immediately after birth

and continued for 6 weeks. It is recommended that the infant

undergo diagnostic virologic testing using either HIV DNA PCR

or RNA virologic assays at a minimum at ages 14 to 21 days,

1 to 2 months, and 4 to 6 months. Antibody testing should not be

performed on the infant because maternal HIV antibody crosses

the placenta and will be detectable in all HIV-exposed infants up

to 18 months of age.75

It is not recommended that HIV-positive women breast-feed

their children in resource-rich settings where clean water and

formula are reasonably available. The risk of transmission from

breast-feeding is consistently higher than formula feeding even

with the use of antiretroviral prophylaxis.164

Postexposure Prophylaxis

CASE 73-6

QUESTION 1: L.T. is a 47-year-old nurse at an HIV clinic.

While drawing routine labs on a newly diagnosed HIV+ male

patient, not yet started on HAART, she accidently stuck herself with a contaminated needle. Are interventions available

to prevent L.T. from contracting HIV from the needlestick?

What drugs should be utilized, and for how long?

Occupational postexposure prophylaxis (PEP) recommendations are dependent on the type of exposure and the risk factors

associated with that exposure. For example, percutaneous exposure poses more of a concern than mucous membrane exposure.

A needle stick with a large hollow-bore needle is higher risk

that a solid needle, a deep penetrating wound is considered a

high-risk exposure compared to a superficial injury, and a exposure to a large volume of infectious fluid is more concerning

than exposure to a low volume. Patient-specific factors must also

be considered, such as whether the HIV-positive patient is on

HAART therapy and has a suppressed viral load or whether the

HIV-positive patient currently has a high viral load.

Basic two-drug PEP is generally recommended for less severe

percutaneous exposures (solid needle or superficial injury) from

an HIV-positive patient who is suppressed on antiretrovirals, a

patient with an unknown HIV status who has HIV risk factors, or

for mucous membrane exposures. Basic two-drug PEP generally

consists of two NRTIs such as zidovudine, stavudine, or tenofovir

with lamivudine or emtricitabine.165

1715Pharmacotherapy of Human Immunodeficiency Virus Infection Chapter 73

TABLE 73-8

Human Immunodeficiency Virus Internet Resources

Government Sites

American Foundation for AIDS Research: http://www.amfar.org

AIDSinfo from US DHHS: http://www.aidsinfo.nih.gov

Centers for Disease Control and Prevention: http://www.cdc.gov

Consensus Panel Guidelines Online: http://www.aidsinfo.nih.gov

Government HIV Mutation Charts: http://hiv-web.lanl.gov

National Institute of Allergy and Infectious Diseases: http://www.

niaid.nih.gov

National Prevention Information Network: http://www.cdcnpin.

org

United Nations AIDS Website: http://www.unaids.org/

University Sites

Johns Hopkins AIDS Service: http://www.hopkins-aids.edu

University of California, HIV/AIDS Program: http://hivinsite.ucsf.

edu

University of Stanford HIV Drug Resistance Database: http://hivdb.

stanford.edu/

AIDS Treatment/Advocacy Groups

Project Inform: http://www.projinf.org

San Francisco AIDS Foundation: http://www.sfaf.org/index.html

Other Relevant Sites

The AIDS Map: http://www.aidsmap.com

AIDS Education Global Information System: http://www.aegis.com

Clinical Care Options: http://www.clinicalcareoptions.com

HIV Drug Interactions: http://www.hiv-druginteractions.org

HIV and Hepatitis: http://hivandhepatitis.com

HIV Pharmacology: http://www.hivpharmacology.com

HIV Resistance Web: http://www.hivresistanceweb.com

HIV Treatment Information: http://www.i-base/info

Medscape: http://www.medscape.com

Physician’s Research Network: http://www.prn.org

The Body for Clinicians: http://www.thebodypro.com

Retrovirus Conference: http://www.retroconference.org

Expanded three-drug PEP is recommended for more severe

percutaneous exposures (large-bore hollow needle or deep

puncture wound) from suppressed HIV-positive patients and

more-than-three–drug PEP is indicated for percutaneous exposures where the patient has a high viral load or acute infection

or from similar patients if there is a large volume mucous membrane exposure. In these instances, the choice of agents to use for

PEP is generally dependent on the patient’s regimen and resistant

profile.165

L.T. should start immediately on an expanded basic regimen

of at least three drugs consisting of two of the NNRTIs recommended for basic two-drug PEP with the addition of a PI, preferably lopinavir–ritonavir. This entire regimen should be continued

for a total of 4 weeks. It would also be a good idea to look at the

specific patient from which the exposure occurred. If he had

a great deal of known antiretroviral drug resistance, then L.T.

may need to be put on different antiretrovirals according to the

patient’s resistance profile. HIV antibody testing using ELISA

should be performed on L.T. at baseline exposure, 6 weeks,

12 weeks, and 6 months after exposure. She should also have

baseline and follow-up labs performed to assess antiretroviral

toxicity. At a minimum, these should include a complete blood

count, renal and hepatic function tests, and fasting glucose while

on the protease inhibitor. Additional laboratory tests should be

performed based on the individual drugs chosen.165

Additional guidelines exist for non-occupational HIV exposures and follow similar risk and stratification treatment

paradigms. In those instances where a person seeks care within

72 hours of exposure to blood, genital secretions or other potentially infected body fluids of persons known to be HIV-infected

and the exposure represents a substantial risk for HIV transmission then the person is started on PEP in a similar fashion as with

an occupation exposure and continued for 4 weeks with similar

monitoring and HIV testing.166

KEEPING CURRENT

The management of HIV infection continues to evolve. Additional important emerging data are in HIV prevention and cure.

