Induction therapy for acute myeloid leukemia in younger adults
Author
Richard A Larson, MD Section Editor
Bob Lowenberg, MD, PhD Deputy Editor
Rebecca F Connor, MD
Last literature review version 19.1: January 2011 | This topic last
updated: February 17, 2011
INTRODUCTION — Once the diagnosis of acute myeloid leukemia (AML) is
established, induction chemotherapy is given with the goal of rapidly
restoring normal bone marrow function. Among patients with acute
myeloid leukemia (AML), treatment regimens and outcomes may differ
between younger and older adults. Although there is no clear dividing
line between younger and older adults when dealing with AML, in most
studies, "older adults" was defined as over age 60.
The initial treatment of younger adults with de novo AML will be
reviewed here. The following exceptions, which require modification of
standard treatment regimens, are discussed separately:
* Treatment of older adults with AML. (See "Treatment of acute
myeloid leukemia in older adults".)
* Treatment of therapy-related AML. (See "Therapy-related
myeloid neoplasms: Acute myeloid leukemia and myelodysplastic
syndrome".)
* Treatment of acute promyelocytic leukemia (FAB M3). (See
"Initial treatment of acute promyelocytic leukemia in adults" and
"Clinical manifestations, pathologic features, and diagnosis of acute
promyelocytic leukemia in adults".)
* Treatment of relapsed or resistant AML. (See "Treatment of
relapsed or refractory acute myeloid leukemia".)
Induction therapy aims to reduce the total body leukemia cell
population from approximately 1012 to below the cytologically
detectable level of about 109 cells. It is generally assumed, however,
that a substantial burden of leukemia cells persists undetected (ie,
presence of "minimal residual disease"), leading to relapse within a
few weeks or months if no further therapy were administered. The role
of this postinduction or "remission consolidation" therapy is
discussed separately. (See "Remission criteria in acute myeloid
leukemia and monitoring for residual disease", section on 'Definition
of complete remission (CR)' and "Post-remission therapy for acute
myeloid leukemia in younger adults".).
PRETREATMENT EVALUATION — Because of the rigorous nature of the
chemotherapy required for the successful treatment of AML, particular
attention should be paid in the history and physical examination to
the presence of co-morbid conditions in the patient which could
complicate overall management [1
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/1>
].
History — While all elements of the patient's history are pertinent to
the problem at hand, some are particularly relevant to complications
that might arise during treatment. These include:
* A prior history of a hematologic disorder (eg, myelodysplastic
syndrome, myeloproliferative disorder, Fanconi anemia) or a malignancy
treated with chemotherapy and/or radiation therapy (eg, Hodgkin
lymphoma, breast cancer). Such patients with "secondary" or
treatment-related AML have a relatively worse prognosis, which is also
influenced by a higher incidence of unfavorable cytogenetics.
Treatment failure is generally a consequence of drug resistant
leukemia as well as problems associated with prolonged marrow aplasia.
(See "Cytogenetics in acute myeloid leukemia", section on
'Therapy-related myeloid neoplasms (MDS/AML)' and "Prognosis of acute
myeloid leukemia", section on 'Antecedent hematologic disorders'.)
* A history of congestive failure or other cardiac disease would
mandate careful monitoring of the large amounts of intravenous fluids
that accompany the initial chemotherapy, antibiotics, blood and
platelet transfusions, hydration in preparation for the use of
amphotericin B or for treatment of hyperuricemia, and parenteral
nutrition during the three to four weeks of chemotherapy-induced
pancytopenia. Significant prior cardiac disease could also influence
the decision to use cardiotoxic drugs (eg, anthracyclines) during
induction therapy.
* Prior transfusions or multiple previous pregnancies may
presage difficulties with adequate transfusion support or herald the
occurrence of transfusion reactions after red cell or platelet
administration, due to the presence of alloantibodies to antigens
present in normal blood donors but absent in the patient. (See
"Refractoriness to platelet transfusion therapy", section on
'Etiology'.)
* Careful appraisal for possible drug allergies (eg, penicillin
and other antibiotics) is critical, since virtually every patient will
require antibiotic therapy.
