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5 days. In light of these studies, many therapists, when using dauno- characteristics, did not show clinically relevant differences in outcome
2
rubicin, use the 90 mg/m dose for 3 days in younger patients, and this when compared to a standard cytarabine and anthracycline containing
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is in keeping with the current National Comprehensive Cancer Net- arm. Thus, the standard practice guideline for AML, other than pro-
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work (NCCN) guidelines. This benefit of higher dose applies only myelocytic leukemia, recommends standard-dose cytarabine plus an
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to younger and favorable or intermediate-risk patients. Dexrazox- anthracycline antibiotic as treatment. 587
ane may be given during induction to reduce the risk of cardiotoxicity Hematopoietic Cytokines to Enhance Chemotherapy G-CSF
in patients at higher than usual risk because of a history of coronary and granulocyte-monocyte colony-stimulating factor (GM-CSF), when
artery disease or congestive heart failure, but this is rarely used in used in untreated leukemia, can increase the percentage of leukemic
adults. Other regimens that incorporate fludarabine with cytarabine cells in the DNA synthetic phase, resulting in blast population expan-
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can be used in those patients for which an anthracycline would not be sion during short-term administration. This process could render the
ideal. cells more sensitive to simultaneous chemotherapy, but clinical bene-
High-Dose versus Standard-Dose Cytarabine High-dose cyta- fit from growth-factor priming has not been observed 618,619 despite an
rabine does not increase complete remission rates and increases toxicity increased ratio of intracellular cytosine arabinoside triphosphate to
compared to conventional doses, especially in older patients (for doses of deoxycytidine-5′-triphosphate and enhanced cytarabine incorporation
these regimens, see “Intensive Consolidation Therapy” below). Patients into the DNA of AML blasts. Remission rates or overall survival did
619
receiving high-dose cytarabine have more leukopenia, thrombocytope- not differ among adult patients who received cytarabine plus idarubicin
nia, gastrointestinal problems, and eye toxicity. Disease-free survival or cytarabine plus amsacrine with or without G-CSF given concurrently,
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and overall survival may be better than that achieved with standard but relapse rates decreased in patients who received G-CSF. GM-CSF
therapy, leading some investigators to suggest use of high-dose therapy priming in a younger patient group treated with timed-sequential
for induction in patients younger than age 50 years, but this approach is therapy increased complete remission rates but did not impact overall
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not a standard one, and these studies do not take into account the role survival. Thus, these growth factors are not generally considered use-
of high-dose cytarabine in postremission therapy. Some studies show ful as enhancers of chemotherapy. A study did, however, suggest that an
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that marrow blast clearance is higher after an induction with high-dose improved event-free survival and overall survival was noted in patients
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cytarabine and that there is an improvement in disease-free survival for treated with high-dose cytarabine during remission induction, and
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patients 50 years of age or younger. When high-dose cytarabine was complete remissions have occurred in hypoplastic AML after G-CSF
compared to intermediate doses in induction therapy, no improvement treatment without chemotherapy. 623
in outcome was noted, and higher incidences of grades 3 and 4 toxic Reinduction Therapy Patients who have persistent leukemia after
effects were noted. A trial in younger patients with multiple arms; the first course of induction chemotherapy generally are given the same
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fludarabine, high-dose cytarabine, and G-CSF (FLAG regimen) with regimen a second time. The effect is usually assessed by marrow aspirate
idarubicin resulted in a higher remission rate than did standard dauno- and biopsy 7 to 10 days after completion of chemotherapy (the “14-day
rubicin plus cytarabine with or without etoposide. Relapse rates were marrow” examination). For those with hypocellular marrow and no evi-
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also less with the high-dose cytarabine induction (38 vs. 55 percent). dence of residual leukemic blasts, recovery of normal counts is awaited,
A superior remission rate and survival was achieved in younger patients and for those with a hypocellular marrow and a small number of resid-
(<46 years) induced with a regimen containing high-dose cytarabine, ual blasts, additional therapy may be delayed until count recovery or
82 versus 76 percent rate of remission and a 52 versus 43 percent rate until another marrow assessment. For those with significant amounts
of overall survival. These differences were also seen in secondary AML of leukemic cells remaining, repeating the original induction therapy or
602
cases and in those with FLT3-ITD mutations. Also, complete remis- use of a high-dose cytarabine regimen can be considered. The patient’s
sion rates of greater than 60 percent have been noted with high-dose long-term outcome is worse if two courses of treatment are required,
cytarabine in patients with poor-risk cytogenetics. 603,604 even if a complete remission is achieved. Approximately 40 percent of
Timed Sequential Therapy and Other Drugs Timed sequential patients with persistent AML after one course of induction therapy have
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therapy, which uses agents in a scheduled sequence rather than con- a complete remission after a second course, and disease-free survival
currently, may prolong remission duration. 605–607 Timed sequential che- at 5 years is approximately 10 percent. In some European centers, two
motherapy combining mitoxantrone intravenously (IV) on days 1 to 3, courses of induction chemotherapy are given routinely, but the impact
etoposide IV on days 8 to 10, and cytarabine IV on days 1 to 3 and on remission rates or overall survival is uncertain. The longer the time
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8 to 10 resulted in a complete remission in 60 percent of patients, but to remission after the first induction therapy, the shorter the duration of
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treatment-related death in 9 percent of patients. Median disease-free disease-free survival. High-risk cytogenetic abnormalities, antecedent
survival was 9 months. 605 hematologic disorders, and other poor prognostic factors can be used
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Adding ATRA, gemtuzumab ozogamicin, fludarabine, to assign nonresponders to an experimental chemotherapy regimen
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cladribine or topotecan 611,612 to induction regimens has not improved designed to treat refractory disease, rather than repeating induction
results significantly. A recent randomized study showed that the addi- therapy. In one study, overall response to reinduction was 53 percent.
tion of the purine analogue cladribine, but not fludarabine, to dauno- Those patients with poor risk cytogenetics and those with a marrow
rubicin and cytarabine improved the remission rate and prolonged blast percentage of 60 percent or greater following the 7-plus-3 regimen
613
survival in patients younger than 60 years of age. The addition of induction treatment were found to have a low probability of achieving
bortezomib to daunorubicin and cytarabine in those 60 to 75 years of a complete remission with reinduction. Mortality during induction
627
age resulted in a remission rate of 65 percent. This was a single-arm trial therapy correlates with age and, perhaps, leukocyte count. 629
628
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with dose escalation of bortezomib. There are preliminary reports
suggesting that the addition of gemtuzumab ozogamicin to standard
induction chemotherapy may increase disease-free survival in patients Special Considerations during Induction Therapy
9
with low- and standard-risk cytogenetic abnormalities, and inhibi- Hyperleukocytosis Patients with blast counts greater than 100 × 10 /L
615
tors of FLT3 ITD are now being examined, but no data are available require prompt treatment to prevent the most serious complications of
regarding utility of this approach. A recent prospective comparison of hyperleukocytosis: intracranial hemorrhage or pulmonary insufficiency.
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five different treatment strategies, adjusted for differences in prognostic Hydration should be administered promptly to maintain urine flow

Kaushansky_chapter 88_p1373-1436.indd 1396 9/21/15 11:01 AM