The overwhelming data presented at scientific meetings and

in journals has made staying informed about current issues and

new developments a daunting task. As a result, many clinicians, even those actively caring for patients who are HIV

infected, remain cautious and often confused regarding therapeutic options.

New technologies for the dissemination of medical information are constantly evolving. The Internet has allowed clinicians

worldwide to exchange ideas, teach new concepts, and obtain

access to limited resources. In addition, many research centers,

patient advocacy groups, and academic institutions have posted

sites on the Internet that have resulted in access to large amounts

of high-quality medical information. This new technology has

also allowed, however, for the dissemination of incomplete, misleading, or inaccurate information. Therefore, clinicians must

remain cautious and carefully evaluate the information obtained

from various websites.

When evaluating the quality of a website, clinicians should

look for a few basic standards.

 Author qualifications. Is the author qualified to write the article or perform the research? Is his or her affiliation or relevant credentials provided?

 Attribution. Are references provided to confirm statements?

Is all relevant copyrighted information noted?

 Currency. When was the content posted? Is the website

updated regularly?

 Disclosure. Who owns the website? Is there a conflict of

interest between what is being posted and any commercial

interest?

Any Internet site that fails to meet these basic competencies

should be viewed with caution. In general, the most accurate and

informative websites for HIV-specific information come from

academic institutions, government organizations, medical societies, and patient advocacy groups. Table 73-8 lists high-quality

websites that provide timely and accurate information. A periodic

evaluation of these sites often provides sufficient information to

stay up-to-date on current issues and controversies.

CONCLUSION

Despite significant advances made in the treatment of patients

infected with HIV, a cure continues to be out of reach. Although

the pharmacologic management of HIV is rapidly evolving, a

basic understanding of viral pathogenesis and drug interactions

provides a framework that can be used to evaluate new information as it becomes available.

2Section 15 Psychiatric Disorders

an increased dosage of fluoxetine (60 mg/day) for 5 additional

weeks.158 At the end of the study period, 49% of the patients

receiving 20 mg converted to full responders, suggesting that

3 weeks is an inadequate period to confidently assess patient

response. Because 50% of the patients receiving 60 mg/day converted to full responders, it may also be inferred that dosage

increases are not necessary in many patients.

Drug Selection

SEROTONIN NOREPINEPHRINE REUPTAKE

INHIBITORS

CASE 83-2, QUESTION 2: After a careful interview and

workup, it was determined that F.H. is suffering from an

acute episode of major depression with a probable history

of dysthymia as well (i.e., double depression). She denies

substance abuse, which is supported by a subsequent toxicology screen. From her medical chart and interview, it is

confirmed that she received a therapeutic trial of nortriptyline and fluoxetine with inadequate clinical benefit. She is

not interested in psychotherapy. Her provider decides to

start venlafaxine (37.5 mg XR preparation daily). Is this a

reasonable choice for F.H.?

Because 30% to 40% of patients will effectively achieve remission and about 20% to 25% of patients will stop an antidepressant

because of side effects, it is safe to say that most patients started

on a given antidepressant ultimately need a significant adjustment or change to their original regimen.159 Clinicians, therefore, are obligated to have a thorough understanding of several

antidepressant medications and classes if they are to facilitate

successful outcomes.

In F.H.’s case, she has previously failed a therapeutic trial of

nortriptyline and is currently expressing vague suicidality, so an

alternate TCA would not be a reasonable choice (see full discussion of TCAs in the text that follows). Although she has also failed

a fluoxetine trial, open-label studies and large controlled investigations suggest that 50% to 70% of patients who are unresponsive

or intolerant of one SSRI will experience a therapeutic response

to a different SSRI.158,160,161 For example, in the STAR∗D trial,

patients failing an initial course of citalopram were just as likely

to respond if they were randomly assigned to a subsequent trial of

a different SSRI (sertraline) as they were to other antidepressant

classes (venlafaxine and bupropion, specifically).162 If a different

SSRI is to be initiated, it may be wise to opt for one with fewer

activating properties than fluoxetine (e.g., sertraline, paroxetine,

citalopram, escitalopram) because F.H. is complaining of feeling

jumpy and irritable. Alternatively, a medication from a different

antidepressant class possesses the hypothetical benefit of a unique

mechanism of action (e.g., venlafaxine, bupropion). Because of

the severity of F.H.’s depressive symptoms, a sense of urgency

should prevail and an alternate treatment is justified.

Venlafaxine was the first member of a relatively new class of

antidepressants released in the United States known as SNRIs.

Duloxetine, which possesses a very similar mechanism of action,

was the second SNRI approved for the treatment of depression,

and desvenlafaxine, the active metabolite of venlafaxine, recently

became the third member of this class.163 Studies in severe melancholic depression and treatment-resistant depression suggest that

venlafaxine is at least as effective as other antidepressants in

these populations, and it has emerged as a valuable alternative agent.164–166At dosages less than 150 mg/day, venlafaxine’s

therapeutic effects are mediated exclusively from the blockade

of serotonin reuptake. Therefore, associated adverse effects at

these dosages are qualitatively and quantitatively very similar to

those found with SSRIs: GI distress, sleep disturbances, and sexual

dysfunction. At higher dosages, effects on norepinephrine occur,

and this can lead to the emergence of different adverse effects

(e.g., tachycardia and hypertension). Duloxetine and desvenlafaxine enhance the activity of these two neurotransmitters as well,

though their mechanism of action is not believed to be dosedependent.167

Venlafaxine has a relatively brief plasma half-life (5–8 hours)

and is demethylated to an active metabolite (O-desmethylvenlafaxine) that has a short half-life as well (11 hours). This

metabolite, desvenlafaxine, was approved by the FDA in 2008

for the treatment of depression. Desvenlafaxine is commercially

available as an extended-release tablet that has a similar mechanism of action as venlafaxine. It has no affinity for muscarinic, histaminic, cholinergic, or adrenergic receptors and has a terminal

half-life of 11 hours.168 Desvenlafaxine is not affected by CYP2D6

inhibitors; however, CYP3A4 inhibitors may reduce clearance

of the drug.168 Duloxetine also has a relatively short half-life

(12 hours) and, as with the SSRIs, withdrawal reactions may occur

when duloxetine is abruptly discontinued after chronic administration. Venlafaxine is not a potent inhibitor of cytochrome