* A history of prior herpes simplex infections
Studies — In addition to a history and physical examination, it is our
practice to perform the following pretreatment studies in patients
with AML (table 1):
* Laboratory studies include a complete blood count with
differential, chemistries with liver and renal function and
electrolytes, glucose, prothrombin time (PT), activated partial
thromboplastin time (aPTT), fibrinogen, lactate dehydrogenase (LDH),
calcium, phosphorus, uric acid, albumin and total protein, serum
lysozyme, and serology for herpes simplex virus (HSV), cytomegalovirus
(CMV), hepatitis A, hepatitis B, hepatitis C, and HIV infection. Human
leukocyte antigen (HLA) typing should be performed for patients who
are candidates for hematopoietic cell transplantation (HCT).
* Unilateral bone marrow aspiration with or without biopsy is
recommended for all patients. This sample should be sent for
pathologic review, immunophenotyping, cytochemistry, and cytogenetics.
Mutation analysis for c-KIT, FLT3-ITD, CEBPA, and NPM1 mutations
should be performed, if available. A core needle biopsy is
particularly useful if the marrow cannot be aspirated. Bilateral
biopsies are generally not required for AML, although they may be
informative if bone marrow necrosis is present. (See "Prognosis of
acute myeloid leukemia".)
* Central venous access must be placed. Two or three independent
ports aid medical management of transfusions, chemotherapy,
antibiotics, and other intravenous support. (See "Placement of central
venous catheters".)
* Dental evaluation for possible infection foci is warranted [2
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/2>
].
* A chest x-ray, an electrocardiogram (EKG) and a study of
cardiac function (eg, ejection fraction measured by echocardiogram or
MUGA) should be performed at baseline, especially for patients with a
cardiac history, prior anthracycline exposure, or cardiovascular
symptoms.
* Men and women with childbearing potential should receive
counseling about the potential effect of treatment on their fertility
and options for fertility-preserving measures. Women should have a
serum pregnancy test. Given the urgent need for treatment, options for
women are limited, but men can often participate in sperm banking.
(See "Preservation of fertility in patients undergoing cytotoxic
therapy".)
* Lymphocytotoxic (anti-HLA) antibody screen for multiparous
women and multi-transfused patients
* Patients with neurologic signs or symptoms should undergo
imaging studies to evaluate for meningeal disease, myeloid sarcoma
(chloroma), or central nervous system bleeding. Lumbar puncture is
indicated in symptomatic patients to examine the cerebrospinal fluid
(CSF) for leukemic involvement. This procedure is not routinely
performed in asymptomatic patients because of the risk of bleeding and
the theoretical possibility of introducing malignant cells into a
sanctuary site. If lumbar puncture is performed, CSF should be sent
for both cytology (examination of stained cytospin slides) and flow
cytometry.
The speed with which intensive remission induction chemotherapy should
begin varies with the individual patient's condition and treatment
options. In general, it is far more important to stabilize a patient's
condition and correct or control co-morbidities such as infection,
bleeding, hyperuricemia, renal dysfunction, anemia, and
thrombocytopenia, than it is to immediately start chemotherapy. Oral
hydroxyurea can be used for cytoreduction of an elevated peripheral
blast cell count while these problems are addressed. This interval of
several days also allows for complete genetic screening where the
results will have an impact on the choice of treatment.
CHEMOTHERAPY — Combination chemotherapy is the primary treatment
modality for patients with AML. There is no role for surgery or
radiation therapy in the induction phase. Options for induction
chemotherapy include standard or high dose cytarabine in combination
with an anthracycline. Approximately half of patients will require a
second induction cycle to obtain a complete remission. A "double
induction" regimen where induction chemotherapy is quickly repeated
for a second cycle is most frequently employed in Europe. The
following sections review these different treatment options.
For younger adults with newly diagnosed AML, we recommend remission
induction treatment with a combination of an anthracycline such as
daunorubicin for three days and "standard" dose cytarabine for seven
days (table 2) rather than an anthracycline plus high dose cytarabine
(HDAC). While HDAC may increase the complete remission rate in
patients less than 60 years of age, it does so at the cost of
increased toxicity. Treatment-related mortality, the rate of early
relapse, and overall survival are not clearly improved. This is
described in more detail below. (See 'High dose cytarabine' below.)
Standard dose cytarabine — The most commonly used induction regimens
for AML are the so-called "7+3" regimens, which combine a seven-day
continuous intravenous infusion of cytarabine (100 or 200 mg/m2 per
day) with a short infusion or bolus of an anthracycline given on days
one through three. The most commonly used anthracycline in this
regimen is daunorubicin, but other anthracyclines (eg, doxorubicin,
idarubicin) or synthetic anthracycline analogues (eg, mitoxantrone)
have been used.
