TRIPASS XR تري باس

 

and is generally well tolerated.33 Most of the clinical data for

rasburicase is in the pediatric population; however, data suggest

that rasburicase is equally effective in adults.33,34 In many adult

centers, doses of 3 or 6 mg are commonly used.35–39 Although

rasburicase has demonstrated excellent efficacy and tolerability,

its optimal role in the prevention and management of hyperuricemia in adults remains to be defined because of its high cost

and lack of a randomized trial comparing its effect with other

interventions.

Although J.V.’s serum potassium was low on admission, it

has increased significantly as a result of TLS. For this reason,

replacement potassium therapy by any method is not recommended before chemotherapy in patients in whom TLS is highly

likely. In extreme circumstances, dialysis may be required to

correct severe metabolic and electrolyte disturbances associated

with TLS. J.V.’s kidneys continued to function throughout. Even

though J.V.’s creatinine was above the normal range, his urine

output did not decline substantially and he was able to proceed

without further intervention.

Myelosuppression

CASE 92-1, QUESTION 5: J.V. received allopurinol therapy and aggressive hydration throughout his induction chemotherapy. The metabolic abnormalities gradually

resolved as his WBC count declined and tumor lysis diminished. What other complications may occur during induction

therapy and can they be treated?

Patients receiving cytarabine and daunorubicin induction

therapy develop profound anemia, granulocytopenia (e.g.,

WBC count <100 cells/μL), and thrombocytopenia (<20,000

platelets/μL) shortly after therapy is initiated, which usually persist for approximately 21 to 28 days. Additionally, all infectious

complications must be considered life-threatening in severely

immunocompromised patients such as J.V.

Filgrastim (granulocyte colony-stimulating factor [G-CSF])

and sargramostim (granulocyte-macrophage colony-stimulating

factor [GM-CSF]) stimulate leukemic cells as well as normal

granulocyte precursors in vitro; however, several studies have

demonstrated that these agents, when used as an adjunct to

AML chemotherapy, are safe and do not adversely affect disease outcome.40,41 Most studies have demonstrated that colonystimulating factors (CSFs) can modestly decrease the length of

profound neutropenia, and sometimes reduce the incidence of

infection-related morbidity, the duration of systemic antibiotic

and antifungal therapy, and the number of hospitalization days.

Despite the reduction in short-term neutropenia-related complications, administration of CSFs after induction chemotherapy

does not appear to have an impact on the rate of CR or the

long-term outcomes of the disease. Refer to Chapter 90, Adverse

Effects of Chemotherapy and Targeted Agents, for additional

information about CSFs.

Severe thrombocytopenia may result in bleeding episodes that

range in severity from oozing gums to massive hemorrhage.

Serious bleeding complications can usually be avoided if patients

receive platelet transfusions when their platelet counts decrease

to less than 10,000 cells/μL or when patients experience bleeding.

Currently, there are no data to support the use of interleukin (IL)-

11 (oprelvekin) or investigational thrombopoietic agents in this

setting.

Other common drug-induced complications that may occur

during induction therapy include nausea and vomiting, mucositis, fever, and skin rash (see Chapter 6, Nausea and Vomiting,

Chapter 7, Pain and Its Management, and Chapter 90, Neoplastic Disorders and Their Treatment: General Principles, for additional information and their management).

Postremission Therapy

RATIONALE

CASE 92-1, QUESTION 6: After completion of his induction

chemotherapy, J.V.’s WBC count fell to less than 100 cells/μL

and his platelet count fell to 5,000 cells/μL. He received

platelet transfusions approximately every 2 to 3 days to

prevent bleeding complications. On day 9, he developed

a fever of 38.8◦C. He was started immediately on empiric,

broad-spectrum antibiotic therapy for fever and neutropenia, and it subsequently resolved. On day 29, his WBC

count was 5,600 cells/μL with a normal differential, and his

platelet count was 168,000 cells/μL. He received packed red

blood cell transfusions on two separate occasions when his

Hgb fell to less than 8 mg/dL. A repeat bone marrow aspirate showed no evidence of persistent leukemia, and J.V.

was told that his leukemia was in remission. Nevertheless,

his hematologist recommended additional chemotherapy,

and J.V. questions why this is necessary. Is postremission

therapy necessary, and if so, what therapeutic options are

available to J.V.?

Although greater than 60% of patients treated for AML

achieve CR after induction therapy, the median duration of the

remission is only about 12 to 18 months, and only 20% to 40%

of patients have a DFS exceeding 5 years.20 Short remissions

have been attributed to proliferation of clinically undetectable

leukemic cells. Thus, the rationale for administering chemotherapy after remission is to eradicate these residual cells.

In adult AML, postremission therapy (also referred to as consolidation therapy) includes three to four cycles of chemotherapy. Clinical trials have shown that high-dose postremission

therapy results in a higher percentage (30%–40%) of long-term

(>2–5 years) diseasefree survivors than either no or low-dose

postremission chemotherapy in patients generally younger than

60 years of age.42,43 Postremission therapy regimens usually

include HiDAC alone or in combination with one or more agents

such as an anthracycline or etoposide. Patients 60 years of age and

older or those with comorbid disease may not be able to tolerate this intensive postremission therapy. In these circumstances,

the risk of life-threatening toxicity may outweigh the potential

benefits of postremission chemotherapy. Allogeneic HCT has

also been studied in the postremission treatment of AML and is

addressed in Chapter 96, Hematopoietic Cell Transplantation.

