American MiniHandbook of Hematologic Malignancies

Beaven, MD Division of Medical Oncology, Department of Medicine Duke University Medical Center Durham, North Carolina Gerard C.. Blobe, MD, PhD Division of Medical Oncology, Department o

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Oxford American Mini-Handbook

of Hematologic Malignancies

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This material is not intended to be, and should not be considered,

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Oxford American Mini-Handbook

of Hematologic Malignancies

Gary H Lyman, MD, MPH,

FRCP (Edin)

Professor of Medicine and Senior Fellow

Duke Center for Clinical Health Policy ResearchDuke University

Durham, North Carolina

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The Library of Congress has cataloged the Oxford American Handbook

Oxford American handbook of oncology / edited by Gary H Lyman

p ; cm — (Oxford American handbooks)

Adapted from: Oxford handbook of oncology 2nd ed 2006

Includes bibliographical references and index

ISBN 978-0-19-536061-2 (ﬂ exicover : alk paper)

1 Cancer—Handbooks, manuals, etc 2 Oncology—Handbooks, manuals, etc

I Lyman, Gary H., M.D II Oxford handbook of oncology III Title: Handbook

of oncology IV Series

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Disclosures

Dr Lyman has been on the Speakers’ Bureau as well a grants/research support recipient at Amgen He has also been on the Speaker’s Bureau at Ortho Biotech

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Contributors ix

Part I Introduction

1 Molecular cancer pathology 3

2 Molecular alterations in cancer 5

Part II The hematological malignancies

4 Acute myeloid leukemia (AML) 21

5 Acute lymphoblastic leukemia (ALL) 29

Part III Chronic leukemias and

12 Management strategies for NHL 93

13 Non-Hodgkin lymphoma and acquired

Part V Treatment and management

for hematological malignancies

14 Hematopoietic stem cell transplantation 105

Contents

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Anne W Beaven, MD

Division of Medical Oncology, Department of Medicine

Duke University Medical Center

Gerard C Blobe, MD, PhD

Carlos M DeCastro, MD

Louis F Diehl, MD

Phuong L Doan, MD

Department of Medicine

Phillip Febbo, MD

Daphne Friedman, MD

Contributors

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David Rizzieri, MD

Division of Cellular Therapy

Marvaretta M Stevenson

Division of Medical Oncology and Cellular Therapy

J Brice Weinberg, MD

Division of Hematology, Department of Medicine

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Part 1

Introduction

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be referred to as oncogenesis Genetic alterations can take the form

of mutations (changes in the sequence of the DNA code), deletions (loss of sections of DNA), ampliﬁ cations (multiple copies of the same DNA section), or epigenetic changes (altering the methylation status

of DNA, resulting in activation or repression of genes in the region)

In the aggregate, multiple changes in the DNA of cancer cells alter normal cellular physiology so as to allow limitless proliferation, in-dependence from external growth-promoting or growth-inhibiting inﬂ uences, avoidance of programmed cell death (apoptosis), and re-cruitment of blood vessels (angiogenesis) Mutations in DNA repair genes appear to be a necessary feature of most cancers

For cancer to spread beyond the site of origin, additional changes, including loss of cellular polarity, decreased intracellular adhesion, and migratory and/or invasive characteristics, are often required

Most normal human cells can be transformed into tumor-forming cells by the introduction of four changes: the activation of telomerase (an enzyme that protects the ends of replicating chromosomes), the viral protein Large T (which inhibits p53 and Rb proteins), the viral protein small t (which inactivates the signaling protein PP2A), and the

expression of an activated Ras oncogene Although this represents a

minimal number of genetic changes required for human cells to acquire tumor-like characteristics, the development of a cancer in a person is likely to require additional changes

Carcinogenesis

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Recent work suggests that colon cancers have, on average, nine mutations in cancer-related genes Thus, while the genetic basis of cancer has been established, there remains a far from complete under-standing of the oncogenic process

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Types of molecular alterations

