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Chapter 30 Aplastic Anemia 407

and 100,000 platelets/µL. In a randomized trial of patients with suspected, broad-spectrum parenteral antibiotic therapy should begin
AML, the risk of major bleeding was no different when 10,000 or immediately. Any regimen may require modification based on the
20,000 platelets/µL was chosen as the threshold, whereas the lower results of cultures, new symptoms or signs, or a deteriorating clinical
value led to a 20% reduction in platelet use. Any prophylaxis program course. Bacteremia is present in only 20% of febrile neutropenic
must be modified to address the individual patient, but a goal of episodes, and in only approximately 40% of those can a microbiologic
maintaining platelet counts >10,000 platelets/µL is reasonable. cause or localizing physical findings be identified. Early discontinu-
Major surgery can be accomplished in the setting of thrombocytope- ation of antibiotics when cultures are unrevealing in persistently
nia. In one study blood loss and morbidity rates were low even at neutropenic patients is dangerous. Some experienced practitioners
platelet counts of less than 30,000 platelets/µL. use prophylactic antibiotics to reduce febrile episodes and hospital
admissions.
Patients often remain febrile despite antibiotic therapy, or fever
Anemia reappears. In the absence of additional microbiologic data or clinical
clues from the patient’s complaints or physical examination, anti-
Other than to reduce the risk of graft rejection after receiving an fungal therapy should be instituted in patients who have remained
allogeneic stem cell transplant, there is no reason to allow a patient febrile despite adequate antibacterial therapy. Current infectious
to suffer the symptoms of anemia. After equilibrium is achieved, a disease guidelines recommend introduction of antifungal therapy
constant amount of blood will be required to maintain a given after 5 days, but earlier addition can be advisable in the AA patient,
hemoglobin concentration. Physically fit individuals are usually not especially if there are findings on chest tomography and a positive test
symptomatic at hemoglobin concentrations higher than 7 g/dL; for galactomannan protein. Fungemia during an initial febrile episode
patients with underlying cardiovascular disease should be maintained is rare, but fungal infection becomes more likely with repeated
at a higher level (≥9 g/dL). Iron chelation should be used in patients courses of antibiotics and ultimately is the major cause of death in
with unresponsive chronic anemia who have a reasonable expectation AA patients in whom definitive therapy fails. Candida and Aspergillus
of survival. Chelation may be avoided in the patient who proceeds species account for almost all fungal diseases in AA. Early aggressive
to transplant soon after diagnosis or who responds in a few months treatment of neutropenic patients can reverse fungal disease. Large
to immunosuppressive therapy. In patients with chronic anemia, randomized trials have shown that newer antifungal agents such
institution of a regimen of oral deferasirox (Exjade) or subcutaneous as voriconazole and caspofungin are less toxic and as effective or
deferoxamine (Desferal) at adequate doses may be initiated as transfu- superior compared with amphotericin and liposomal amphotericin
sions accumulate and serum ferritin rises. for treatment of both persistent neutropenic fever and established
Alloimmunization because of blood product administration Candida and Aspergillus infection. Improved survival in severe AA is
increases the probability of graft rejection and mortality after BM in some part caused by better antifungal drug therapies. 12
transplantation. Blood products from potential BM donors such as Polymorphonuclear cells have a relatively brief life span in the
a sibling or a parent (who share histocompatibility antigens) should circulation and their major activity is in infected tissue. There are
be avoided. Small numbers of transfusions do not have a major delete- no simple measures of the therapeutic efficacy of WBC transfu-
rious effect on survival. The 5% risk of graft rejection after transplan- sions. The absolute neutrophil count is not measurably increased
tation in entirely untransfused patients was increased to 15% with by standard transfusions. Several controlled trials performed in the
receipt of 1–40 units and to higher than 25% in more heavily 1970s reported improved survival in patients who received granu-
transfused patients. Graft rejection would be anticipated to be lower locyte transfusions; negative studies may have used relatively low
2
10
with leucocyte-depletion methods of platelet preparations. Speed in numbers of granulocytes transfused (<10 /m /day). Granulocyte
arranging tissue typing and transfer to an appropriate center has a transfusions are expensive and associated with serious toxicity: severe
greater impact on the survival of the patient than the judicious febrile reactions, pulmonary capillary leak syndrome, an increased
transfusion of a few units of RBCs to a severely anemic patient or risk of infection, and inevitable alloimmunization. Administration of
platelets to a bleeding patient. Transfusions should not be withheld G-CSF to normal donors greatly increases the yield of leukapheresis
in an older patient in whom immunosuppressive therapy will be the without adverse effects on the volunteers. Excellent results can be
first-line therapy. obtained from community donors, and the use of allocompatible
granulocytes (as determined by lymphocytotoxicity screening assay)
can further improve clinical results of granulocyte transfusions. Large
Infection numbers of neutrophils can be obtained, allowing dramatic increases
in the absolute granulocyte levels in neutropenic recipients, which
There are very few specific reports of infections and their therapy in can improve clinical outcomes; case reports and phase I and II studies
patients with AA. The duration of neutropenia is the major difference have suggested that G-CSF (G-CSF plus dexamethasone)–mobilized
between the neutropenia of BM failure and that induced by cytotoxic granulocyte transfusions can be helpful in the treatment of life-
chemotherapy. With longer periods of neutropenia, the probability threatening fungal infections in severely neutropenic patients. 13
of serious bacterial or fungal infection increases. A second major
difference is that neutropenia is part of a complex of problems associ-
ated with malignant disease and its therapy. In AA, the immune Definitive Therapy
system is activated, and with the exception of intravenous catheter
placement, the integument is preserved. Studies of cancer patients Hematopoietic Stem Cell Transplantation
have usually identified a low-risk category of neutropenia, determined
by the relatively brief period of neutropenia; by this criterion, almost Allogeneic stem cell transplantation from an HLA-matched sibling
all unresponsive patients with AA are at high risk. donor provides curative therapy for AA patients (Fig. 30.10).
In classic studies of leukemic children, neutropenia was shown to Stem cell transplantation in AA is the subject of a large number
increase susceptibility to bacterial infections, and the number of of reports and reviews. 1,14–16 Cytokine-mobilized peripheral blood
infectious episodes correlated with the degree and duration of neu- has also been used successfully as a stem cell graft but multiple
tropenia. Susceptibility to infection is extremely high with an absolute studies favor BM over mobilized peripheral blood stem cell grafts
17
neutrophil count of less than 200/µL, and this value has been used in AA patients because of the lower risk of chronic GVHD. The
to define a category of very severe AA. As severe granulocytopenia first studies of allogeneic BM transplants conclusively demonstrated
becomes prolonged, infection is inevitable. Recommendations for their value compared with conventional supportive therapy. In a
initiation of empirical antibiotic therapy are similar for AA patients controlled trial reported by the International Aplastic Anemia Study
and other patients with neutropenia. The cardinal rule is, if the Group, patients with severe disease who received transplants early
absolute neutrophil count is less than 500 cells/µL and infection is had an actuarial survival rate of more than 60%, compared with