Protocols that have substituted other anthracyclines, increased the
dose of cytarabine or daunorubicin, or added a third or fourth drug
have not improved response rates (table 2). Specifically, attempts to
improve response with potentially non-cross-resistant drugs have not
been successful (eg, fludarabine, etoposide, topotecan, thioguanine,
mitoxantrone) [3-11
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/3-11>
].
At present, there is no conclusive evidence to recommend one "7+3"
regimen over another [12
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/12>
]. Depending on dose, schedule, and patient selection criteria, they
have similar response rates and share common toxicities such as severe
degrees of myelosuppression with moderate mucositis, and diarrhea
[13-15 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/13-15>
].
Cytarabine plus daunorubicin — The most common remission induction
regimen used for patients with AML is standard dose cytarabine given
by continuous intravenous (IV) infusion for seven days plus
daunorubicin by intravenous push or short infusion daily for the first
three days. Standard "7+3" regimens for patients less than 60 years
old include:
* Cytarabine 100 mg/m2 for 7 days plus daunorubicin 90 mg/m2 for 3 days
* Cytarabine 200 mg/m2 for 7 days plus daunorubicin 60 mg/m2 for 3 days
Depending upon age and patient selection, 60 to 80 percent of younger
adults achieve a complete remission (CR) with this regimen [16-18
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/16-18>
]. Most remissions come after a single course.
In the past, daunorubicin had been commonly employed at a dose of 45
mg/m2 for some induction regimens. Randomized studies suggest that
higher doses of daunorubicin, up to 90 mg/m2 per day, may be more
effective than 45 mg/m2. In addition, dose escalation studies in
patients less than 60 years old have demonstrated that 90 mg/m2 of
daunorubicin can be safely combined with cytarabine and etoposide for
remission induction therapy [19
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/19>
].
A phase III trial of 657 adults (age 17 to 60 years) with untreated
AML randomly assigned induction therapy with seven days of continuous
IV infusion cytarabine (100 mg/m2 per day) plus three once-daily doses
of daunorubicin at either 45 or 90 mg/m2 [20
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/20>
]. Patients who attained a CR were offered consolidation therapy based
upon risk stratification with allogeneic hematopoietic cell
transplantation (HCT) or high-dose cytarabine, with or without
gemtuzumab ozogamicin. When compared with patients assigned to the 45
mg/m2 daunorubicin dose, patients assigned to the 90 mg/m2 dose had
the following significant outcomes:
* A higher CR rate (71 versus 57 percent)
* A longer median overall survival (24 versus 16 months)
* Similar rates of severe (grade 3/4/5) adverse events.
Specifically, there were similar rates of cardiac and hematopoietic
toxicity between the two groups and the higher dose of daunorubicin
did not appear to impair the ability to proceed with consolidation
therapy.
The CR rate for the 45 mg/m2 arm in this study was lower than that
reported in several other clinical trials using 60 mg/m2 of
daunorubicin in younger adults. A similar randomized trial in older
adults performed by another cooperative group also found higher CR
rates with 90 mg/m2 daunorubicin compared with 45 mg/m2 (52 versus 35
percent) [15 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/15>
]. There have been no randomized trials comparing 60 mg/m2 with 90
mg/m2 of daunorubicin. As such, we consider induction regimens
employing either 60 mg/m2 or 90 mg/m2 of daunorubicin to be
appropriate for younger adults with AML.
The combination of cytarabine plus daunorubicin results in severe
pancytopenia in all patients and therefore requires transfusion
support and antibiotics as needed. The median number of days with an
absolute neutrophil count less than 500 and a platelet count less than
50,000 are approximately 16 and 15, respectively. (See 'Cytopenias'
below and 'Infections' below.)
Common non-hematologic side effects seen in the majority of patients
include stomatitis (mostly mild), alopecia, nausea and vomiting (25
percent severe), and diarrhea (mostly mild). Daunorubicin can be
associated with an infusion reaction and cardiac arrhythmias; a
flu-like syndrome and rash due to cytarabine may be seen during
induction. These are discussed in more detail separately. (See
"Infusion reactions to systemic chemotherapy", section on
'Anthracyclines and related agents' and "Infusion reactions to
systemic chemotherapy", section on 'Cytarabine'.)
Cytarabine plus idarubicin — Cytarabine plus Idarubicin, a lipophilic
analogue of daunorubicin, has shown nearly equivalent CR rates,
survival, and cardiotoxicity when compared with cytarabine plus
daunorubicin in prospective randomized trials [21-24
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/21-24>
]. (See "Cardiotoxicity of anthracycline-like chemotherapy agents".)