P-450 isoenzymes, so drug interactions are less of a concern than

with certain SSRIs, but duloxetine is a moderate inhibitor of the

CYP2D6 isoenzyme. All SNRIs have been associated with serotonin syndrome, so clinicians should be aware of the potentially

dangerous drug combinations.169

For F.H., the choice of venlafaxine seems to be prudent. It is

fairly safe in overdose, possesses a unique mechanism of action,

and is generally less activating than fluoxetine (which had provoked some irritability in F.H.). In comparison to SSRIs, venlafaxine possesses a wide therapeutic range and ordinarily requires

more dosage titration (which can increase resource utilization).

A starting dose of 37.5 mg (XR) is reasonable, but baseline vitals

should be recorded for F.H. with every dosage change in order

to monitor the effect of this SNRI on her blood pressure and

heart rate. Most patients respond to daily doses between 150

and 225 mg. Because F.H. is suffering from a relatively severe

depression, it may be wise to increase her daily dose to 75 mg

once she has exhibited good tolerance (i.e., after 4–7 days). In

the event that F.H. has not exhibited a satisfactory response to

75 mg/day after 4 weeks, the dosage may be increased in increments of 37.5 to 75 mg every few weeks to a daily maximum

of 225 mg. Although daily doses of the XL preparation above

225 mg are not recommended by the manufacturer, anecdotal

success and relative safety have been reported for doses as high

as 300 mg daily.170

OTHER AGENTS: BUPROPION AND MIRTAZAPINE

CASE 83-2, QUESTION 3: Are there any other antidepressants to consider if F.H. fails her venlafaxine trial?

Bupropion is an aminoketone with a mechanism of action

that is clearly different from that of any other antidepressant that

has received FDA approval. The direct effects of bupropion on

serotonin transmission are negligible, but it may act by enhancing dopamine and/or norepinephrine activity.171 At therapeutic

dosages, bupropion has an attractive adverse effect profile, limited to occasional nausea and insomnia or jitteriness. Seizures,

which were reported shortly after it was released in 1985, appear

to be very unlikely with therapeutic dosing of bupropion, provided that patients are not predisposed (e.g., history of epilepsy,

bulimia, or recent history of heavy drinking). Bupropion is

one of the few antidepressants that may decrease appetite. A

randomized, placebo-controlled investigation of bupropion in

depressed obese patients observing caloric restriction found that

bupropion was much more likely to induce significant weight

loss than placebo.172 After 26 weeks of treatment, 40% of the

1973Mood Disorders I: Major Depressive Disorders Chapter 83

bupropion-treated patients lost more than 5% of their total body

weight versus 16% with placebo. This weight loss was positively

correlated with an improvement in depressive symptoms.

Bupropion is converted via the cytochrome CYP2B6 isoenzyme to an active metabolite (9 hydroxybupropion). Bupropion

(and its metabolite) appears to have a moderate affinity for inhibiting the CYP2D6 isoenzyme, and significant elevations of venlafaxine and metoprolol have been demonstrated to occur with

concurrent administration. Because of its short half-life (approximately 8 hours for the parent compound and 12 hours for the

active metabolite), therapeutic doses of regular release bupropion must be administered in divided doses. The recommended

starting dose is 100 mg twice a day (BID), increasing to 100 mg

three times a day (TID) after at least 3 days. Individual doses must

not exceed 150 mg and should be given at least 6 hours apart.

An SR preparation is available though it is usually administered

in multiple daily doses as well. For the SR formulation, initial

daily doses are 150 mg every day, increased to 150 mg BID by the

fourth day at the earliest. Individual doses of bupropion SR can

be as large as 200 mg, and divided doses should be given at least

8 hours apart. More recently, a once-daily formulation has been

developed (XL) and the package insert recommends initiating

at 150 mg daily and increasing to 300 mg daily as early as the

fourth day. Maximum daily doses are 450 mg for regular and XL

products, and 400 mg for SR products.

Mirtazapine is a novel antidepressant capable of modulating

serotonin and norepinephrine activity through a complex mechanism of action. In vitro studies reveal that mirtazapine is an antagonist at presynaptic α2-autoreceptors and postsynaptic 5-HT2

and 5-HT3 receptors.173 In addition, it appears to possess some

mild inhibitory properties at serotonin reuptake transporters.