In an effort to prolong survival, chemotherapy (thioguanine, methotrexate) and biologics (IL-2) for a prolonged period

have been investigated. This is often referred to as maintenance

2178Section 17 Neoplastic Disorders

therapy. With the exception of APL, maintenance chemotherapy

has not been shown to improve survival in adult AML. In conclusion, J.V. should receive consolidation therapy after HiDAC

induction because this has been shown to give him the best

chance of long-term survival. Additionally, because J.V. was fortunate enough to be diagnosed with good-risk disease, he will

not require an allogeneic HCT. He will be followed closely with

at least bimonthly CBCs and a bone marrow biopsy at least every

year for 5 years after consolidation. This close follow-up is vital

for catching relapse as early as possible with the intent of going

immediately to an allogeneic HCT and minimizing additional

reinduction therapy if relapse occurs.

HIGH-DOSE CYTARABINE

CASE 92-1, QUESTION 7: Because J.V. does not require an

allogeneic HCT at this time, his hematologist recommends

three courses of HiDAC as postremission therapy. One week

after he was declared to be in remission, J.V. is readmitted

to the hospital to receive HiDAC 3 g/m2 every 12 hours, over

3 hours, on days 1, 3, and 5. What are the potential acute

and delayed toxicities associated with HiDAC, and how can

these effects be prevented?

At conventional dosages of 100 to 200 mg/m2

/day, adverse

effects associated with cytarabine include myelosuppression,

fever, and skin rashes. Occasionally, liver enzymes rise transiently.

The side effect profile for HiDAC (>1 g/m2

/day) by contrast is

very different and can produce major cerebellar, ocular, and skin

toxicities.44,45

CEREBELLAR AND OCULAR TOXICITY

Cerebellar toxicity is a significant problem in patients receiving

HiDAC therapy. See Chapter 90, Adverse Effects of Chemotherapy and Targeted Agents, for details regarding cerebellar toxicity.

Ocular toxicity results from damage to the corneal epithelium,

occurring when cytarabine penetrates the epithelium through

the anterior chamber of the eye or tears. Symptoms include

conjunctivitis, excessive lacrimation, “burning” ocular pain, photophobia, and blurred vision. Artificial tears (two drops every

4–6 hours) administered concurrently with HiDAC generally prevents these symptoms. Corticosteroid eye drops can be used as

an alternative to artificial tears or if symptoms of conjunctivitis

occur.46

DERMATOLOGIC TOXICITY

Dermatologic toxicity may manifest as a rash covering most of

the body or plantar-palmar erythrodysesthesia (PPE).

For a photo of cytarabine-induced PPE, go to

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

This is commonly seen several days after the start of the

cytarabine, but may occur days to weeks after therapy. Desquamation of the palms and soles can occur with PPE, causing significant pain and allowing for pathogenic organisms to

enter the body.47 Treatment varies, but most suggest stopping

the cytarabine if the rash or PPE is severe. Other strategies

include minimizing tight-fitting shoes and socks if the feet are

involved, as well as protecting the affected areas from further

damage.

ACUTE MYELOID LEUKEMIA IN THE ELDERLY

CASE 92-1, QUESTION 8: Would recommendations for

induction and postremission therapy differ if J.V. were

elderly (60 years of age or older)?

As mentioned earlier, the incidence of AML increases with

advancing age. At age 40 years, there is only 1 case of AML per

100,000, but the annual incidence increases to 15% at ages older

than 75 years. The prognosis of patients with AML is also directly

related to age. Older patients are generally less able to tolerate intensive induction and postremission chemotherapy. Older

patients often have comorbid medical conditions and a poor performance status, which are directly associated with worse outcomes with conventional AML therapy.48,49

Many single-institution and cooperative group studies exclude

elderly patients with AML or treat them on a separate lessintensive protocol. Elderly patients are often judged to be poorrisk candidates for intensive chemotherapy without objective

review of available criteria. Because the median age of patients

with AML and myelodysplastic syndrome is 67 years, the results

of regimens studied in younger patients may not be applicable

to the elderly. Some hematologists believe that it is most appropriate to offer older patients supportive care only, low-intensity

therapy, or investigational treatment. Others believe that moderately intensive chemotherapy is beneficial in some candidates.

However, most physicians feel uncomfortable offering intensive

chemotherapy to elderly patients because of the high risk of

induction mortality. Several studies have addressed the outcome

of elderly patients.50–56

An analysis of 2,657 Medicare beneficiaries older than 65 years

of age with AML may accurately reflect past experience with this

population better.57 The mortality rate was 86% and 94% at 1 and

2 years after diagnosis, respectively. Only 30% of these patients

received any form of IV chemotherapy in the 2 years after diagnosis. The study did not distinguish between intensive induction

chemotherapy and palliative therapy. Nevertheless, 89% of all

patients required hospitalization, and they spent 31% of their

remaining days in either a hospital or skilled nursing facility. The

high rate of hospitalization is likely owing to the consequences

of bone marrow failure caused by the AML, even in the absence

of cytotoxic chemotherapy. Nevertheless, many believe aggressive therapy is warranted in most elderly patients given the rapid

progression of the disease, and certain death within weeks if the

disease is not treated.

