Page 1432 - Williams Hematology ( PDFDrive )

1406 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1407

ATRA. Oral arsenic trioxide and tamibarotene, a synthetic retinoid, are associated with an increased risk of AML. 1004,1005 In patients with non-
985
are being examined in relapsed APL. 986,987 Children older than 4 years Hodgkin lymphoma, up to 10 percent of patients treated with either
and adolescents have outcomes with ATRA-treated APL equivalent to conventional chemotherapy or high-dose therapy developed secondary
that of adults, but younger children have more frequent relapses. 988 AML within 10 years. 1006 Secondary leukemia is seen after autologous
marrow or blood stem cell transplants involving high-dose chemother-
SECONDARY ACUTE MYELOGENOUS apy and/or radiotherapy. In a study of 83 patients after autografting, 12
LEUKEMIA had nonclonal cytogenetic abnormalities and 10 had clonal abnormal-
ities, five of whom developed secondary AML. Onset occurred 12 to
Secondary leukemias arise after treatment of another malignancy or an 48 months after autografting. The relative contribution of the underlying
autoimmune disease with cytotoxic chemotherapy or radiation. Second- disease and the conditioning therapy is uncertain. 1007 Clonality analysis
ary AML responds more poorly to chemotherapy and allogeneic stem using an X chromosome gene, based on methylation of the human andro-
cell transplantation than does de novo AML. Secondary AML accounts gen receptor locus in cell samples in patients with lymphoma, found a
for approximately 5 to 10 percent of all AML cases, although this per- clonal marrow cell population 6 months after autologous transplantation
centage is increasing. 980,990 The leukemogenic risk of treatment regimens at a time when no morphologic or clinical evidence of AML was pres-
depends on the agents used. Future development of agents with lower ent. AML appeared later in some patients. 1008 More than 10 percent of
risk of inducing AML is an important goal. 991 patients with non-Hodgkin lymphoma who underwent stem cell rescue
after total body irradiation and cyclophosphamide developed AML at a
Effect of Topoisomerase II Inhibitors median followup of 6 years. 1009 Using a triple FISH assay to detect loss of
Exposure to topoisomerase II inhibitors (e.g., etoposide, mitoxantrone, chromosomal material from 5q31, 7q22, or 13q14, abnormal cells were
amsacrine) can lead to AML with MLL gene rearrangements on chro- detected before high-dose therapy was given to non-Hodgkin lymphoma
mosome 11q32. Inversion 16 is an uncommon aberration in sec- patients. 1010 Thus, some patients are at increased risk for developing sec-
992
ondary AML and, like balanced translocations of chromosome bands ondary AML based on pretreatment chromosome studies.
11q32, 21q22, and t(15;17), is associated with prior chemotherapy
with topoisomerase II inhibitors when seen in the setting of treatment- Treatment of Secondary Leukemia
induced leukemias. The site of breakpoints within the MYH11 gene Secondary leukemia generally is treated similarly to de novo leukemia.
involved in inversion 16 may vary between therapy-induced AML and However, given the lower response rates and remission durations of
AML occurring de novo. The latency period for development of AML secondary leukemia, patients can be treated in clinical trials examining
993
after topoisomerase II inhibitors is approximately 2 years. No relation- new therapies or treated initially with chemotherapy regimens used for
ship with higher cumulative dose has been identified. Studies of single refractory disease. 1011 Some patients may benefit from early allogeneic
nucleotide polymorphisms to ascertain genetic predisposition are ongo- HSC transplantation. 1012 Autologous transplant can be successful if stem
ing. Polymorphisms in detoxification genes and in genes involved in cells are harvested prior to the development of secondary AML. 1013 In
994
995
DNA repair pathways might be involved. Even the use of low-dose or those who have low blood blast counts, allogeneic stem cell transplan-
oral etoposide can be associated with development of secondary AML. tation as initial therapy may be superior to induction chemotherapy
followed by transplantation, but this remains an area of controversy. 1014
Effect of Alkylating Agents and Cisplatin Although patients may have a response rate of approximately 50 percent
Alkylating agents cause secondary AML, often preceded by myelodys- to standard induction chemotherapy, most soon relapse, and long-term
plasia. The mean latency period after onset of treatment is approximately survival is approximately 10 percent. 1015 Secondary AML more often has
6 years. Deletions of all or part of chromosome 5 or 7 are the most com- unfavorable cytogenetic features compared to de novo leukemia. 1016
mon cytogenetic changes. The risk is related to cumulative alkylating
agent dose. Germline aberrancies of NFI and p53 may increase the risk TREATMENT OF Ph CHROMOSOME–POSITIVE
of AML. Cisplatin used for treatment of ovarian cancer also increases
the risk of secondary leukemia. 996 AML
This cytogenetic variant of acute leukemia is characterized by extraor-
Other Cytotoxic Agents dinary drug resistance. Imatinib mesylate in doses of 600 to 800 mg/day
Other drugs that may increase the risk of secondary leukemias include may produce a hematologic remission in a small proportion of patients
997
low-dose weekly methotrexate for rheumatoid arthritis, etanercept with Ph chromosome–positive AML, based on the response in patients
998
therapy, temozolamide, growth hormone administration, 1000 and with CML who go on to a myeloid blast crisis. No formal studies of
999
G-CSF given to patients with congenital, but not idiopathic or cyclic the response to imatinib mesylate of de novo Ph chromosome–positive
neutropenia. 1001 In the latter cases, a cause-and-effect relationship AML have been performed. In myeloid blast crisis of CML, the uncom-
between MDS/AML and G-CSF therapy has not been established. mon full hematologic response (blood and marrow) usually is short
Improved survival duration with G-CSF may allow expression of an lived, measured in weeks or a few months. This outcome also seems to
underlying leukemic predisposition. be the case when therapy with other drugs (e.g., cytarabine, etoposide,
anthracycline antibiotics) is included. Occasional cases in which che-
Other Settings for Secondary Leukemia motherapy has induced remission in Ph chromosome–positive AML
Patients with APL in remission may develop a new MDS (oligoblastic and imatinib mesylate has appeared to help induce and sustain the
leukemia), presumably secondary to therapy. 1002 Series of children with remission have been reported. 1017 Thus, in Ph chromosome–positive
treatment-related myelodysplasia or AML have the same latency period AML, a matched-related or matched-unrelated donor stem cell trans-
as do adults treated with alkylating agents or topoisomerase II inhibitors plant should be considered if the patient is younger than age 50 years.
for AML. 1003 Breast cancer patients receiving doxorubicin and cyclophos- This approach may have the highest probability of a long-term remis-
phamide regimens of such intensity that they required G-CSF support sion. There is little information about the use of second generation BCR-
had increased rates of posttherapy AML. Breast and prostate radiotherapy ABL inhibitors in this setting.

Kaushansky_chapter 88_p1373-1436.indd 1407 9/21/15 11:02 AM