Therefore, the net effect of mirtazapine is to enhance serotonin

and norepinephrine albeit in a manner that is clearly distinct from

any other antidepressants. In a comparative randomized trial

with fluoxetine for moderate to severe depression, mirtazapine

appeared to be much more effective than fluoxetine after 4 weeks

of treatment (58% responders vs. 30% with fluoxetine; p <0.05),

but the differences were no longer significant at 6 weeks (63%

vs. 54%; p = 0.67).174

The most common adverse effects experienced with mirtazapine are sedation and weight gain. Because mirtazapine has

potent antihistaminergic effects, it can be quite sedating. Anecdotally, it has been reported that higher daily doses of mirtazapine (>30 mg) are less sedating than lower doses owing to an

increase in noradrenergic effects. In addition to the substantial

risk of increasing appetite and total body weight, mirtazapine

has been associated with significant increases in total cholesterol

and triglycerides.175 The recommended starting dosage is 15 mg

at bedtime, and the therapeutic dosage ranges from 15 to 45

mg/day.175 Data from controlled trials have demonstrated safety

and efficacy in doses up to 60 mg daily.174,176

Irreversible MAOIs (e.g., phenelzine, tranylepromine) may

also be an alternative for patients who have failed multiple antidepressant trials. Like venlafaxine, TCAs, and mirtazapine, MAOIs

are believed to relieve depressive symptoms by enhancing the

activity of multiple neurotransmitters, which may be desirable

for refractory cases. Because serious drug and dietary interactions

are encountered with MAOIs, candidates for treatment should

be chosen carefully; a full discussion of the clinical usefulness of

MAOIs can be found in the Depression with Atypical Features

section at the end of this chapter.

Antidepressant Augmentation

CASE 83-2, QUESTION 4: Three months later, F.H. reports

that she feels less hopeless on venlafaxine XR (150 mg/day)

TABLE 83-18

Partial Response to Antidepressant Treatment Augmentation

Strategies (with SSRIs)

Ensure completion of full therapeutic trial (4–6 weeks).

Ensure optimal dose of antidepressant.

Consider augmentation therapies:  Bupropion

 Lithium

 Thyroid supplements

 Pindolol (?)

 Buspirone

 Atypical antipsychotics

 Modafinil

 Lamotrigine

SSRI, selective serotonin reuptake inhibitor.

and that her appetite has improved as well. However, she

is still somewhat depressed and lethargic and attempts to

increase her dosage have been limited by nausea and recurring insomnia. What pharmacologic options remain to help

manage her refractory depression?

Because F.H. has obtained considerable relief from her venlafaxine trial but is experiencing dose-limiting side effects, one

would prefer to add a second medication (i.e., augmentation

therapy) rather than changing antidepressants at this time (Table

83-18). A reasonable next step would be to augment her current

venlafaxine regimen with another medication such as lithium,

thyroid hormone, bupropion, or buspirone.

Lithium’s antidepressant properties appear to apply to both

unipolar and bipolar patients. Seven of nine antidepressant augmentation trials with lithium have reported positive therapeutic

effects, usually within 1 week of achieving steady-state dynamics

(i.e., 3–7 days of daily dosing).177 Effective lithium blood levels are

generally within the range used to treat bipolar disorder (0.5–1.2

mEq/L). As with the use of lithium therapy in bipolar disorder, all

appropriate clinical monitoring parameters should be followed

carefully (see Chapter 80, Anxiety Disorders).

Triiodothyronine (T3) also has a long history of use in psychiatric circles for patients exhibiting partial or suboptimal responses

to antidepressant monotherapy. Five of six RCTs support the use

of T3 supplementation for antidepressant augmentation, with

an average effect size of 0.58 reported.178 Triiodothyronine, at a

dosage of 25 mg/day, can accelerate as well as augment antidepressant response, and superior effects have been reported in

female patients, in particular. The response to the thyroid supplementation should be noticeable within 1 to 2 weeks, much

like that found when lithium is used to augment therapy. Thyroxine (T4) may also be effective with typical daily doses of 75

to 100 mcg daily often used. Whether T3 is superior to T4 has

not been resolved, although one study seemed to indicate that

more patients respond to T3 than to T4.

178 In the recently concluded STAR∗D trials, T3 was compared to lithium for antidepressant augmentation with citalopram in patients with two previous treatment failures.179 Remission rates were modest for both

agents in this challenging population (24.7% with T3 vs. 15.9%

with lithium) and there was no significant difference between

these two therapies.

Bupropion has been used as augmentation therapy for many

years and its use is supported by several open-label trials and

one RCT.180,181 Patients who continue to complain of fatigue,

hypersomnia, or executive dysfunction on SSRI or SNRI therapy

are excellent candidates for bupropion augmentation, and the

combination treatment is usually well tolerated. In the STAR∗D

trial, augmentation with bupropion was compared to buspirone

CHRONIC LYMPHOCYTIC LEUKEMIA

1 Common treatment regimens for chronic lymphocytic leukemia (CLL) in patients

without significant comorbidities include combinations of rituximab with

fludarabine, cyclophosphamide, or bendamustine. Patients unable to tolerate a

purine analog are treated with single-agent rituximab, chlorambucil-prednisone, or

pulse steroids.

Case 92-4 (Question 3)

2 Infectious complications are common in patients with CLL. For recurrent infections,

immune globulin treatment may be indicated. Vaccinations to prevent influenza

and pneumococcus are indicated. Live vaccines including varicella zoster virus

must be avoided.

Case 92-4 (Question 5)

MULTIPLE MYELOMA

1 Multiple myeloma (MM) generally begins as a benign condition known as

monoclonal gammopathy of undetermined significance. This condition may

precede MM by years before transforming into a malignant disorder with clinical

manifestations.

Case 92-5 (Question 1)

2 Induction therapy followed by hematopoietic cell transplantation in eligible

patients is the standard of care and has increased overall survival in MM patients.

Case 92-5 (Question 2)

3 Supportive care of MM patients includes the prevention and treatment of skeletal

disease, and should be considered in conjunction with induction therapy.

Case 92-5 (Question 3)

4 MM is not generally curable, even with maintenance therapy. Therefore, relapse

usually occurs, and salvage therapies are commonly used.