The selection of postremission therapy is difficult in elderly

patients because they have a higher risk of morbidity and

mortality, and more important, no clinical trials have demonstrated the benefit of postremission therapy specifically in the

elderly. The intensity of the regimens must often be attenuated

because there is risk of serious toxicities. This is particularly true

with HiDAC therapy because of the increased risk of cerebellar

toxicity in the elderly. Studies have shown that postremission therapy with low-dose cytarabine (100 mg/m2 by continuous infusion

for 5 days) is as effective as HiDAC and better tolerated in elderly

patients.42

Refractory or Resistant Acute Myeloid

Leukemia

CASE 92-2

QUESTION 1: A.W., a 55-year-old man, is approximately

40 days after induction therapy with 7 + 3. Initially, his

counts recovered on day 25, and a bone marrow biopsy

2179Adult Hematologic Malignancies Chapter 92

on day 28 revealed less than 5% blasts; therefore, he was

in remission. Thereafter, a recent CBC showed a significant

drop in his platelet count from 150,000 cells/μL on day 30

to 90,000 cells/μL 10 days later. A subsequent bone marrow biopsy reveals 60% blasts, confirming the diagnosis of

relapsed AML. What are treatment options for A.W. at this

time?

In younger patients, failure to achieve remission or disease

relapse remains the major cause of treatment failure. This reflects

both the failure of current salvage regimens and the absence of

effective strategies to secure long-term DFS in those patients

who achieve a second hematologic remission. A wide range of

salvage options have been studied, but with less than 50% of

patients achieving a second remission and median survival figures

ranging from 3 to 12 months, there remains considerable room

for improvement.58

The treatment of relapse in a patient younger than 75 years of

age with a good performance status generally comprises one of

several salvage options, including clofarabine, intermediate-dose

cytarabine to HiDAC, or combination regimens such as fludarabine, cytarabine, and G-CSF (FLAG), or cladribine, cytarabine,

and G-CSF (CLAG), followed by allogeneic HCT.

A recently completed phase III trial from the Southwest

Oncology Group showed a significantly higher fatal toxicity rate

in patients who received gemtuzumab ozogamicin in combination with standard induction therapy or as consolidation therapy

alone.59 These disappointing results prompted the US Food and

Drug Administration (FDA) to remove commercially available

gemtuzumab ozogamicin from the US market, thereby eliminating a therapeutic option for initial and relapsed or refractory

AML.

Future Chemotherapy in Acute Myeloid

Leukemia: Targeted Therapies?

CASE 92-2, QUESTION 2: The results of A.W.’s cytogenetic

and molecular analysis show that his leukemia is FLT3 positive. What would be the next step for A.W.?

Whereas some clinical factors have an impact on response

to treatment, it is the cytogenetic and molecular heterogeneity of AML that is the major determinant of treatment success

or failure. For A.W., the finding that his AML has a mutation

in the FLT3 gene portends a poor likelihood of long-term survival without new therapies. The estimated 5-year survival is

approximately 10% to 15% among patients with an FLT3 internal tandem duplication mutation.60

FLT3 is a receptor tyrosine kinase (TK) that is mutated in

25% to 30% of AML cases, and is associated with a poor disease outcome. Therefore, it is an attractive molecular target for

the development of new therapeutics. Although more than 20

molecules have been reported to have inhibitory activity against

FLT3,61 only a few of them are currently in phase II or III clinical

trials to assess their efficacy in AML patients: midostaurin,62,63

lestaurtinib,64,65 and sorafenib.66

To date, FLT3 inhibitors have shown only modest efficacy

as monotherapy in patients with relapsed or refractory disease. However, in vitro studies suggest synergism between FLT3

inhibitors and conventional chemotherapy. As a result, several

clinical trials are ongoing to investigate the combination of FLT3

inhibitors in combination with conventional chemotherapy like

daunorubicin and cytarabine along with hypomethylating agents

such as decitabine and azacitidine with the hope of improving

the outcomes of patients with FLT3 mutations in both the initial

and relapse setting.67

For A.W., the best option would be to enroll in an investigational trial that incorporates one of the available FLT3 inhibitors

with chemotherapy. If a trial is not available, then HiDAC or a

combination regimen containing clofarabine or fludarabine followed by an allogeneic HCT would be his best option.

For a PowerPoint presentation about the

treatment of FLT3 positive AML, go to

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

CHRONIC MYELOGENOUS LEUKEMIA

Epidemiology and Pathophysiology

CML is a myeloproliferative disorder characterized by unregulated stem cell proliferation in the bone marrow and an increase

in mature granulocytes in the peripheral blood. The median age

of diagnosis is 50 to 60 years, and there is an annual incidence of

1.0 to 1.5 per 100,000 patients.68 Although seldom seen in pediatric leukemia, CML accounts for 15% of adult leukemia cases.69

The estimated 7- to 10-year survival rate is 80% to 85%, since the

introduction of TK inhibitors.