• Germ-line: Although rare, result in hereditary (or familial) cancers

Somatic

• : Most common, result in sporadic cancers

Genetic

• : Result in changes in the primary DNA sequence

Point mutation (alteration of a base pair)

cially common in hematologic malignancies, see Table 2.1)

Gene ampliﬁ cation (increasing gene copy number) promoted by

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Table 2.1 Recurrent balanced rearrangements in hematological malignancies

Disease Affected gene Rearrangement Hemapoietic tumors

Lymphoid

Anaplastic large

cell lymphoma

NPM-ALK TPM3-ALKTFG-ALK

ATIC-ALKMSN-ALKCLTCL-ALK

t(2;5)(q23;q35)t(1;2)(q25;p23)t(2;3)(p23;q21)inv(2)(p23q35)t(X;2)(q11–12;p23)t(2;17)(p23;q23)Burkitt

lymphoma,

B-cell ALL

MYC (relocation of IgH locus)MYC (relocation of IgK locus)MYC (relocation of IgL locus)

t(8;14)(q24;q32)t(2;8)(p12;q24)t(8;22)(q24;q11)B-cell precursor

acute lymphoid

leukemia

E2A-PBX1E2A-HLFTEL-AML1BCR-ABLMLL-AF4IL3-IgH

t(1;19)(q23;p13)t(17;19)(q22;p13)t(12;21)(p12;q22)t(9;22)(q34;q11.2)t(4;11)(q21;q23)t(5;14)(q31;q32)Extranodal

mucosa-associated

lymphoid tissue

MALT1-API2MALT1-IgHBCL10-IgHBCL10-Igk

t(11;18)(q21;q21)t(14;18)(q32;q21)t(1;14)(p22;q32)t(1;2)(p22;p12)Plasma cell

myeloma

FGFR3-IgH and MMSETMAF-IgH

MAF-IglCCND1-IgHMUM/IRF4-IgH

t(4;14)(p16;q32)t(14;16)(q32;q23)t(16;22)(q23;q11)t(11;14)(q13;q32)t(6;14)(p25;q32)Pre-T cell

HOX11 (Relocation to TCRD/G)HOX1–1L2 CALM-AF10NUP98-RAP1GDS1

t(8;14)(q24;q11)t(7;19)(q35;p13)t(1;14)(p32;q11)t(14;21)(q11;q22)t(11;14)(p15;q11)t(11;14)(p13;q11)t(10;14)(q24;q11)t(5;14)(q35;q32)t(10;11)(p13;q21)t(4;11)(q21;p15)

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Oncogenes (see Table 2.2)

• Derived from normal cellular genes

Encode proteins that control cell growth and/or survival

t(1;22)(p13;q13)t(3;5)(q25;q34)t(3;21)(q26;q22)Reproduced with permission from Gasparini P, Sozzi G, Pierotti MA (2007) The role of

chromosomal alterations in human cancer development J Cell Biochem 102:320–331.

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Growth factors and growth factor receptors

• Either overexpression of the growth factor or constitutive activation

of the growth factor receptor occurs

Signal transduction molecules

• Either nonreceptor protein kinases or guanosine-triphosphate binding proteins (G proteins)

Nonreceptor protein kinases include both tyrosine kinases (ABL,

•

SRC) and serine/threonine kinases (AKT, RAF)

Usually activating mutations (constitutive or increased activity)

•

Transcription factors

Growth factors and growth factor receptors

Signal transduction molecules

Table 2.2 Examples of oncogenes

Oncogene Cancer Alteration

Growth factor receptors

EGFR Colon, lung Ampliﬁ cation, mutationNEU Breast, lung Ampliﬁ cation, mutation

Signal transduction molecules

constitutive activationH-RAS, K-RAS, N-RAS Colon, lung,

pancreas

Viral homologue, mutation

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Tumor suppressor genes (see Table 2.3)

• Encode proteins in pathways that normally control cellular stasis (growth, survival)

homeo-Usually loss of function or decreased function relative to normal

tion), epigenetic, or both

Can result in either familial cancer syndromes or sporadic cancers

•

Regulators of apoptosis

Tumor suppressor genes (see Table 2.3)