Case 92-5 (Questions 4, 5)

LYMPHOMA

1 Non–Hodgkin lymphomas (NHLs) arise from either B, T, or natural killer cells;

approximately 80% are B-cell neoplasms. Aggressive NHLs are potentially curable

and are typically treated with rituximab, cyclophosphamide, doxorubicin,

vincristine, and prednisone.

Case 92-6 (Questions 1, 2)

2 Indolent NHLs respond well to therapy but the disease eventually recurs and is

generally incurable.

Case 92-7 (Question 2)

3 Hodgkin lymphoma (HL) is a highly curable, chemotherapy-sensitive disease, and

administration of full doses given on schedule is critical. The most commonly used

regimen includes doxorubicin, bleomycin, vinblastine, and dacarbazine.

Case 92-8 (Question 2)

ACUTE MYELOID LEUKEMIA

Epidemiology

Acute myeloid leukemia (AML, also known as acute myelogenous leukemia and, less commonly, as acute non–lymphocytic

leukemia) consists of a group of relatively well-defined

hematopoietic neoplasms involving precursor cells committed

to the myeloid line of cellular development.

In the United States and Europe, the incidence has been

stable at 3 to 5 cases per 100,000. AML is the most common

acute leukemia in adults and accounts for approximately 80%

of cases in this group of neoplasms. In contrast, AML accounts

for less than 10% of acute leukemias in children younger than

10 years of age. In adults, the median age at diagnosis is approximately 67 years. The incidence increases with age with approximately 1.3 and 12.2 cases per 100,000 for those younger than

or older than 65 years, respectively. The male to female ratio is

approximately 5:3.1,2 See the surveillance, epidemiology, and

end results (SEER) data for AML at http://seer.cancer.gov/

statfacts/html/amyl.html#prevalence.

Pathophysiology

AML is characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into more mature cellular elements. As a result, there is an accumulation of leukemic

blasts in the bone marrow, peripheral blood, and occasionally

in other tissues, with a variable reduction in the production

of normal red blood cells, platelets, and mature granulocytes.

The proliferation of malignant cells, along with a reduction in

normal hematopoietic cells, results in a variety of systemic consequences including anemia, bleeding, and an increased risk of

infection. Please refer to the following patient education video for

2174Section 17 Neoplastic Disorders

TABLE 92-1

Pretreatment Molecular Entities Shown to Predict Disease

Outcome in Adults With Acute Myeloid Leukemia and a

Normal Karyotype

Gene Mutation Frequency (%) Prognosis

NPM1 45–63 Favorable

FLT3 23–33 Poor

C/EBPa 8–19 Favorable

MLL 5–30 Poor

Source: Baldus CD et al. Clinical outcome of de novo acute myeloid leukaemia

patients with normal cytogenetics is affected by molecular genetic alterations: a

concise review. Br J Haematol. 2007;137:387.

additional information: http://www.careflash.com/video/

acute-myeloid-leukemia.

Based on karyotype status (characterization of the chromosome such as shape, type, or number), two major groups of

AML can be identified: (a) those with an abnormal karyotype,

which accounts for approximately 50% to 60% of patients, and

(b) those that demonstrate a normal karyotype by conventional

cytogenetic testing, which accounts for the remainder of AML

patients.3,4

Among patients with an abnormal karyotype, 25% have balanced (no gain or loss of chromosomal material) translocations,

e.g., t(8;21), t(15;17), or inv(16), and 27% showed unbalanced

(gain or loss of genetic material) abnormalities, e.g., −5/del(5q),

−7/del(7q), or complex karyotype. Within the normal cytogenetic category, 45% to 63% have NPM (nucleophosmin) mutations (localized on chromosome 5, band q35), 23% to 33% show

FLT3 (FMS-like tyrosine kinase 3) mutation (localized on chromosome 13, band q12), 5% to 30% haveMLL tandem duplications

(localized on chromosome 11, band q23), and 8% to 19% have

C/EBP (CCAAT enhancer binding protein) α mutations (localized on chromosome 19, band q13.1).5

The outcomes of patients with an abnormal karyotype are

generally poor regardless of the molecular findings. However,

the prognosis of patients with normal karyotype in the presence

of each of these mutations is different as shown in Table 92-1.

Patients with a normal karyotype and an NPM mutation alone

have a favorable prognosis, with 60% surviving longer than

11 years.6 In contrast, the presence of a normal karyotype with

either FLT3 or MLL mutations is generally associated with a poor

prognosis. In addition, the coexistence of FLT3 and NPM mutations does not improve the prognosis.5

Clinical Presentation and Diagnosis

Patients with AML generally present with symptoms related

to complications of pancytopenia (e.g., anemia, neutropenia,

and thrombocytopenia), including weakness and easy fatigability, infections of variable severity, and hemorrhagic findings

such as gingival bleeding, ecchymoses, epistaxis, or menorrhagia.

Combinations of these symptoms are common. It is often difficult to date the onset of AML precisely, at least in part because

individuals have different symptomatic thresholds for seeking

medical attention. It is likely that most patients have had more

subtle evidence of bone marrow involvement for weeks, or perhaps months, before diagnosis. This can sometimes make the

distinction between de novo leukemia and leukemia associated

with a prior hematologic disorder such as a myelodysplastic syndrome somewhat arbitrary.

Although a presumptive diagnosis of AML can be made

by examination of the peripheral blood smear when there are

circulating leukemic blasts, a definitive diagnosis usually

requires a bone marrow aspiration and biopsy. Morphologic,

immunophenotypic, cytogenetic, and molecular studies must

be performed in every case. The information derived from these

studies is critical for making the correct diagnosis as well as determining prognosis.

Overview of Treatment

Once the diagnosis of AML is established, induction chemotherapy is given with the goal of rapidly restoring normal bone marrow function. Treatment regimens and outcomes 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” is defined as older than 60 years of age.