A collaborative overview of five trials involving 1052 patients,
comparing idarubicin with daunorubicin or other anthracyclines, found
that idarubicin was associated with higher rates of CR (62 versus 53
percent) and five-year survival (13 versus 9 percent) [25
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/25>
]. There are concerns, however, that these comparative trials failed
to use equitoxic doses of anthracyclines; a higher daunorubicin dose
should have been used to directly compare with the idarubicin dose
used. Idarubicin may have greater cytotoxicity than daunorubicin
against leukemia cells that express the multidrug resistance (MDR)
phenotype [26 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/26>
].
Cytarabine plus mitoxantrone — Mitoxantrone is an anthracenedione, a
synthetic anthracycline analogue. It has been useful in combination
with conventional and high doses of cytarabine, both for primary
treatment and in relapsed disease [3,5,6
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/3,5,6>
]. It has also been used daily for five days (10 to 12 mg/m2/d)
together with etoposide and in high single doses (40 to 60 mg/m2) [7
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/7>
].
Gemtuzumab — The immunoconjugate gemtuzumab ozogamicin (GO), a
monoclonal CD33 antibody conjugated to calicheamicin has been
investigated in the setting of newly diagnosed AML. After a
feasibility study showed high CR rates with acceptable toxicity,
several prospective randomized trials incorporating GO into induction
and consolidation therapy were initiated [27
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/27>
]. So far only preliminary results are available for one of these
studies and therefore the drug cannot be generally recommended. The US
Food and Drug Administration has required that gemtuzumab be removed
from the market in the United.
High dose cytarabine — High dose cytarabine (HDAC) refers to
cytarabine doses of 1000 to 3000 mg/m2 administered intravenously over
one to three hours every 12 hours for 8 to 12 doses. This compares to
standard dose cytarabine, which is 100 mg/m2 per day given as a
seven-day continuous infusion. Two prospective randomized cooperative
group trials have evaluated the use of HDAC in combination with an
anthracycline for induction therapy in newly diagnosed AML (table 2).
* A trial by the Australian Leukemia Study Group randomly
assigned patients with AML to receive cytarabine at either standard or
high doses, in combination with daunorubicin and etoposide [28
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/28>
]. When compared with patients who received standard dose cytarabine,
patients who received HDAC demonstrated:
* Similar rates of complete remission (71 versus 74 percent) and
overall survival
* Significantly higher rates of complete remission after just
one induction (60 versus 48 percent)
* Significantly longer disease-free survival (DFS); for patients
who obtained a complete remission the estimated rate of five-year DFS
was 49 versus 24 percent.
* Significantly higher rates of leukopenia, thrombocytopenia,
nausea, vomiting, and eye toxicity
* In another prospective trial, 665 patients with newly
diagnosed AML were randomly assigned to receive induction therapy with
daunorubicin plus either HDAC or standard-dose cytarabine followed by
consolidation therapy [29
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/29>
]. There was no difference in the complete remission rate (45 to 58
percent). Patients who received HDAC had higher rates of
treatment-related mortality (12 versus 5 percent) and neurologic
toxicity. Young patients who were able to receive HDAC induction
followed by HDAC consolidation had superior four-year survival rates
when compared with patients who received standard dose cytarabine
followed by HDAC (52 versus 34 percent, respectively).
While HDAC may increase the initial complete remission rate in
patients less than 60 years of age, it does so at the cost of
increased toxicity [30
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/30>
]. Treatment-related mortality, the rate of early relapse, and overall
survival are not clearly improved [31
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/31>
]. We do not use HDAC routinely; however, HDAC alone could be
considered for patients who are not candidates for anthracyclines
during induction.
Double induction chemotherapy — Double induction chemotherapy refers
to the readministration of induction chemotherapy after the first
cycle of induction chemotherapy regardless of the initial response to
treatment. This approach has been used by some centers in Europe.
The effect of double induction therapy was explored in 725 patients
aged 16 to 60 (median age 44) with de novo AML [5
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/5>
]. All patients received induction treatment with TAD (6-thioguanine,
cytarabine (Ara-C), daunorubicin). This was followed on day 16 with
either a second induction course of TAD (TAD-TAD) or a course of HAM
(high dose Ara-C plus mitoxantrone) (TAD-HAM). Patients in complete
remission (CR) received a consolidation course of TAD followed by
monthly maintenance chemotherapy for three years. For patients who
achieved a CR who were less than 50 years of age with a
histocompatible sibling donor, allogeneic hematopoietic cell
transplantation was offered in place of maintenance chemotherapy.