Clinical Presentation and Diagnosis

Presenting symptoms include fatigue, abdominal pain, fever,

anorexia, and weight loss. On physical examination, the most

common finding is splenomegaly. Approximately 25% to 50%

of patients are asymptomatic at presentation, and the initial suspicion for CML is based solely on an abnormal CBC.70 Bone

marrow biopsy reveals the cytogenetic hallmark of CML, the

Philadelphia chromosome, which is present in more than 95%

of cases.71 Cytogenetic analysis reveals a translocation of chromosomes 9 and 22 t(9;22)(q34;q11).72 This translocation creates a

new protein (BCR-ABL) that has unregulated TK activity, thereby

promoting leukemia development. The three major mechanisms

that have been implicated in the malignant transformation by

unregulated TK include abnormal cell cycling, inhibition of apoptosis, and increased proliferation of cells.72 Identification of the

Philadelphia chromosome helps confirm the diagnosis of CML

and helps with monitoring the efficacy of treatment. The natural

history of CML can be divided into three distinct phases: chronic

phase, accelerated phase, and blast phase. Greater than 90% of

patients are diagnosed in chronic phase, which is the earliest

phase of the disease.

Treatment

The ultimate goal of therapy is to cure patients of their disease, and allogeneic HCT remains the only curative therapy for

CML to date. However, HCT is associated with a substantial

risk of morbidity and mortality. Therefore, TK inhibitors are

first line therapy in most patients even though they are not

curative. The primary goals of the TK inhibitors are to prolong survival, prevent progression of disease, and attain a complete hematologic or cytogenetic remission. Imatinib, nilotinib,

and dasatinib are TK inhibitors that achieve complete hematologic and cytogenetic response rates and are first-line treatment options in chronic-phase CML patients. Nilotinib and dasatinib are approved for the treatment of patients with resistant

2180Section 17 Neoplastic Disorders

TABLE 92-2

Definition of Complete and Partial Hematologic Response in

Chronic Myelogenous Leukemia

Partial Response

Complete

Response

Peripheral leukocyte

count

<10 × 109

/L <10 × 109

/L

Platelet count <50% pretreatment count

(but >450 × 109

/L

<450 × 109

/L

Immature cells Present Absent

Splenomegaly Present (but <50%

pretreatment extent)

Absent

Source: NCCN National Comprehensive Cancer Network. Clinical Practice

Guidelines in Oncology: Chronic Myelogenous Leukemia. 2012; V1.2012.

http://www.nccn.org/professionals/physician gls/f guidelines.asp.

Accessed May 2, 2011.

Philadelphia chromosome–positive chronic- or acceleratedphase CML. Treatment for patients who progress from chronic

to accelerated or blast phase is determined based on mutational

changes in the BCR-ABL protein and bone marrow cytogenetics. Owing to the sustained response rates achieved by the TK

inhibitors, the exact timing of HCT is controversial, although

patients in the accelerated or blast phase at presentation or those

progressing during TK inhibitor therapy are generally referred

for HCT.73 Historically, patients undergoing transplantation in

the accelerated and blast phases achieved a 40% and 10% 5-year,

leukemiafree survival, respectively.69,73

Quantitative polymerase chain reaction assay is used to monitor BCR-ABL transcript levels for early detection of recurrence of

the CML disease. Increased transcript levels at 6 and 12 months

after transplant are associated with a 43% increased risk of relapse

compared with a 3% risk of relapse in patients without level

elevations.69 For those who relapse after HCT, initiation of a TK

inhibitor has improved long-term outcomes. Additional information regarding HCT and the preparative regimens used for

patients undergoing allogeneic HCT for CML can be found in

Chapter 96, Hematopoietic Cell Transplantation.

Assessment of response to CML therapies are based on both

hematologic (Table 92-2) and cytogenetic (Table 92-3) responses.

Response definitions were created when interferon was the primary treatment for CML, leading some clinicians to use major

molecular response as another marker of response.70 Major

molecular response is defined as undetectable BCR-ABL mRNA

by polymerase chain reaction assay and a greater than 3-log

decrease in BCR-ABL mRNA.69

TABLE 92-3

Definition of Cytogenetic Response in Chronic Myelogenous

Leukemia

Cytogenetic Response

Philadelphia (Ph)

Chromosome–Positive

Metaphase Cells (%)

Complete 0

Partial 1–35

Major (includes complete and partial

responses)

0–35

Minor >35

Source: NCCN National Comprehensive Cancer Network. Clinical Practice

Guidelines in Oncology: Chronic Myelogenous Leukemia. 2012; V1.2012.

http://www.nccn.org/professionals/physician gls/f guidelines.asp.

Accessed May 2, 2011.

Signs and Symptoms

CASE 92-3

QUESTION 1: S.E., a 66-year-old white woman, recently

had a routine CBC drawn during her annual checkup. Her

CBC showed a WBC count of 60,000 cells/μL with 90%

neutrophils, a hematocrit of 32%, and a platelet count of

300,000 cells/μL. The only pertinent physical finding was

splenomegaly. On further workup, a bone marrow aspirate

revealed a hypercellular marrow with less than 10% blasts.