The objective of induction therapy is to reduce the total body

leukemia cell population from approximately 1012 to less than

the cytologically detectable level of about 109 cells. It is generally

assumed, however, that a substantial burden of leukemia cells

persists undetected (i.e., presence of “minimal residual disease”),

leading to relapse within a few weeks or months if no further

therapy were administered. The traditional goal of treatment of

AML is to produce and maintain a complete remission. Criteria

for this are platelet count higher than 100,000 cells/μL, neutrophil

count higher than 1,000 cells/μL, and bone marrow specimen

with less than 5% blasts.7

The most commonly used induction regimens for AML are

the “7+3” regimens, which combine a 7-day continuous intravenous (IV) infusion of cytarabine (100 or 200 mg/m2

/day) with

a short infusion or bolus of an anthracycline given on days 1

through 3. The most commonly used anthracycline in this regimen is daunorubicin, but idarubicin may be used instead.

Sixty to 80% of adult patients with newly diagnosed AML will

attain a complete remission with intensive induction chemotherapy. However, without additional cytotoxic therapy, virtually all

of these patients will relapse within a median of 4 to 8 months. In

contrast, patients who receive postremission therapy may expect

4-year survival rates as high as 40% in young and middle-aged

adults with good-risk disease.8 High-dose cytarabine (HiDAC)

has been the consolidation chemotherapy of choice for more

than a decade for younger patients with good- or intermediaterisk disease. Attempts to improve on survival rates attained with

HiDAC by substituting other agents with different mechanisms of

action have not been successful.9 For patients with an abnormal

karyotype or with adverse molecular mutations, consolidation

with HiDAC followed by an allogeneic hematopoietic cell transplant (HCT) with a suitably matched donor is the treatment of

choice whenever possible. For patients older than 75 years of age,

there is no specific standard of care except to enroll in a clinical

trial when available. For the large number of patients who are

60 to 75 years of age, most clinicians will base induction and

consolidation therapy recommendations on a patient’s performance status, patient’s wishes, and prognostic factors such as

cytogenetics and mutation analysis.10

Twenty to 30% of young adult patients and 50% of older

adult patients with newly diagnosed AML will fail to attain a

complete response (CR) with intensive induction chemotherapy

as a result of drug resistance or death. In addition, a large percentage of patients who initially attain a CR will relapse. The therapy

that provides the best chance to cure a patient with relapsed

or refractory AML is an allogeneic HCT. The best outcomes

appear to be with a myeloablative preparative regimen administered after attaining a CR. However, some patients may be cured

with myeloablative HCT even without attaining a CR although

their chance of long-term survival is reduced. Nonmyeloablative

preparative regimens are considered for patients who are not

2175Adult Hematologic Malignancies Chapter 92

candidates for myeloablative HCT but have attained a CR.11 See

Chapter 96, Hematopoietic Cell Transplantation, for a complete

discussion of HCT for leukemia. Please refer to the following

online reference for more details about the treatment and prognosis of AML: http://www.cancer.gov/cancertopics/pdq/

treatment/adultAML/healthprofessional/page4.

Signs and Symptoms

CASE 92-1

QUESTION 1: J.V., a 35-year-old man, presented to the

emergency department with increasing fatigue and fever

and an inability to eat. This past week, a peripheral blood

smear (complete blood count [CBC]) revealed a white blood

cell (WBC) count of 180,000 cells/μL with a differential of

more than 90% leukemic blasts (normal, 0%), a hemoglobin

(Hgb) of 7.8 g/dL, and a platelet count of 46,000 cells/μL.

A bone marrow aspirate and biopsy confirmed the diagnosis of AML (FAB-M2, myeloid with maturation; 60% blasts,

myeloperoxidase positive; CD13 and CD33 positive). All

serum chemistry values were within normal limits, with the

exception of potassium (K), 3.2 mEq/L; phosphorus, 5.5

mg/dL; and lactate dehydrogenase (LDH), 3,500 units/mL.

Physical examination was remarkable for oral leukoplakia

from oral candidiasis and poor dentition. Which signs and

symptoms exhibited by J.V. are consistent with AML?

J.V.’s symptoms of increasing fatigue and fever of 1 week’s

duration are consistent with a rapid reduction in red blood cells

leading to anemia (Hgb, 7.8 g/dL) and a low neutrophil count

leading to infection (oral candidiasis). Although his WBC count

is high, the differential reveals that more than 90% are blasts,

which are immature, nonfunctional cells of myeloid or lymphoid origin. Circulating blast cells are typically not present in

early chronic leukemias or mild-to-moderate infections. However, blasts may be observed on the peripheral blood smear in

patients with anemia associated with primary bone marrow dysfunction (myelodysplastic syndromes). Blasts are also present in

patients with severe infection, stress, or trauma, and in those

with chronic myelogenous leukemia (CML) in transformation

to acute leukemia. J.V.’s platelet count is also low, which may

lead to bleeding or bruising. Collectively, these are presenting

signs and symptoms of acute leukemia.

J.V.’s symptoms are consistent with either AML or acute lymphocytic leukemia (ALL). However, patients with ALL also commonly present with lymphadenopathy and hepatosplenomegaly,

which J.V. does not have. It is important to distinguish between

these two disorders because treatment regimens differ greatly.

AML is more common in adults than in children. Because J.V. is

35 years old it is more likely that he has AML. For additional information on ALL, see Acute Lymphoblastic Leukemia of Childhood section in Chapter 91, Pediatric Malignancies.