Patients treated with either regimen had similar rates of complete
remission (68 percent) and five-year overall survival (31 percent).
Treatment with TAD-HAM was significantly better than TAD-TAD only for
a previously defined unfavorable subgroup (serum lactate dehydrogenase
>700 U/L, day 16 bone marrow blasts >40 percent, or unfavorable
cytogenetics); in these patients, TAD-HAM was associated with higher
rates of CR (65 versus 49 percent) and five-year survival (25 versus
18 percent).
The relative benefits provided from double induction chemotherapy
compared with a single course of intensive post-remission chemotherapy
or prolonged maintenance therapy are not clear [32
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/32>
]. Relatively low doses of chemotherapy given for maintenance,
although well tolerated, may delay relapse but do not appear to
increase the cure rate [33
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/33>
].
This was best demonstrated in a separate study of 832 patients with de
novo AML achieving CR following a TAD-HAM-TAD combination [33
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/33>
]. Treatment with monthly maintenance for three years, as compared
with one course of intensive consolidation therapy, led to superior
relapse-free survival in the subgroup of patients with poor prognosis
disease, although overall survival was not affected.
We do not administer double induction chemotherapy but routinely apply
two cycles of induction chemotherapy, if needed. We evaluate response
to the initial induction treatment with a bone marrow aspiration and
biopsy seven days after completion of induction chemotherapy. The
second course of induction is started with no further delay if
cytologically evident persisting disease (greater than 5 to 10 percent
of the marrow volume) is found. (See 'Evaluation of response' below.)
MONITORING DURING TREATMENT — Chemotherapy for AML is highly toxic,
primarily to the hematopoietic system and most patients will have a
prolonged hospital stay and will require blood product support. The
following are offered as guidelines for monitoring during induction
chemotherapy:
* Daily laboratory testing should be performed and generally
includes a complete blood count and chemistries with renal function,
glucose, and electrolytes. Calcium, phosphorus, and uric acid levels
should be monitored until normal. Liver function tests should be
assessed at least weekly.
* Patients receiving high dose cytarabine need a daily
neurologic examination during and for several days after
administration to evaluate cerebellar function. Commonly used tests
include finger-to-nose testing and monitoring of the patient's
signature, speech, and gait over time.
SUPPORTIVE CARE — Improvements in supportive care, especially the use
of transfusions and antibiotics, have enhanced the outlook for both
young and older patients with leukemia.
Anti-emetic prophylaxis — The ability of patients to tolerate
chemotherapy has improved considerably as the result of highly
effective anti-emetic medications. Even beyond improving patient
comfort, anti-emetic therapy enables patients to maintain their oral
hydration and nutritional status and avoid the risks of
gastrointestinal bleeding or even a Mallory-Weiss tear from forceful
vomiting. For young adults receiving cytarabine and daunorubicin or
high-dose cytarabine for AML, we prefer to premedicate with 16 mg of
ondansetron as monotherapy administered without steroids [34,35
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/34,35>
]. (See "Prevention and treatment of chemotherapy-induced nausea and
vomiting", section on 'Induction therapy for acute leukemia'.)
Cytopenias — All patients treated with traditional induction
chemotherapy will develop anemia and thrombocytopenia requiring
intervention. Red cells and platelets should be replaced as necessary.
Myeloid growth factors (eg, filgrastim, granulocyte colony-stimulating
factor) are not routinely used during remission induction chemotherapy
for AML [36 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/36>
].
Transfusions — In general, we transfuse packed red blood cells to
symptomatic patients with anemia or asymptomatic patients with a
hemoglobin ≤8 g/dL. We aim to maintain the hemoglobin between 8 and 10
g/dl. We transfuse platelets prophylactically for patients with
platelet counts <10,000/microL or to any patient with signs of overt
bleeding, such as oral purpura. Blood products should be leukocyte
depleted and irradiated to minimize the risk of immunologic mediated
events and infection, respectively. Cytomegalovirus (CMV) negative
patients who are candidates for hematopoietic cell transplantation
(HCT) should receive CMV negative blood products. (See "Indications
for red cell transfusion in the adult" and "Clinical and laboratory
aspects of platelet transfusion therapy", section on 'Hypoproductive
thrombocytopenia' and "Leukoreduction to prevent complications of
blood transfusion".)