Cytogenetic analysis confirmed a diagnosis of Philadelphia

chromosome–positive CML. Explain S.E.’s high WBC count.

What are the possible clinical consequences of these abnormal values?

Approximately 40% to 50% of patients are asymptomatic at

presentation, and the initial suspicion for CML is based solely

on an abnormal CBC.70 However, if symptomatic, patients may

complain of fatigue, abdominal pain, fever, anorexia, and weight

loss. The most common physical finding is splenomegaly, which

results from increased activity of the reticuloendothelial system to remove the increased numbers of WBCs. Approximately

50% to 70% of patients present with a leukocyte count greater

than 100,000 cells/μL. Consequences of hyperleukocytosis and

hyperviscosity may include priapism, headaches, tinnitus, and

cerebrovascular accidents. The presence of the Philadelphia chromosome is critical in the diagnosis of CML since the majority of

cases will have this cytogenetic abnormality.

Clinical Course and Prognosis

CASE 92-3, QUESTION 2: What is the prognosis for S.E. and

others with newly diagnosed CML?

Early in the disease (chronic phase), patients exhibit leukocytosis and associated symptoms as described previously. Chronic

phase is defined as less than 10% blasts and promyelocytes in

the bone marrow and peripheral blood.71 The duration of the

chronic phase may range from a few months to many years.

Because symptoms may be nonspecific and relatively minor,

CML may remain undiagnosed until patients progress into more

advanced stages. The annual transition rate from chronic phase

to accelerated phase is 5% to 10% in the first 2 years and 20% in

subsequent years.71 Common signs and symptoms suggestive of

this transition include increased leukocytosis, anemia, increased

splenomegaly, fever, and bone pain. Because less than 10% blast

cells are present in S.E.’s bone marrow, she is in the chronic phase

of the disease. Therefore, S.E.’s prognosis is good and her projected 8-year overall survival (OS) is 85% if treated with the TK

inhibitor imatinib.74

During the second phase of the disease, the accelerated phase,

leukocytosis progresses (despite therapy), and an increased number of immature leukocytes (blasts) appear in the peripheral

blood. Patients may report significant symptoms. The estimated

4-year OS is 53% for accelerated-phase CML patients started on

the TK inhibitor imatinib.71 The accelerated phase will generally

progress to the blast phase in less than 6 weeks if not treated.

The final phase of the disease (blast phase or blast crisis) is characterized by a predominance of immature cells. Blast crisis is

defined as more than 20% blasts in the peripheral blood or bone

marrow by the WHO or more than 30% blasts in the blood

or bone marrow with or without extramedullary disease by the

International Bone Marrow Transplant Registry.69–71 During this

phase, CML is indistinguishable from AML with the exception of

2181Adult Hematologic Malignancies Chapter 92

cytogenetics. In blast crisis, patients often experience bone pain,

fatigue, fever, infections, and bleeding complications. The blast

phase is often refractory to conventional induction chemotherapy regimens for AML, and the median survival is approximately

6 months.68

Treatment

CASE 92-3, QUESTION 3: What therapy is appropriate for

S.E.’s chronic-phase disease?

HYDROXYUREA

As mentioned above, the ultimate goal of therapy for CML is cure,

and allogeneic HCT remains the only curative therapy. However,

in newly diagnosed patients who present with very high leukocyte counts (>100,000 cells/μL), the initial goal of therapy is to

immediately reduce leukocytosis and its related symptoms.71

In patients presenting with a leukocyte count greater than

20,000 cells/μL, hydroxyurea is still the most common agent

used for initial leukocyte reduction. Treatment is initiated with

2 g/day PO, and the dosage is titrated to a WBC count of less than

20,000 cells/μL with a goal of 5,000 to 10,000 cells/μL.71 A

small dosage decrease often permits a considerable rise in leukocyte count in 1 or 2 days. Hydroxyurea is well tolerated and is

relatively free of nonhematologic side effects. Although effective for initial control of high leukocyte counts, hydroxyurea

is inferior to other treatments for long-term control of CML.

Because S.E. presented with a WBC of 60,000 cells/μL, she will

receive hydroxyurea for 3 to 5 days before transitioning to a TK

inhibitor.

TYROSINE KINASE INHIBITORS

In 2001, the FDA approved imatinib mesylate (400 mg PO daily),

a first-generation TK inhibitor, for the treatment of patients with

CML. Since that time, two second-generation TK inhibitors,

dasatinib (100 mg PO daily) and nilotinib (400 mg PO twice

daily), have been approved. In the current National Comprehensive Cancer Network (NCCN) Guidelines, imatinib, nilotinib,

and dasatinib are first-line treatment options for patients presenting with chronic-phase CML.69 The following online video discusses the current treatment strategies for CML: http://www.

youtube.com/watch?v=MGqyY57uTvU.