Classification and Diagnosis

For a definitive diagnosis of AML, the bone marrow aspirate must

contain more than 20% leukemic blast cells. A normal bone marrow aspirate would typically contain less than 5% blasts. Eight

major variants of AML are defined by the French-AmericanBritish (FAB) classification system based on morphologic characteristics. More recently, the World Health Organization (WHO)

has developed a classification system that expands the number of

AML subtypes and better incorporates genotypic information,

which is important in determining prognosis.12

For a PowerPoint presentation that includes

additional information about AML, go to

http://thepoint.lww.com/AT10e.

Cells of myeloid origin commonly contain myeloperoxidase

enzymes and express surface markers CD13, CD33, CD14, and

CD15. Specific clonal chromosomal abnormalities are associated with several AML subtypes. These aberrations include gains

or losses of whole chromosomes on the long (q) or short (p)

arms, as well as a variety of structural rearrangements (e.g.,

translocations, inversions, insertions). A number of cytogenetic

abnormalities in AML are associated with molecular-clinical syndromes, which are now under investigation at the genetic level.

The translocation t(15;17) is the cytogenetic hallmark of acute

promyelocytic leukemia (APL or AML-M3). This translocation

splits the retinoic acid receptor gene on chromosome 17 and

blocks expression of retinoic acid–controlled genes required for

cell differentiation. Treating patients who have APL with all-trans

retinoic acid (ATRA, tretinoin) has resulted in complete morphologic responses. This example shows how defining cytogenetic

or chromosomal abnormalities in acute leukemia can be critical to understanding its pathophysiology and identifying optimal

treatments. Currently, three chromosomal abnormalities are recognized as being associated with a better prognosis13,14: t(8;21),

t(15;17), and inversion (inv) 16. In contrast, several chromosomal

abnormalities have been associated with a relatively poor prognosis, including inv 3, deletion (del) 5, del(5q), del(7), and del(7q);

trisomy 8; and complex (three or more unrelated cytogenetic

abnormalities) cytogenetics. Additionally, molecular abnormalities such as FLT3, which is generally unfavorable, and NPM1 and

C/EBPa, which are generally favorable, are central in the evaluation of AML patients.15 These findings are increasingly being used

to guide treatment decisions. For example, patients with cytogenetic and molecular findings associated with a poor prognosis

may be considered for more aggressive postremission therapy

such as high-dose chemotherapy with HCT. Other poor prognostic signs in AML include age older than 60 years at the time

of diagnosis, a pre-existing hematologic disorder (e.g., myelodysplastic syndrome), prior exposure to a chemotherapy agent (e.g.,

a secondary leukemia), and poor baseline performance status.16

J.V. has FAB-M2 (myelomonocytic) AML. Approximately 10%

to 20% of patients with FAB-M2 acute leukemia have a translocation of t(8;21)(q22;q22).13 This translocation is usually seen in

young patients such as J.V. and is associated with a better response

to therapy. J.V.’s bone marrow has been sent for cytogenetic

and molecular analysis; however, results will not be available for

approximately a week. Although neither the cytogenetic nor the

molecular analysis will alter the planned induction therapy for

J.V., these findings in combination with other prognostic features,

as discussed previously, will influence postremission therapy recommendations.

Treatment

GOAL OF THERAPY

CASE 92-1, QUESTION 2: What is the goal of treatment,

and what type of therapy is indicated for J.V. at this time?

The leukemic cells populating J.V.’s blood are abnormal

and incapable of fighting infection. Their rapid proliferation is

suppressing red blood cell and megakaryocyte production in

the bone marrow. J.V. is at substantial risk for life-threatening

infections and bleeding complications. The goal of the initial

2176Section 17 Neoplastic Disorders

chemotherapy is to clear the bone marrow and peripheral blood

of all blast cells in the hope that normal blood cell components

can regenerate.

INDUCTION THERAPY

Standard induction chemotherapy for AML includes an anthracycline (either daunorubicin or idarubicin) and cytarabine, an

antimetabolite. One commonly used regimen includes daunorubicin 90 mg/m2

/day on days 1 to 3 as an IV bolus injection, plus

cytarabine 100 mg/m2

/day as a continuous IV infusion on days

1 to 7.17 This combination (7 + 3) is one of the most effective

chemotherapy regimens used to treat adult AML, with CR rates

of 60% to 80%.13 Continuous infusions of cytarabine are preferred because these regimens produce higher response rates

than bolus injections during induction therapy.18,19 Using higher

doses of cytarabine by increasing the number of days of therapy

to 10, doubling the daily dose to 200 mg/m2, and using (HiDAC)

(0.5–6.0 g/m2

/day) has not shown consistent improvement in CR

rates or survival.20 Adding etoposide for 7 days may increase the

CR rate, response duration, and survival in patients younger than

55 years.21 However, other investigators have not shown a benefit

with the addition of etoposide to the standard 7 + 3 induction

regimen.22

If a patient presents with a very high WBC count, he or she

may experience complications associated with hyperviscosity of

the blood (e.g., ringing ears, stroke, blindness, or headache as a

result of impaired oxygen delivery to the central nervous system

[CNS], pulmonary infarction). Because it may take several days

for cytarabine and daunorubicin to substantially decrease the

WBC count, the patient may receive hydroxyurea 2 to 4 g orally

(PO) or undergo leukapheresis to rapidly reduce the WBC count.

Leukapheresis is not routinely done unless the patient is experiencing symptoms of hyperviscosity or has a WBC 100,000 cells/

μL or greater on diagnosis.

Because J.V.’s initial WBC was 180,000 cells/μL, leukapheresis

was initiated together with concomitant hydroxyurea 2 g twice

daily. Approximately 12 hours after initiating leukapheresis, J.V.’s

WBC had decreased to 85,000 cells/μL, and he was stable enough

to proceed to induction therapy with daunorubicin and cytarabine. The leukapheresis and hydroxyurea were subsequently discontinued.

