Page 492 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 30 Aplastic Anemia 413

or hematologic improvement. When added to immunosuppressive immunosuppressive therapy. Whether eltrombopag (and functionally
therapies, androgens failed to result in any increase in response rates. related recombinant c-mpl ligand Nplate) adversely impact the risk
Androgens continue to be helpful in occasional patients when used of later MDS and AML is not yet established. Ongoing trials combine
as a second-line therapy. Most hematologists have observed patients eltrombopag with immunosuppression as first treatment in SAA and
who appeared to respond or even to develop hormone dependence. have produced very high response rates and complete response rates,
Androgen therapy remains popular in developing countries because as well as earlier blood count recovery.
it is inexpensive, well tolerated, and seemingly effective. Various
preparations of androgens at different doses have resulted in similar
response rates of 35% to 60% after 6 months of therapy. Sex hor- PROGNOSIS
mones increase telomerase gene transcription and danazol has been
effective in marrow failure due to telomeropathy. 27 The initial blood cell counts of a patient with AA are important
Useful androgens include nandrolone decanoate, oxymetholone, indicators of prognosis. The popular “Camitta” criteria used to define
and danazol. The hemoglobin response is frequently more impressive severe disease are the presence of two of the following three: neutro-
than improvements in granulocyte or platelet levels. An adequate trial phil count of less than 500 cells/µL, platelet count of less than 20,000
is considered to be a full dose given for at least 3 months. Complica- cells/µL, and corrected reticulocyte level of less than 1% (<40,000
tions occur infrequently, although some are serious and can limit cells/µL). In the more modern era absolute reticulocytes (>25,000/
effective therapy, especially in the elderly. The associated liver cho- uL) and absolute lymphocytosis predicted a good response to immu-
lestasis is usually reversible. Hepatotoxicity (e.g., bile duct prolifera- nosuppression and survival. The robustness of the platelet and reticu-
tion, peliosis, atypical hepatocyte hyperplasia, tumors) can occur but locyte response after immunosuppression also correlates with
is less common with parenteral formulations. Children appear to long-term survival. Clonal evolution, especially –7del(7q), is a poor
tolerate high doses of androgens without lasting effects on growth or prognostic factor, and age-adjusted telomere length of leukocytes at
maturation. diagnosis may predict this serious complication. 26
The rate of spontaneous recovery is difficult to estimate, but most
observers believe it to be low. Untreated severe disease is almost
Hematopoietic Growth Factors invariably fatal. In contrast, moderate AA has a good prognosis, and
some patients with minimal blood cell count depression recover
Hematopoietic growth factor production is normal or increased in normal blood cell counts with limited or no therapy.
most patients with AA. Nevertheless, many patients are treated with
pharmacologic high doses of cytokines, often with uncertain justifica-
tion. G-CSF and GM-CSF in some cases can increase neutrophil SUGGESTED READINGS
numbers in patients with AA. In general,,neutrophil responses to
growth factors are transient, dependent on their continuous admin- Adkins DR, Goodnough LT, Shenoy S, et al: Effect of leukocyte compat-
istration, and usually restricted to patients with quantitatively less ibility on neutrophil increment after transfusion of granulocyte colony-
severe forms of AA. Nevertheless, occasional bilineage and trilineage stimulating factor-mobilized prophylactic granulocyte transfusions and
responses have been observed. Children may be more sensitive to the on clinical outcomes after stem cell transplantation. Blood 95:3605, 2000.
effects of prolonged administration of G-CSF. Bacigalupo A. How I treat acquired aplastic anemia. Blood 129:1428–1436,
A concern has been the possibility that prolonged administration 2017.
of G-CSF might increase the probability of late clonal disease, espe- Chen J, Lipovsky K, Ellison FM, et al: Bystander destruction of hematopoi-
cially monosomy 7. In retrospective analyses of Japanese children and etic progenitor and stem cells in a mouse model of infusion-induced bone
adults with severe AA, this syndrome appeared to occur most fre- marrow failure. Blood 104:1671, 2004.
quently among patients who had received growth factor; a modest Deeg HJ, Leisenring W, Storb R, et al: Long-term outcome after marrow
increase in the risk of myelodysplasia and leukemia and monosomy 7 transplantation for severe aplastic anemia. Blood 91:3637, 1998.
was also seen in European cases. The mechanism of G-CSF’s relation- Desmond R, Townsley DM, Dumitriu B, et al: Eltrombopag restores tri-
ship to monosomy 7 may be selection of aneuploid cells bearing an lineage hematopoiesis in refractory severe aplastic anemia that can be
isoform of G-CSF; these cells are less sensitive to G-CSF, but when sustained on discontinuation of drug. Blood 123:1818–1825, 2014.
triggered by the cytokine they proliferate but do not differentiate. Dumitriu B, Feng X, Townsley DM, et al: Telomere attrition and candi-
Anemia and pancytopenia in rare patients have responded to date gene mutations preceding monosomy 7 in aplastic anemia. Blood
prolonged administration of high doses of erythropoietin alone, 125:706–709, 2015.
GM-CSF and erythropoietin, and with IL-3 and G-CSF. In one Heckman KD, Weiner GJ, Davis CS, et al: Randomized study of prophylac-
randomized protocol, the combination of G-CSF and high doses of tic platelet transfusion threshold during induction therapy for adult acute
erythropoietin improved hemoglobin values, mainly in patients with leukemia: 10,000/microL versus 20,000/microL. J Clin Oncol 15:1143,
moderate disease. 1997.
Growth factors have also been combined with definitive medical Herbrecht R, Denning DW, Patterson TF, et al: Voriconazole versus ampho-
therapy to improve neutrophil counts during the early phase of tericin B for primary therapy of invasive aspergillosis. N Engl J Med
immunosuppression. Neither small pilot trials nor large randomized 347:408, 2002.
studies have shown substantial benefit for the routine use of GM-CSF Hughes WT, Armstrong D, Bodey GP, et al: 2002 Guidelines for the use of
or G-CSF in preventing infection, improving the response rate to antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis
immunosuppression, or in survival. A brief therapeutic trial of G-CSF 34:730, 2002.
or GM-CSF is often used in severely neutropenic patients who are International Agranulocytosis and Aplastic Anemia Study: Risks of agranu-
persistently or seriously infected in the hope of clinical benefit. locytosis and aplastic anemia: A first report of their relation to drug use
Growth factors, alone or in combination, are occasionally effective in with special reference to analgesics. JAMA 256:1749, 1986.
chronically refractory patients. Kojima S, Matsuyama T, Kato S, et al: Outcome of 154 patients with severe
New thrombopoietic factors may have utility in AA. An oral c-mpl aplastic anemia who received transplants from unrelated donors: the Japan
agonist peptide, eltrombopag, increased not only platelet counts but Marrow Donor Program. Blood 100:799, 2002.
led to erythrocyte and granulocyte improvement in almost half of 25 Marsh J, Schrezenmeier H, Marin P, et al: Prospective randomized mul-
patients with chronic refractory severe AA. The mpl receptor is ticenter study comparing cyclosporin alone versus the combination of
expressed by hematopoietic stem cells, and laboratory and clinical antithymocyte globulin and cyclosporin for treatment of patients with
data indicate physiologic stimulation of stem cells by thrombopoietin. nonsevere aplastic anemia: a report from the European Blood and
This study led to the Food and Drugs Aadministration approval of Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party.
labeling of eltrombopag as a salvage therapy for AA refractory to Blood 93:2191, 1999.