Imatinib occupies the adenosine triphosphate binding site of

several TK molecules and prevents phosphorylation of substrates

that are involved in regulating the cell cycle. Approval was based

on the pivotal International Randomized Study of Interferon and

STI571 (IRIS) trial, which compared imatinib with the combination of interferon (IFN)-α plus low-dose cytarabine in patients

with newly diagnosed CML in the chronic phase. A total of

1,106 patients were randomly assigned to either imatinib (400 mg

PO daily) or IFN plus cytarabine.75 All primary and secondary

end points of the trial, including rates of complete hematologic

remission, major and complete cytogenetic response, and freedom from progression to the accelerated phase or blast crisis,

demonstrated superiority of imatinib versus IFN plus cytarabine.

In addition to superior efficacy, imatinib was very well tolerated.

The most common toxicities reported with imatinib are superficial edema, nausea, muscle cramps, and rashes. More mature data

from this trial, with a median follow-up of 60 months, demonstrated an 89% OS of patients who received imatinib as initial

therapy.76 This landmark trial clearly showed the superiority of

imatinib compared with IFN plus cytarabine in the treatment of

patients with newly diagnosed CML in chronic phase. Based on

these results, TK inhibitors are now first-line standard of care for

patients with newly diagnosed CML in chronic phase.

Dasatinib binds the BCR-ABL protein in the active confirmation, making it 325 times more potent than imatinib.74 Approval

was based on the international DASISION (Dasatinib versus Imatinib study in treatment-na¨ıve CML patients) trial, which compared dasatinib 100 mg PO once daily with imatinib 400 mg PO

once daily with food in a randomized 1:1 fashion in 519 patients

with chronic-phase CML.77 The primary objective of complete

cytogenetic response at 12 months and the secondary objective

of a major molecular response by 12 months were statistically

superior for dasatinib versus imatinib. Dasatinib demonstrates

a similar safety profile compared with imatinib, with a higher

incidence of pleural effusion and thrombocytopenia and a lower

incidence of rash and diarrhea.74

Nilotinib is structurally similar to imatinib but 30 times more

potent as a result of an improved structural fit in the receptor

pocket.74 Approval was based on the international ENESTnd

(Evaluating nilotinib efficacy and safety in clinical trials—newly

diagnosed patients) trial, which randomly assigned 846 patients

with chronic-phase CML in a 1:1:1 fashion to either imatinib

(400 mg PO once a day with food) or nilotinib (300 mg or 400 mg

PO twice a day). The primary objective of major molecular

response at 12 months and the key secondary objective of a

complete cytogenetic response by 12 months were statistically

superior for both doses of nilotinib compared with imatinib.78

Nilotinib demonstrates a similar safety profile compared with the

other TK inhibitors, with a higher incidence of rash, headache,

pruritus, and alopecia and a lower incidence of nausea, diarrhea,

vomiting, edema, and muscle spasm.78

Clinicians and patients must carefully evaluate the potential

risks and benefits of each treatment modality to make the best

therapeutic decision for each individual situation. Because S.E.

presented in chronic-phase CML, initiation of imatinib, nilotinib,

or dasatinib are appropriate choice. Imatinib 400 mg once daily

will be initiated.

Relapsed and Refractory Disease

CASE 92-3, QUESTION 4: On routine follow-up at

6 months, cytogenetics analysis of S.E.’s bone marrow

demonstrates 10% Philadelphia chromosome–positive cells

(partial cytogenetic response). Therefore, her imatinib dose

is increased to 400 mg twice a day. Six months later, a repeat

bone marrow biopsy continues to show 10% Philadelphia chromosome–positive cells, demonstrating continued

partial cytogenetic response. Her WBC count is normal.

Because the disease appears to be refractory to the higher

imatinib dose, what treatment options are available for

S.E.?

Although primary hematologic resistance is rare, primary

cytogenetic resistance at 6 months is seen in 15% to 25% of

patients started on imatinib therapy. Primary cytogenetic resistance is defined as failure of the patient to achieve any level of

cytogenetic response at 6 months, major cytogenetic response at

12 months, and complete cytogenetic response at 18 months.69

Resistance that occurs outside of these parameters is classified as

secondary resistance. In secondary resistance, disease progression is multifactorial and thought to be largely related to mutational changes in the BCR-ABL protein. Based on the 6-year

follow-up data from the IRIS trial, progressionfree survival was

91% for patients who achieved a complete cytogenetic response

compared with 58% in patients achieving a minor cytogenetic

response.79 As in S.E.’s case, dose escalation of imatinib from

2182Section 17 Neoplastic Disorders

TABLE 92-4

Binet Classification

Stage Lymphocytosisa Anemiab Thrombocytopeniac Number of Involved Nodes (Max 5)d Median Survival (Years)

A + – – <3 12

B + – – ≥3 7

C +± ± Any 2–4

a

Lymphocytes >5 × 109

/L in peripheral blood and >30% of total cells in the bone marrow. b

Hemoglobin <11 g/dL in men and <10 g/dL in women excluding immune-mediated etiology. c

Platelets <100,000/μL. d

Maximum of five—cervical, axillary, inguinal, spleen, and liver—are counted as one area.

Source: Binet JL et al. A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer. 1981;48:198.