TRETINOIN AND ARSENIC TRIOXIDE FOR

ACUTE PROMYELOCYTIC LEUKEMIA

CASE 92-1, QUESTION 3: Would induction therapy for

other subtypes of AML differ from that described previously?

Induction therapy with 7 + 3 is standard for all types of AML,

with one exception: APL or AML-M3. APL is uniquely characterized by the t(15;17) translocation that fuses the PML gene on

chromosome 15 to the retinoic acid receptor-alpha (RAR-α) gene

on chromosome 17. In clinical trials, ATRA has induced complete remission in approximately 90% of patients with APL.23

Serial bone marrow aspirations after initiation of ATRA therapy

demonstrate progressive differentiation without hypoplasia.23,24

Unfortunately, ATRA typically induces brief remissions. A number of trials have investigated combination treatment with

chemotherapy and ATRA.25,26 Current evidence supports the

use of concurrent ATRA plus conventional chemotherapy for

induction, with ATRA starting 2 days before chemotherapy. In

addition, postremission therapy should include at least two cycles

of an anthracycline-based regimen.26,27 Maintenance therapy

with intermittent ATRA has been shown to decrease the relapse

rate.25,28

ATRA therapy, although avoiding life-threatening myelosuppression, can produce significant toxicities, including the retinoic

acid syndrome (RAS), which manifests as fever, weight gain, respiratory distress, lung infiltrates, pleural or pericardial effusion,

hypotension, and acute renal failure.29 If RAS develops, corticosteroid therapy (dexamethasone 10 mg twice a day for at least

3 days) should be initiated.30 In patients receiving concurrent

ATRA and chemotherapy, ATRA may be stopped if the patient

has received ATRA for at least 20 days or if symptoms of RAS are

life-threatening or not improving with dexamethasone. Patients

with leukocytosis seem to be more likely to experience RAS.

Concurrent use of chemotherapy and ATRA has been reported

to reduce the likelihood of RAS.30 ATRA also causes dryness of

the lining of the mouth, rectum, and skin; hair loss; skin rash;

blepharon conjunctivitis; corneal erosions; muscle weakness; nail

changes; depression; elevated liver enzymes; and high cholesterol. Despite the risk of serious complications and death during

induction therapy, the long-term diseasefree survival (DFS) rate

of patients with APL is superior compared with other AML subtypes. Approximately 75% of patients who receive ATRA-based

induction and maintenance therapy are alive 3 to 5 years after

diagnosis.28

COMPLICATIONS OF INDUCTION THERAPY

Tumor Lysis Syndrome

CASE 92-1, QUESTION 4: Twenty-four hours after J.V.’s

induction chemotherapy was initiated, the following laboratory values were obtained:

WBC count, 78,000 cells/μL

K, 5.3 mEq/L

Phosphorus, 6.0 mg/dL

Uric acid, 9.8 mg/dL

Calcium, 6.0 mg/dL

Creatinine, 1.6 mg/dL

Why have these laboratory values changed so suddenly?

Could this have been minimized or prevented? How should

these metabolic disturbances be managed?

J.V. presented with a very high number of peripheral blood

blasts. On administration of chemotherapy, patients with a hypercellular bone marrow and high number of blast cells can have a

rapid lysis of the blast cells and the release of cellular contents.

This can result in tumor lysis syndrome (TLS), which is associated

with metabolic abnormalities such as hyperuricemia, hyperphosphatemia, hypocalcemia, and uremia. These disturbances may

lead to arrhythmias and acute renal failure. In most cases, TLS

occurs 12 to 24 hours after chemotherapy is initiated. TLS may

occur after therapy for other malignancies, particularly in those

with a high tumor burden, such as high-grade lymphomas and

ALL. TLS rarely occurs after therapy for solid tumors.

Patients should receive IV hydration (3–4 L/day) beginning

24 to 48 hours before chemotherapy to maintain renal perfusion,

optimize the solubility of tumor lysis products, and compensate

for fluid losses caused by fever or vomiting. Alkalinization of

the urine with the addition of sodium bicarbonate to the IV

fluids may also reduce or prevent uric acid from precipitating in

the renal tubules and collection ducts by maintaining the urate

in its ionized state, but is not currently recommended for all

patients. This is because the increased pH may increase the risk

of precipitating calcium phosphate in both soft tissue and kidney

tubules, and it may aggravate hypocalcemia.31,32

Allopurinol, a xanthine oxidase inhibitor that blocks the

metabolism of uric acid, should be started before chemotherapy

2177Adult Hematologic Malignancies Chapter 92

to prevent or minimize the complications of TLS. The recommended adult dosage is 300 to 600 mg/day. J.V.’s serum uric acid

and electrolytes should be monitored at least two to three times

a day for 24 to 48 hours after initiating chemotherapy. If severe

abnormalities occur, more aggressive measures should be initiated. Allopurinol may be discontinued if the serum uric acid is

within normal limits, the LDH has normalized, and the WBC

count is low. Rasburicase, a recombinant urate oxidase product,

can also be used as prophylaxis in patients who are at high risk of

developing TLS or for the treatment of patients who present with

or develop TLS. Rasburicase acts as a catalyst in the enzymatic

oxidation of uric acid to allantoin, which is five to ten times more

soluble than uric acid and undergoes rapid renal excretion. The

recommended dose of rasburicase for both prevention and treatment of TLS is 0.2 mg/kg/dose IV. Rasburicase results in a rapid

reduction in serum uric acid (within 4 hours of administration)