Table 2.3 Examples of tumor suppressor pathways and genes

Tumor suppressor

pathway/genes

Familial cancer syndrome

Sporadic cancer

Hedgehog (PTC) Gorlin syndrome Breast, esophageal,

gastric, medulloblastoma, pancreatic HIF-1 (VHL) von Hippel–Lindau

Most cancersTP53 pathway Li-Fraumeni syndrome Breast, colon, lung,

many othersTransforming growth

factor-B (TGFBR2,

SMAD4)

Hereditary polyposis colon cancer

non-Colorectal, gastric, pancreaticWnt (APC) Familial adenomatous

polyposis coli

Colorectal, gastric, pancreatic, prostate

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MicroRNA genes (see Table 2.4)

• Encode a single strand of RNA that anneals to mRNA to either degrade the mRNA or block translation of the mRNA

Many microRNA genes occur in chromosomal regions involved in

lating tumor suppressor genes

Downregulated microRNA genes function as tumor suppressor

•

genes by downregulating oncogenes

MicroRNA genes (see Table 2.4)

Table 2.4 Examples of microRNA genes

MicroRNA Target (effect) Cancer

MiR21 PTEN (decreased) Breast, lung,

prostate

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Deregulation of the cell cycle

One critical step in oncogenesis includes changes in genes that regulate cell growth and behavior so as to facilitate uncontrolled proliferation The process of cell division is very similar in cancer and normal cells, but in many cases cancers exhibit loss of control of the cell cycle

Cell cycle phases

The normal somatic cell cycle consists of two alternate phases

Cells may become quiescent and nondividing by leaving the cell cycle

at G1 to enter a G0 phase It is thought that cancer progenitor cells (also referred to commonly as cancer “stem cells”) are often in the G0 phase

Many of the molecules that drive and regulate the cell cycle have

been identiﬁ ed One important group consists of proteins called cyclins

that can propel cells through the cycle by the activation of dependent kinases (CDKs)

cyclin-Regulation of the cell cycle normally ensures that cells have precise control of DNA duplication and subsequent cell division, protecting

Deregulation of the cell cycle

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or inaccurate replication often result initially in cell cycle arrest.

Cell cycle control is essential to protect the integrity of normal genes

G1–S transition

Exactly when a cell moves from G1 to S is tightly controlled to sure survival, with factors such as cell size, metabolic state, growth factor availability, and DNA damage affecting whether a transition takes place The most important checkpoint in the cell cycle is the restriction point, just before entry into S phase Passage through this checkpoint is regulated by a number of growth factors and a number

en-of critical genes, including p53.

p53 plays a key role in maintaining genomic stability Normal cells

with DNA damage become arrested in G1 and/or undergo programmed

cell deaths (apoptosis) under the control of this gene p53 is the most

commonly mutated gene in human cancer, which is not surprising since loss of control of genomic stability is a central feature of cancers

p53

• controls passage between M1 and S phase

“Guardian of the genome”

marily by ampliﬁ cation of the MYC gene, but many more common types

of cancers also have ampliﬁ cation of the MYC oncogene Interestingly, if MYC is ampliﬁ ed in a normal cell, apoptosis often results.

A second change decreasing normal cell checkpoints is required in most cells in order for MYC to increase proliferation without causing apoptosis

Cell cycle in cancer

Cancer cells characteristically demonstrate abnormalities in cell cycle and its control Key features include:

Uncontrolled proliferation with no physiological requirement

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ence of damaged DNA

Genomic instability with accumulation of multiple gene mutations

•

Independence from external growth-promoting

and growth-inhibiting signals

Many normal cells enter the cell cycle (or delay entering the cell cycle)

through growth signals from their environment Either through

endo-crine (signals from distant cells) or paraendo-crine (signals from adjacent

cells) mechanisms, normal cells have a host of membrane-bound,

cy-toplasmic, and nuclear receptors that detect and relay growth signals

to the cells, either stimulating or inhibiting initiation of the cell cycle

Independence from these external growth signals is a common feature

of cancer cells

Receptor tyrosine kinases (RTKs) are membrane-bound proteins

that relay growth signals Members of this family of proteins commonly

overexpressed in cancers include:

Epidermal growth factor receptor 1 (EGFR/Her1)

Almost all cancers have constitutive activation of an RTK or

down-stream signaling member of an RTK pathway

A paradigmatic example of how this mechanism is important in cancer

oncogenesis includes small deletions of the EGFR gene encoding for

the intracellular portion of the receptor The subsequent change in the

protein results in constitutive activation that is independent of any

ex-tracellular signals These mutations have been found primarily in lung

cancers, but similar activating mutations in other family members or

other components of the pathways involved in sensing growth signals

are found in most cancers

Overall, changes in the sensing of external growth signals include:

Constitutive activation of pro-growth RTKs

•

Inactivating mutations, deletion, or epigenetic silencing of

growth-•

inhibiting factors

Independence from external growth-promoting

and growth-inhibiting signals

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promoting signaling pathways

A paradigm of the last point, constitutive activation of downstream members of growth-promoting signaling pathways, includes activating

mutations of the RAS oncogene In normal cells, RAS is activated by

RTKs when they detect growth-promoting factors In many types of cancers, most notably colon, pancreatic, and lung cancers, a speciﬁ c

mutation of the RAS gene results in constitutive activation.

Limitless replication

Most cells undergo a limited number of replications before becoming terminally differentiated and eventually experiencing programmed cell

death (called apoptosis; see next page) If human cells are grown in

tis-sue culture with supportive media that provide all their nutritional and metabolic requirements, they will grow and proliferate for approx-imately 10 to 15 population doublings, then stop dividing and expe-

rience senescence, characterized by a nonproliferative, metabolically

inactive cell

During DNA replication and cell division, the ends of each chromosome become shorter in the daughter cells It is thought that this progressive shortening eventually results in the loss of critical DNA sequence and senescence

A protein complex referred to as telomerase is now known to

pro-tect the ends of each chromosome during cell division by replacing the lost ends with repetitive DNA sequence Cancers have been shown to routinely overexpress telomerase, thus protecting them from progres-sive shortening of the chromosomes and facilitating effectively limit-less proliferation Although telomerase is most commonly found to be activated in cancers, approximately 15% of tumors use an alternative mechanism that remains poorly understood

Telomerase protects the ends of the chromosome, replacing lost

•

genetic material after each replication

Most cancers have increased telomerase activity

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Evasion of apoptosis

Apoptosis refers to programmed cell death and represents the natural

end to most cells in the human body Evasion from apoptosis is one mechanism by which normal cells can become transformed

Two basic apoptotic pathways exist The intrinsic pathway generally results from cells sensing DNA damage or other internal stress and activating cytochrome C release from the cellular mitochondria, with the subsequent activation the apoptosome complex and a cascade of

proteases called the caspases.

The extrinsic pathway is triggered by external signals such as TRAIL

or CD95 ligand but also eventually results in activation of the caspases Inhibition of the intrinsic apoptotic pathway and/or insensitivity to the extrinsic apoptotic pathways is critical to the development and pro-gression of cancer cells

Follicular lymphoma is a cancer that results from the overexpression

of bcl-2 through a genetic translocation—the aberrant juxtaposition of two pieces of DNA generally located on different chromosomes or

parts of chromosomes In follicular lymphoma, the bcl-2 gene is placed

adjacent to a gene that is generally expressed at much higher levels

As a result, bcl-2 is expressed at much higher levels and signiﬁ cantly

decreases intrinsic activation of apoptosis

Establishing angiogenesis

Without recruiting new blood vessels, the size and extent of a tumor

is severely limited The recruitment and development of blood sels (angiogenesis) is a universal characteristic of cancer cells Often, cancer cells will express factors promoting blood vessel growth This has been observed in different laboratory experiments: When cancer cells are compared to normal cells, they more rapidly and robustly establish blood vessels

ves-Growth factors that can be used to recruit blood vessels include:

Vascular endothelial growth factor (VEGF I and 2, especially

impor-•

tant in hematologic malignancies, see Figure 3.1)

Platelet-derived growth factor (PDGF

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carcinoma and in sporadic clear-cell carcinoma, mutations in the von

Hippel–Lindau (VHL) gene are found approximately 85% of the time VHL normally acts to suppress the activity of a gene called hypox-

ia-induced factor 1 A (HIF1a) When cells experience hypoxia, VHL

releases HIF1a, which acts as a transcription factor and increases the expression of genes that encourage new blood vessel formation (VEGF

and others) The mutations of VHL found in familial and sporadic renal cell carcinoma also result in the release of HIF1a and the constitutive

activation of signals encouraging new blood formation

In hematological malignancies, angiogenesis occurs in the bone row, which is composed of malignant cells, endothelial cells, pericytes,

mar-ﬁ broblasts, and other cell types These in turn closely interact with the extracellular matrix Inhibition of angiogenesis therefore has not only a hypoxic effect, as a result of limited oxygen delivery, but also the effect

of disrupting the interaction of these cellular components with their microenvironment and the paracrine effects they exert to maintain the malignant phenotype

Figure 3.1 VEGF Signaling in Hematologic Malignancies This research was

originally published in Blood Podar K, Anderson KC (2005) The

pathophysio-logic role of VEGF in hematopathophysio-logic malignancies: therapeutic implications Blood

Hypoxia mutRas Bcr-Abl

CD40/

VEGFR-1

HIF-1α c-maf

IGF-1 IL-6

p53

VEGF-A

ICAM1/LFA-1 VCAM1/VLA4

B

C

D

E F

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Invasion and metastasis

Most patients who die from cancer die from complications due to the metastatic spread of cancer cells throughout the body Together with all the characteristics discussed above, cancer cells are frequently found to have the following characteristics:

Some molecular changes associated with metastasis include:

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Part II

The hematological malignancies

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The median age at diagnosis is 67 years AML causes 80% of acute leukemia cases in adults.

Etiology

In most individuals with AML, the cause is unknown

Environmental factors have been associated with the development of AML, including:

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Central nervous system involvement is rare, but can occur

•

Altered mental status may develop in the setting of hyperleukocytosis

•

Diagnosis and classiﬁ cation

In many instances, diagnosis of AML is made by the primary care provider

Anemia with a low or normal reticulocyte count, penia, and leukopenia are commonly found on examination of periph-eral blood Less frequently, leukocytosis is present at diagnosis

thrombocyto-Although myeloblasts are present in the peripheral blood, their identiﬁ cation requires careful evaluation in patients with leukopenia

By contrast, myeloblasts are readily identiﬁ ed in the bone marrow, where they represent between 20% and 95% of marrow cells in AML.The diagnosis of AML relies on specimens from bone marrow and peripheral blood:

assumed an important role in the diagnosis of AML

Various systems have been developed to classify AML:

The FAB system categorizes AML based on the distinctive subgroups

•

described under Pathology (see p 22)

The World Health Organization (WHO) classiﬁ cation of AML is

•

based on molecular characteristics of the disease deﬁ ned at the time

of diagnosis and a patient’s clinical history (see Box 4.1)

Diagnosis and classiﬁ cation

Box 4.1 WHO classiﬁ cation of acute myeloid leukemia

Acute myeloid leukemia with recurrent genetic abnormalities,

•

including t(8;21), inv(16), and t(15;17)

Acute myeloid leukemia with multilineage dysplasia

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Poor-risk cytogenetic ﬁ ndings include monosomy chromosome 5

or 7, del(5q), and complex karyotype

A normal karyotype and other karyotypes not classiﬁ ed as either good or poor risk are categorized as standard risk

Speciﬁ c gene mutations also carry prognostic signiﬁ cance Mutation

of FLT3, for example, is associated with decreased survival whereas NPM1 mutation is associated with improved survival.