400 mg daily to 400 mg twice daily is the preferred option for

patients presenting with cytogenetic resistance at 6 months as

demonstrated by a suboptimal cytogenetic response.69 Low levels of residual disease demonstrate the need for chronic TK

inhibitor therapy generally for the lifetime of the patient owing

to the high risk of relapse on discontinuation.80 Dasatinib or nilotinib are more active than imatinib for patients who have mutational changes in BRC-ABL. Because S.E. has not responded to

the higher dose of imatinib, dasatinib 100 mg daily or nilotinib

400 mg twice daily would be appropriate treatment options for

S.E.’s cytogenetic relapse. She should be continued on therapy

indefinitely, assuming she responds, along with continued routine cytogenetic evaluations.

CHRONIC LYMPHOCYTIC LEUKEMIA

Epidemiology and Pathophysiology

Leukemias are hematologic malignancies that are derived from

cytogenetic alterations in hematopoietic cells and are classified

based on the cell of origin (myeloid or lymphocytic) and clinical

course. Chronic lymphocytic leukemia (CLL) is a disorder of

mature but functionally incompetent lymphocytes. Lymphomas

are also disorders of lymphocytes; therefore, some molecular

abnormalities are shared between the diseases.

CLL is the most common type of leukemia in adults, with

approximately 15,000 new cases annually and 4,400 deaths.81

CLL is a disease of the older population, and the median age

at diagnosis is 65 years, with 90% of patients older than age

50 at diagnosis.82,83 CLL is characterized by overproduction of

functionally incompetent B-cell lymphocytes derived from a single stem cell clone in the bone marrow. These lymphocytes

accumulate in the blood, bone marrow, lymph nodes, and

spleen.

Presentation, Diagnosis, and Overview

of Treatment

Chronic leukemias follow a relatively insidious onset and course

compared with acute leukemias. Approximately 40% of patients

are asymptomatic at presentation and are diagnosed by routine

CBC (lymphocytosis, anemia, or thrombocytopenia).64 Symptomatic patients commonly experience night sweats, fatigue,

weight loss, fever, and painful lymphadenopathy. Patients often

seek medical attention for infection caused by immune suppression or bleeding caused by thrombocytopenia.

Predicting the clinical course of CLL remains a challenge as

some patients experience an indolent course and maintain a good

quality of life, whereas others experience more aggressive disease

and debilitation. Therefore, survival is variable and depends on

the stage of disease at diagnosis. CLL is staged based on peripheral lymphocyte counts; enlargement of lymph nodes, liver, and

spleen; and the presence of anemia or thrombocytopenia. The

two most commonly used staging systems in clinical practice

are shown in Tables 92-4 and 92-5. The Rai classification is

the most clinically useful because it contains prognostic information (Table 92-5). Low-risk patients (Rai stage 0) have survival

similar to that of age-matched control subjects. Intermediaterisk patients (stages I and II) have shorter survival, and high-risk

patients (stages III and IV) have poor prognosis. The Binet system

(Table 92-4) is based on the number of involved sites, platelets,

and hemoglobin and provides prognostic information.

Selection of therapy is in part determined by the presence

or absence of cytogenetic abnormalities such as del(11q) or

del(17p), comorbidities, and age. Common first-line therapies are

TABLE 92-5

Modified Rai Classification

Median

Hepatomegaly or Survival

Risk Stage Lymphocytosisa Anemiab Thrombocytopeniac Lymphadenopathy Splenomegaly (Years)

Low 0 + – – – –10

Intermediate I + – – + – 7

II + – – ± +

High III + + – ± ± 1.5–4

IV +± + ± ±

a

Lymphocytes >5,000/μL in peripheral blood and >30% of total cells in the bone marrow. b

Hemoglobin <11 g/dL excluding immune-mediated etiology. c

Platelets <100,000/μ/L

Source: Rai KR et al. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46:219.

2183Adult Hematologic Malignancies Chapter 92

chlorambucil with or without prednisone; bendamustine and rituximab; and cyclophosphamide and prednisone with or without rituximab in patients older than or equal to 70 years.

Fludarabine, cyclophosphamide, and rituximab (FCR) and fludarabine and rituximab are commonly used in patients younger

than 70 years. Relapsed disease is often treated with combinations

of the same drugs used for initial treatment. Although patients

with CLLs may survive for years with suppressive therapies, these

disorders are curable in only a fraction of patients who are candidates for immune-based approaches using chemotherapy and

HCT.

Signs and Symptoms

CASE 92-4

QUESTION 1: G.R., a 66-year-old man, presents to his physician with a persistent semiproductive cough and increased

fatigue. A routine CBC revealed an Hgb of 13.0 g/dL,

a WBC count of 34,000 cells/μL (80% lymphocytes), and

a platelet count of 175,000 cells/μL. Blood pressure was

120/70 mm Hg, heart rate 64 beats/minute, and respiratory rate 23 breaths/minute. He was afebrile. Physical examination was unremarkable. He was prescribed azithromycin

for possible community-acquired pneumonia and scheduled

for a return visit in 3 weeks. At that time, his CBC results

were Hgb 13.2 g/dL, WBC count 32,000 cells/μL (82% lymphocytes), and platelets 168,000 cells/μL. Physical examination was unchanged, the chest radiograph was clear, and

his cough had resolved. G.R. was referred to a hematologist

for evaluation of his persistent lymphocytosis. What is the

most likely cause of persistent lymphocytosis in G.R.?