Growth factors — Growth factors such as granulocyte-macrophage
colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating
factor (G-CSF) are not used routinely in patients undergoing induction
chemotherapy for AML. Their use in this setting has been studied both
in an attempt to decrease the duration of neutropenia and to
potentially sensitize or "prime" leukemia cells for chemotherapy
[36-43 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/36-43>
]. An alternative hypothesis is that growth factors may disrupt the
adhesion of leukemia blasts to the bone marrow niche thereby making
them more susceptible to chemotherapy circulating in the blood.
Virtually all trials showed a modest reduction in the duration of
severe neutropenia following the use of these growth factors, but
there has been no effect on the nadir, and the impact on the incidence
of severe infection, antibiotic usage, and the duration of
hospitalization has been variable [36,37,44
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/36,37,44>
]. There were no other significant effects on treatment outcome.
Differences in dose and schedule, specific growth factor and
chemotherapy agents used, and the particular disease (ie, AML or ALL)
and age group studied prevent firm conclusions.
A prospective, multicenter trial evaluated the use of G-CSF, given
immediately before and during chemotherapy but not after chemotherapy,
in 640 patients ≤60 years of age with newly-diagnosed AML [45
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/45>
]. Patients underwent double induction therapy with a combination of
cytarabine, idarubicin, and amsacrine. They were randomly assigned to
receive or not receive G-CSF during induction. Patients assigned to
receive G-CSF had the following outcomes when compared with those not
assigned to G-CSF:
* Similar rates of complete remission (79 and 83 percent,
respectively) and four-year overall survival (40 versus 35 percent,
respectively)
* Significantly higher rates of four-year disease-free survival
after the first CR (42 versus 33 percent) with a decreased rate of
relapse
* In a subgroup analysis, G-CSF priming did not improve outcome
in those with an unfavorable karyotype. However, among patients with
standard-risk AML there was improved overall survival and disease-free
survival.
This benefit on subset analysis was confirmed with the growth factor
GM-CSF in another multicenter prospective trial [43,46
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/43,46>
]. However, the long-term safety of these agents in leukemia patients
remains to be determined.
For the time being, the use of myeloid growth factors during remission
induction chemotherapy for AML is not routinely recommended [36
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/36>
]. (See "Prophylaxis of infection during chemotherapy-induced
neutropenia" and "Fever in the neutropenic adult patient with cancer",
section on 'Myeloid growth factors'.)
Infections — The prolonged period of neutropenia associated with
chemotherapy in patients with AML is frequently associated with
neutropenic fevers and a high risk of infection with bacteria or fungi
and viral reactivation. In order to minimize the risk of infection,
patients are typically placed on "neutropenic precautions" with or
without the addition of prophylactic antibiotics, antifungals, or
antivirals. In addition, patients should be screened for possible
infectious foci (eg, dental status).
Precautions — The majority of infections acquired during induction
therapy are due to endogenous flora. Even so, precautions are taken to
limit exposure to exogenous pathogens. As such, patients are routinely
placed on "neutropenic precautions," the components of which vary by
institution. (See "Fever in the neutropenic adult patient with
cancer", section on 'Environmental precautions'.)
Most commonly, these precautions include the following:
* A high-efficiency particulate air (HEPA)-filtered room
* Diet free of raw fruit or fresh vegetables
* No sick visitors
* No fresh flowers
* No smoking
While routinely part of "standard precautions," hand washing by all
visitors and caregivers cannot be over-emphasized and should be
strictly enforced. Most of the other precautions have not been tested
in prospective, randomized trials but have been used because they are
relatively simple to institute and are logical ways to limit exposure
to potential pathogens.
The benefit of a neutropenic diet was examined in a prospective,
randomized trial of 153 patients with newly diagnosed AML undergoing
induction therapy [47
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/47>
]. Patients were randomly assigned to diets either containing raw
fruits or vegetables (raw diet) or not (cooked diet). Patients
randomly assigned to the cooked diet had similar rates of major
infection when compared with those who received the raw diet (35
versus 29 percent, respectively). There was no difference in overall
survival.
Prophylaxis — The Infectious Disease Society of America (IDSA)
recommends that herpes simplex virus (HSV)-seropositive patients with
leukemia receive acyclovir antiviral prophylaxis [48
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/48>
]. The use of prophylactic antibiotics and antifungals varies by
institution. Some institutions administer prophylaxis with
fluoroquinolones and/or antifungals (eg, fluconazole, itraconazole,
posaconazole, voriconazole, or amphotericin B) during the period of
neutropenia [49
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/49>
]. The effectiveness of these interventions varies among institutions
depending upon the local flora and results of surveillance cultures.