Poor prognostic factors include:

initi-An echocardiogram is obtained to assess cardiac function prior to chemotherapy, as anthracycline agents used in treatment of AML can

be cardiotoxic

Prognosis

Treatment

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If the WBC count is >100,000/mm, cytoreduction with hydroxyurea

to minimize complications of hyperleukocytosis may be achieved

Allopurinol should be administered to treat or prevent cemia if the uric acid level is elevated or a high percentage of blasts are present in the bone marrow or peripheral blood

hyperuri-Finally, effective antiemetic therapy has been an important advance

in the care patients with AML

Induction chemotherapy

The goal of AML treatment is to eradicate the malignant cell tion, thus allowing normal stem cells to repopulate the bone marrow.The standard induction regimen used to achieve remission in AML—the so-called 7 & 3 regimen—includes cytarabine for 7 days and daunorubicin for 3 days The anthracycline idarubicin or the anthraqui-none mitoxantrone can be substituted for daunorubicin

popula-A complete remission with <2% marrow blasts, neutrophil count

>1000/mm3, and platelet count >100,000/mm3 is the goal of induction therapy If a patient harbors residual leukemia after induction therapy,

a second course of chemotherapy similar to the ﬁ rst is given

Patients with t(8;21) are particularly responsive to high-dose bine Patients who receive high-dose cytarabine receive corticosteroid eye drops to prevent conjunctivitis and are monitored for cerebellar toxicity

cytara-No consistent role for maintenance chemotherapy in AML has been deﬁ ned

A general scheme for treatment of AML includes the following:

Induction Rx Consolidation Rx ? Role of maintenance Rx

Diagnosis l Remission l Long term remission/Cure

Stem cell transplantation in AML

Stem cell transplantation represents an important treatment modality

in the management of patients with AML It can be employed during

ﬁ rst remission in patients considered at high risk for relapse, based on prognostic features

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Stem cell transplantation is also an option for patients in second remission following disease relapse

Autologous transplantation

In autologous transplantation, stem cells are collected from the patient

in remission and reinfused following high-dose chemo and/or therapy Residual leukemia cells can be purged from the stem cell har-vest, although this technique has not yielded improvements in survival

compat-An HLA-matched sibling represents the ideal donor, but in only 10%–20% of cases is such a match available Other potential donors include HLA-matched unrelated donors and HLA-mismatched family members

Patients deemed too old or frail for myeloablative regimens are candidates for nonmyeloablative transplantation, a technique that relies

primarily on the graft-versus-leukemia effect of donor cells

Treatment of acute promyelocytic leukemia

The management of acute promyelocytic leukemia (APL) warrants ditional discussion because it differs from that of other forms of AML.With current therapy, APL is associated with high rates of response

ad-and survival t(15;17), which results in formation of the PML/RAR-A

fusion gene, is the genetic hallmark of APL

With regard to clinical features of the disease, the presence of seminated intravascular coagulation (DIC) at diagnosis distinguishes APL from other forms of acute leukemia DIC places the patient at risk for severe, life-threatening hemorrhage and thus is managed as a medical emergency

dis-Induction chemotherapy regimens for APL combine all-trans

reti-noic acid (ATRA), which targets the PML/RAR-A fusion product, with daunorubicin and cytarabine Patients who respond to induction then receive daunorubicin and cytarabine as post-remission therapy, fol-lowed by maintenance ATRA for up to 1 year

Recent evidence suggests arsenic trioxide has activity against APL in the induction and post-remission settings

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Emerging therapies in AML

With further characterization of genetic events underlying AML, novel therapies for the disease are emerging

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal

antibody, is now approved for use as monotherapy in patients t60 years with relapsed AML who are not considered candidates for cyto-toxic chemotherapy Ongoing research seeks to deﬁ ne the therapeutic role of multidrug-resistance modulators:

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