CLL is usually included in the differential diagnosis of any

adult with persistent lymphocytosis (>5,000 lymphocytes/μL in

peripheral blood). Additional causes of lymphocytosis include

transient reactions to acute infections and viruses such as

influenza or mononucleosis, as well as other hematologic malignancies, including lymphoma and ALL.

To differentiate between benign and malignant lymphocytosis, examination of the peripheral blood or bone marrow morphology by a hematologist or pathologist may be required.

Patients with CLL commonly have lymphocytosis in both the

peripheral blood and bone marrow, whereas patients with other

disorders have a high percentage of atypical lymphocytes in the

peripheral blood alone. The absence of fever or additional signs

of infection without significant diagnostic or physical examination findings, together with the presence of mature peripheral blood lymphocytes, make CLL the most likely diagnosis

for G.R. Immunophenotyping and cytogenetics of involved cells

are required to establish the diagnosis and to provide prognostic

information and determine therapy. Bone marrow biopsy with

aspirate may be useful to determine the definitive diagnosis.84

Staging and Prognosis

CASE 92-4, QUESTION 2: G.R.’s bone marrow examination reveals normal cellularity with greater than 40% of

nucleated cells lymphocytes. The immunophenotype indicates that peripheral blood lymphocytes are predominately

B cells and are positive for CD5, CD19, and CD20. A diagnosis of CLL is confirmed. Is G.R.’s presentation consistent

with CLL? What is the prognosis for G.R.’s disease? What

treatment is indicated at this time? G.R.’s cells were sent

for routine cytogenetic analysis, which revealed a chromosome abnormality (deletion 11q). How does this affect his

management?

G.R. has fatigue, infection, and lymphocytosis without

lymphadenopathy, and these are consistent with low-risk CLL

based on his Modified Rai stage. Given his stage, G.R. has an

expected survival of at least 10 years.82,85

An accepted treatment modality for early-stage disease

includes a conservative, watchful waiting approach. No clear

advantage has been demonstrated in treating asymptomatic

patients in early-stage disease with alkylator-based chemotherapy as compared with deferred treatment.86 The survival of

patients with smoldering CLL is similar to an age- and sexmatched normal population.87,88

There is significant heterogeneity in the clinical course of

CLL that is in part attributable to the biological differences

between tumors. Scientific advances have led to the discovery of

chromosomal abnormalities (deletions 11q or 17p), gene mutations (unmutated immunoglobulin variable region and p53), and

serum or cell surface markers (increased β2 microglobulin, zetaassociated protein-70, and CD38 expression) that may confer

poor prognosis.89–92 The deletion 13q is the most common cytogenetic abnormality, occurring in 55% of patients, and it has a

favorable prognosis (survival >10 years). The deletion 11q and

deletion 17p occur in 18% and 7%, respectively, with shorter survival times of approximately 7 and 3 years, respectively. Current

national guidelines take into account some of these factors in

their treatment recommendations.

Despite his early stage by the Modified Rai classification, G.R.

had an 11q deletion, conferring a worse prognosis; he would be

encouraged to start treatment. However, as a result of having

minimal symptoms, G.R. chooses to delay treatment until he

becomes symptomatic.

Treatment

CASE 92-4, QUESTION 3: G.R. returns to the hematologist every 3 months and has no new symptoms or infectious complications for about 2 years. At that time, physical

examination reveals enlargement of cervical, inguinal, and

axillary lymph nodes; hepatomegaly; and splenomegaly. His

WBC has increased from 34,000 cells/μL 6 months ago to

68,000 cells/μL today (85% lymphocytes). His Hgb is 11.7

g/dL, and his platelet count is 140,000 cells/μL. What treatment is now indicated?

Indications for treatment initiation in CLL include significant

anemia or thrombocytopenia, progressive disease demonstrated

by lymphadenopathy, hepatomegaly, splenomegaly, a lymphocyte doubling time of less than 6 months, persistent B symptoms (fever, night sweats, and weight loss), threatened end-organ

function, and recurrent infection. Patient performance status,

comorbid conditions, pharmacoeconomic variables, and social

support should all be taken into consideration when selecting

treatment. Cytogenetic results will also be considered. Because

G.R. has experienced significant lymphadenopathy and hepatosplenomegaly, he should initiate treatment at this time to

prevent further deterioration of his hematologic and immune

function.

INITIAL THERAPY

CHLORAMBUCIL

Therapy for CLL has historically included use of an alkylating

agent, most often oral chlorambucil or cyclophosphamide, with

2184Section 17 Neoplastic Disorders

or without prednisone. A variety of daily and intermittent dosing

schedules have been reported. The overall response (OR) rate

to chlorambucil was approximately 40% to 60%, but only 3%

to 5% achieved a CR.82 Chlorambucil use has diminished, and

the use of purine analogs, such as fludarabine and cladribine, is

more common in clinical practice; however, chlorambucil with

or without prednisone is recommended for patients older than

or equal to 70 years, or in younger patients if they have significant

comorbidities.93

FLUDARABINE