option for patients who are not eligible for splenectomy. If one In secondary AIHA, the treatment goal depends on the type and
explains the benefits and risks of the two second-line treatments to a severity of the underlying disease. The treatment goal may vary from
patient, he or she usually favors rituximab because it is a noninvasive palliative treatment of AIHA to cure by eradication of the underlying
outpatient treatment, and splenectomy remains an option in case disease. Preferred treatment options are listed in Table 46.6.
of failure.
Treatment of Patients With Refractory or Recurrent Warm Autoimmune Hemolytic Anemia Associated
Disease After Splenectomy or Rituximab With Systemic Lupus Erythematosus
In patients failing splenectomy, an accessory spleen should be
excluded. Patients who are refractory to splenectomy or with recur- Steroids used at a similar dosage as in primary WAIHAs induce high
rence after splenectomy can be retreated with steroids, assuming that response rates. Maintenance treatment with azathioprine, cyclophos-
the disease has become more responsive. This may work well in phamide, or both may be required. Rituximab is effective against
patients with previous requirement of lower steroid doses (≤15 mg/ WAIHAs and SLE but may be associated with a higher risk of pro-
day of prednisone). The other option is to initiate treatment with gressive multifocal leukoencephalopathy in this setting.
rituximab immediately.
Patients who are refractory to rituximab should undergo splenec-
tomy, if eligible. There are no data on the influence of initial remission Warm Autoimmune Hemolytic Anemia Associated
duration on the efficacy of retreatment. In patients relapsing late (>1 With Chronic Lymphocytic Leukemia
year) after rituximab, retreatment with the antibody maybe a good
option. In previously untreated CLL with isolated DAT-positive anemia but
A potentially interesting drug for second-line treatment (which no other treatment indication, treatment with prednisone as in
has also been used as first-line treatment along with steroids) is primary WAIHAs is the first choice. In case of refractoriness or
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danazol, an attenuated androgen (see Table 46.6). It has established relapse, rituximab monotherapy is moderately effective but produces
efficacy in C1 esterase deficiency, and efficacy has been claimed in response rates of more than 80% in combination with cyclophospha-
several immune diseases, including WAIHAs. Initial very promising mide and dexamethasone. Cyclosporine also has good activity. In
results (ORR: 60% to 70%) in AIHA could not be confirmed in refractory AIHA or in AIHA with advanced or progressive CLL,
subsequent studies, but it may worthwhile to carry out further studies treatment of the underlying disease with a rituximab-containing
because the toxicity seems to be relatively low with the exception of regimen according to International Workshop on Chronic Lympho-
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a potentially increased risk for hepatocellular carcinoma. cytic Leukemia guidelines is recommended. In elderly or comorbid
The advantage of high-dose Igs is low toxicity but remission rates patients with active CLL, chlorambucil with prednisone with or
are low, and routine use in patients with AIHA is not recommended without rituximab is a good choice. In general, fludarabine-containing
in a recent guideline. regimens should be used with caution in the presence of a positive
DAT result or overt AIHA. In this case, bendamustine with (or
Treatment Options Beyond Second-Line Therapy in without) rituximab is a good alternative. Alemtuzumab has proven
activity against CLL and AIHA, and is a good second-line option,
Primary Warm Autoimmune Hemolytic Anemia particularly in patients with associated PRCA. The tyrosine kinase
inhibitor ibrutinib was effective in a patient with WAIHAs and
Given the nature of the disease, the use of immunosuppressive treat- CLL. 42
ments of all kinds seems logical. Response rates of up to 60% have
been reported, but data are frequently based on low patient numbers
or anecdotal reports. Cyclophosphamide was very effective in two Warm Autoimmune Hemolytic Anemia in Other
studies. Other published data of treatment with azathioprine or Non-Hodgkin Lymphomas
cyclophosphamide are less favorable, with only about one-third of
patients having any response. Evaluation is even more complicated AIHA in NHLs does not respond well to steroids in general and
by the fact that patients frequently received concomitant treatment splenectomy is only effective in SMZLs. Sustained responses in most
with steroids. Dosing of azathioprine is difficult because of the narrow other lymphoma subtypes have been obtained with lymphoma-
therapeutic window, hypersensitivity because of genetic defects, and specific treatment with or without rituximab.