Chapter 104. Acute and Chronic Myeloid Leukemia (Part 9) pptx

Chapter 104. Acute and Chronic
Myeloid Leukemia
(Part 9)

Treatment of Promyelocytic Leukemia
Tretinoin is an oral drug that induces the differentiation of leukemic cells
bearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about
10% of patients treated with these drugs die from DIC induced by the release of
granule components by dying tumor cells. Tretinoin does not produce DIC but
produces another complication called the retinoic acid syndrome. Occurring
within the first 3 weeks of treatment, it is characterized by fever, dyspnea, chest
pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxia. The
syndrome is related to adhesion of differentiated neoplastic cells to the pulmonary
vasculature endothelium. Glucocorticoids, chemotherapy, and/or supportive
measures can be effective for management of the retinoic acid syndrome. The
mortality of this syndrome is about 10%.
Tretinoin (45 mg/m
2
per day orally until remission is documented) plus
concurrent anthracycline chemotherapy appears to be among the safest and most
effective treatments for APL. Unlike patients with other types of AML, patients
with this subtype benefit from maintenance therapy with either tretinoin or
chemotherapy.
Arsenic trioxide produces meaningful responses in up to 85% of patients
refractory to tretinoin. The use of arsenic trioxide is being explored as part of
initial treatment in clinical trials of APL. Additionally, studies combining arsenic
trioxide with tretinoin in the absence of chemotherapy are ongoing.
The detection of minimal residual disease by RT-PCR amplification of the
t(15;17) chimeric gene product appears to predict relapse. Disappearance of the
signal is associated with long-term disease-free survival; its persistence predicts
relapse. With increases in the sensitivity of the assay, some patients with persistent

abnormal gene product have been found who do not suffer a relapse. Studies are
underway to determine whether a critical threshold level of transcripts uniformly
predicts for leukemia relapse.
Postremission Therapy
Induction of a durable first CR is critical to long-term disease-free survival
in AML. However, without further therapy virtually all patients experience
relapse. Once relapse has occurred, AML is generally curable only by SCT.
Postremission therapy is designed to eradicate residual leukemic cells to
prevent relapse and prolong survival. Postremission therapy in AML is often based
on age (younger than 55–65 and older than 55–65). For younger patients, most
studies include intensive chemotherapy and allogeneic or autologous SCT. High-
dose cytarabine is more effective than standard-dose cytarabine. The Cancer and
Leukemia Group B (CALGB), for example, compared the duration of CR in
patients randomly assigned postremission to four cycles of high (3 g/m
2
, every 12
h on days 1, 3, and 5), intermediate (400 mg/m
2
for 5 days by continuous
infusion), or standard (100 mg/m
2
per day for 5 days by continuous infusion)
doses of cytarabine. A dose-response effect for cytarabine in patients with AML
who were ≤60 years was demonstrated. High-dose cytarabine significantly
prolonged CR and increased the fraction cured in patients with favorable [t(8;21)
and inv(16)] and normal cytogenetics, but it had no significant effect on patients
with other abnormal karyotypes. For older patients, exploration of attenuated
intensive therapy that includes either chemotherapy or reduced intensity allogeneic
SCT has been pursued. Postremission therapy is a setting for introduction of new
agents (Table 104-3).

Table 104-
3 Selected New Agents under Study for Treatment of Adults
with AML

Class of Drugs Example Agent(s)
MDR1 modulators Cyclosporine, LY335979
Demethylating agents Decitabine, 5-azacytidine, zebularine
Histone deacetylase
inhibitors
Sube
roylanilide hydroxamic acid (SAHA),
MS275, LBH589, valproic acid
Heavy metals Arsenic trioxide, antimony
Farnesyl transferase
inhibitors
R115777, SCH66336
FLT3 inhibitors SU11248, PKC412, MLN518, CHIR-258
HSP-90 antagonists 17-allylaminogeldanamycin (17-
AAG) or
derivatives
BCR-ABL
PDGFR/KIT inhibitors
Imatinib (ST1571, Gleevec), dasatinib,
nilotinib
Telomerase inhibitor GRN163L
Cell cycle inhibitors Flavopiridol, CYC202 (R-
Roscovitine),
SNS-032
Nucleoside analogues Clofarabine, troxacitabine
Humanized antibodies Anti-CD33 (SGN33), anti-DR4, anti-

DR5,
anti-KiR
Toxin-conjugated
antibodies
Gemtuzumab ozogamicin (Mylotarg)
Radiolabeled antibodies

Yttrium-90-labeled human M195