The possibility of benefit is balanced by the concern for selecting
for drug-resistant organisms. Pneumocystis pneumonia and CMV
infections, which commonly require prophylaxis in patients with ALL or
following hematopoietic cell transplantation, are rarely observed in
AML patients. (See "Prophylaxis of infection during
chemotherapy-induced neutropenia", section on 'Antimicrobial
prophylaxis'.)
Treatment — Patients who develop neutropenic fever require prompt
evaluation and immediate administration of parenteral antibiotics
tailored to the prominent organisms and resistance patterns of the
institution. (See "Fever in the neutropenic adult patient with
cancer".)
Tumor lysis — There is a risk of tumor lysis syndrome in patients
treated for AML. The risk is highest among patients with
hyperleukocytosis but can be observed in any subtype. This syndrome is
best prevented via appropriate treatment with intravenous hydration to
ensure adequate urine flow (>100 ml/hour), rasburicase or allopurinol,
and correction of any electrolyte disturbances and elements of
reversible renal failure (table 3). (See "Tumor lysis syndrome",
section on 'Prevention'.)
Menorrhagia — Premenopausal women are at risk for severe and prolonged
menorrhagia during induction therapy. (See "Heavy or irregular uterine
bleeding during chemotherapy".)
Other complications — Other complications that may develop during AML
treatment, such as electrolyte abnormalities, hyperleukocytosis,
disseminated intravascular coagulation, necrotizing enterocolitis, and
involvement of the eyes, joints, and central nervous system, are
presented separately. (See "Overview of the complications of acute
myeloid leukemia".)
EVALUATION OF RESPONSE — The initial response to treatment is
typically evaluated seven days after the final doses of induction
chemotherapy with a unilateral bone marrow aspirate and biopsy. A core
biopsy is required to assess marrow cellularity:
* If hypoplasia with a cellularity less than 5 percent is
documented, most patients will recover with normal hematopoiesis. A
repeat aspiration and biopsy is performed once adequate values for
absolute neutrophil count (>1000/microL) and platelet count
(>100,000/microL) are obtained and the patient is independent from red
cell transfusions. (See "Remission criteria in acute myeloid leukemia
and monitoring for residual disease".)
* If the bone marrow cellularity is above 5 percent at this time
and indeterminate for residual AML, a repeat bone marrow is
recommended in 7 to 14 days.
* If residual leukemic blasts (greater than 5 to 10 percent of
the marrow volume) were found on the bone marrow aspirate or biopsy, a
second cycle of induction is recommended if the patient can tolerate
immediate retreatment. If the initial induction therapy had been
cytarabine plus daunorubicin, these same drugs are usually employed
for five and two days, respectively. One meta-analysis of sequential
cooperative group protocols conducted between 1983 and 1993 suggested
that patients who attain a complete remission (CR) after this second
cycle of induction have a similar prognosis to those who attain a CR
with initial induction [50
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/50>
].
The central nervous system (CNS) can be a sanctuary site for occult
disease. Once a complete remission is documented by bone marrow
aspiration and biopsy, a lumbar puncture to evaluate for CNS
involvement is recommended particularly for patients with a high white
blood cell count (>100,000/microL) at the time of diagnosis. This
should also be considered for patients with a monoblastic phenotype,
inv(16), or CD56 positivity. A review of the treatment of this
complication can be found elsewhere. (See "Involvement of the central
nervous system with acute myeloid leukemia".)
POST-REMISSION TREATMENT — Attainment of a complete remission is the
first step in the treatment of AML. However, relapse can be expected
in the following weeks to months if no further therapy is given.
Postinduction or "remission consolidation" therapy is an essential
component of the treatment of AML. This is presented separately. (See
"Post-remission therapy for acute myeloid leukemia in younger
adults".)
SPECIAL SCENARIOS
Pregnancy — AML is occasionally diagnosed during pregnancy. If
detected during the first trimester, immediate termination of
pregnancy followed by treatment of the leukemia is advisable, as
combination chemotherapy given during this time is associated with an
unacceptably high incidence of fetal abnormalities and/or fetal loss.
As an example, a literature review reported rates of fetal death,
malformation, or spontaneous abortion of 4, 11, and 7 percent,
respectively, when anthracyclines were given during the first
trimester [51 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/51>
].
