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Chapter 30 Aplastic Anemia 411

reached low levels in the circulation by the time host antibody alone, more complete responses, and better 5-year survival rates for
appears. A short course of therapy is easier to administer, associated responding patients at 80% to 90%. Children do especially well with
with less serum sickness, and equally effective as the same dose given combined therapy, elderly patients less so, partly because of greater
over a more prolonged course. Thymoglobulin, rabbit ATG, has been toxicity and poor tolerance of pancytopenia related complications in
approved for use in the United States. While rabbit ATG is more the presence of comorbidities.
potent by weight than horse ATG, a randomized trial (using most In disease refractory to initial therapy with ATG and CSA, a repeat
commonly applied dosing of thymoglobulin at 3.5 mg/kg × 5 days) course of rabbit ATG and CSA or alemtuzumab can be administered
showed it markedly inferior to horse ATG in achieving hematologic as a salvage regimen and can rescue about a third or more of patients.
response, and survival was poorer as well. 25
ALGs are immunosuppressive. ATGs contain a heterogeneous mix
of antibody specificities for lymphocytes. Horse sera fix human Cyclophosphamide
complement efficiently, and all preparations are T-cell cytotoxic in
vitro, with little difference among ATGs or among lots for lympho- Cyclophosphamide in high doses (45–50 mg/kg/day for 4 days) and
cyte killing in vitro. In vitro ALGs efficiently inhibit T-cell prolifera- “moderate” dose (50 mg/kg/day × 2 days) without stem cell rescue
tion and block IL-2 and IFN-γ production and IL-2 receptor can induce hematologic recovery in severe AA, with an overall
expression. ATG induces Fas-mediated apoptosis of T cells, especially response rate claimed similar to that achieved with ATG therapy but
after activation. In patients the administration of ATG results in rapid a higher proportion of complete responses and less relapse and clonal
reduction in the number of circulating lymphocytes, usually to less evolution. However, cyclophosphamide severely depresses the neutro-
than 10% of starting values, and lymphopenia persists for several days phil count, resulting in prolonged hospitalization for suspected or
after discontinuing therapy. Although lymphocyte numbers return to actual infection and a higher risk of invasive fungal infections and
pretreatment values by 3 months, reductions in activated lymphocyte death in comparison to ATG and CSA.
numbers in recovered patients persist. It seems likely that these
inhibitory effects on T cells are responsible for the efficacy of ALGs
in AA. Nevertheless, the ability of ATG to stimulate lymphocyte Corticosteroids
function by acting as a mitogen may also have a role in their thera-
peutic efficacy. Notably, rabbit ATG can stimulate T regulatory cell Methylprednisolone in modest doses (1 mg/kg/day) is administered
development in vitro and in patients, although this effect in AA is with ATG to ameliorate the symptoms of serum sickness. Very-high-
overwhelmed by rabbit ATG’s more potent CD4 cell depletion in dose corticosteroids regimens can be effective, especially in recently
comparison to horse ATG. diagnosed patients. High-dose methylprednisolone has also been
added to ATG therapy, with inconsistent results. However, ATG is
associated with better response rates and many fewer associated toxic
Cyclosporine effects than high-dose steroid therapy and is generally preferable as
initial therapy. Modest doses of corticosteroids do not have roles in
Several groups reported anecdotal success with cyclosporine (CSA) the treatment of AA except in combination with ATG.
therapy combined with androgens in individual patients with AA, in
many of whom other therapies had failed. Some studies suggested
efficacy of CSA in patients refractory to ALG or ATG alone, with Late Complications of Immunosuppressive Therapy
salvage rates of approximately 50%. The optimal regimen has not
been determined. In the United States CSA has usually been used in Relapse after immunosuppressive therapy is common. About one-
high doses (12 mg/kg/day for adults and 15 mg/kg/day for children), third or more of responding patients may be expected to require
with adjustment according to plasma drug concentrations and serum reinstitution of immunosuppressive drugs or another course of ATG.
creatinine levels. In Europe lower doses (3–7 mg/kg/day) have been Relapse can manifest as a gradual decline in one blood count, need
reported to be equally efficacious. Hematologic improvement can for transfusion after a period of transfusion-independence, or abrupt
occur in a few weeks or months. A 6-month trial is warranted. recurrence of severe pancytopenia. Most relapse responds to retreat-
Remissions, when achieved, usually have been durable, but some ment, and there is no clear relationship with inferior survival.
patients relapse when cyclosporine is discontinued. Most patients A much more serious complication is the development of late-
who relapse will respond to the reinstitution of CSA; the lowest onset clonal hematologic disorders, especially myelodysplasia and
possible dose should be sought by tapering, but some patients may AML. Some of these events likely represent part of the natural history
require long-term maintenance treatment. of AA. Before recent improvements in treatment, leukemia was
CSA has considerable toxicity. Hypertension and azotemia are the considered an unusual complication but late-onset clonal disorders
most common serious side effects; hirsutism and gingival hypertrophy do not appear to be the result of the introduction of immunosup-
are also frequent complaints. Increasing serum creatinine levels are pressive therapy. In European and National Institutes of Health trials,
an indication for dose reduction. Chronic CSA nephropathy charac- the overall rate of clonal evolution is 12% to 15% at about a decade.
terized by interstitial fibrosis and tubular atrophy can be irreversible. Children appear to be at similar risk for the development of clonal
The risk of nephropathy is increased by high doses and longer dura- complications as adults, and evolution to MDS can occur in respond-
tion of therapy and occurs more commonly in older than in younger ers and in refractory patients. MDS that develops after AA can
patients. CSA, especially in combination with corticosteroids, con- transform to AML but can also be surprisingly indolent. Cytogenetic
verts patients with AA to a temporary immunodeficiency state and analyses are almost always abnormal in clonal evolution. Monosomy
puts them at high risk for opportunistic infections. Monthly aerosol- 7 is the most frequent finding and confers a poor prognosis; in
ized pentamidine prophylaxis can prevent Pneumocystis carinii contrast to trisomy 8. Clinically monosomy 7 was more likely to
pneumonia in patients receiving CSA. occur in primarily refractory patients and had a poor prognosis,
whereas patients with trisomy 8 often remain CSA-responsive and
have good prospects for survival. Trisomy 6 and 13q– also behave
Combined or Intensive Immunosuppressive Therapy benignly in most cases. A PNH clone can be detected in up to 50%
of patients at the time of presentation. Usually the clone size remains
The combination for the treatment of AA of an agent that lyses stable and it may decrease; over time, only a minority of patients will
lymphocytes (ATG) with a drug that blocks lymphocyte function is develop a large clone and the hemolytic or thrombotic form of PNH.
rational. The strategy has resulted in a striking increase in the response Both the presence of somatically mutated clones in the marrow and
rate to immunosuppressive therapy in randomized and multicenter rapid telomere attrition have been associated as risk factors with the
trials, to 60% to 80% at 1-year compared to about 40% with ATG development of MDS and AML after treatment of AA.