The management of patients diagnosed later in pregnancy, such as late
in the second trimester or during the third trimester, poses a
difficult therapeutic dilemma. In the latter group of patients, if the
leukemia is relatively indolent, it is sometimes possible to manage
patients conservatively with leukapheresis and/or transfusion, with
induction of labor and delivery of a viable fetus as soon as possible
[52 <http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/52>
]. However, it is often difficult if not impossible to predict whether
the AML will take an indolent course for some weeks. The hazard of a
delay of adequate AML treatment until delivery should be carefully
considered as it may imply a significant risk to the mother.
There have been many reports of patients treated with chemotherapy
later in their pregnancy [51,53-57
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/51,53-57>
]. The majority of these women have not aborted. There have been no
reports of leukemia occurring in the children, nor an increased
incidence of fetal abnormalities in infants who have been exposed to
full-dose antileukemia chemotherapy during the later stages of
gestation. A literature review of 160 pregnant patients treated with
anthracyclines for a variety of malignancies, reported the delivery of
normal infants in 73 percent of patients [51
<http://www.uptodate.com/contents/induction-therapy-for-acute-myeloid-leukemia-in-younger-adults/abstract/51>
]. Common unfavorable fetal outcomes included fetal death (9 percent),
prematurity (6 percent), and malformations (3 percent).
Therapy-related AML — Therapy-related myeloid neoplasms account for
approximately 10 to 20 percent of all cases of AML, myelodysplastic
syndrome (MDS), and myelodysplastic syndrome/myeloproliferative
neoplasms (MDS/MPN). This is presented separately. (See
"Therapy-related myeloid neoplasms: Acute myeloid leukemia and
myelodysplastic syndrome".)
CLINICAL TRIALS — Often there is no better therapy to offer a patient
than enrollment onto a well-designed, scientifically valid,
peer-reviewed clinical trial. Additional information and instructions
for referring a patient to an appropriate research center can be
obtained from the National Cancer Institute or any of the national
cooperative group headquarters: Cancer and Leukemia Group B
(www.calgb.org <http://www.calgb.org/> ), the Eastern Cooperative
Oncology Group (ecog.dfci.harvard.edu <http://ecog.dfci.harvard.edu/>
), or the Southwest Oncology Group (swog.org <http://swog.org/> ).
INFORMATION FOR PATIENTS — Educational materials on this topic are
available for patients. (See "Patient information: Acute myeloid
leukemia (AML) treatment in adults".) We encourage you to print or
e-mail this topic, or to refer patients to our public website
www.uptodate.com/patients, which includes this and other topics.
SUMMARY AND RECOMMENDATIONS
The treatment of acute myeloid leukemia (AML) begins with an initial
course of intensive combination chemotherapy referred to as "remission
induction therapy" with a goal of obtaining a complete remission.
For younger adults with newly diagnosed AML, we recommend remission
induction treatment with a combination of an anthracycline such as
daunorubicin for three days and "standard" dose cytarabine for seven
days (table 2) rather than an anthracycline plus high dose cytarabine
(Grade 1B). Depending upon age and patient selection, 60 to 80 percent
of younger adults achieve a complete remission with this regimen.
Equicytotoxic doses of other anthracycline-like drugs (eg, idarubicin,
mitoxantrone) are probably equally effective. There is little evidence
that adding a third drug (eg, etoposide) improves short or long-term
effectiveness, and this may result in additional toxicity. (See
'Standard dose cytarabine' above.)
Induction chemotherapy is highly toxic, primarily to the hematopoietic
system, and requires careful monitoring to evaluate for cytopenias,
infections, bleeding, tumor lysis syndrome, electrolyte imbalances,
and other complications. (See 'Monitoring during treatment' above and
'Supportive care' above.)
The initial response to treatment is evaluated 7 to 10 days after
completion of induction chemotherapy with a unilateral bone marrow
aspirate and biopsy. A lumbar puncture should be performed at the time
of documented complete remission for a subset of patients. (See
'Evaluation of response' above.)
Attainment of a complete remission is the first step in the treatment
of AML. However, relapse can be expected in the following weeks to
months if no further therapy were given. Postinduction or "remission
consolidation" therapy is an essential component of the treatment of
AML. This is presented separately. (See "Post-remission therapy for
acute myeloid leukemia in younger adults".)
Use of UpToDate is subject to the Subscription and License Agreement
<http://www.uptodate.com/contents/license> .
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