90 Acute Lymphoblastic Leukemia

Question 1

TRUE OR FALSE

Most cases of ALL occur in children, but most deaths from ALL occur in adults.

Answer 1

TRUE

Most cases of ALL occur in children, but most deaths from ALL occur in adults.

Question 2

Heritable cancer predisposition syndromes associated with increased ALL

Answer 2

Li Fraumeni syndrome with germline TP53 mutation

Question 3

Approximately 61% of patients with ALL are diagnosed before the age of _________

Answer 3

before the age of 20 years

Only 20% of adult acute leukemias are ALL, but about one-third of ALL cases are in adults

Question 4

Almost all ALL patients with Down syndrome have a deletion of

Answer 4

IKZF1.31

Genetic abnormalities more commonly associated with Down syndrome, such as +X, del(9), and CEBPD rearrangement

Question 5

Autosomal recessive genetic diseases associated with increased chromosomal fragility and a predisposition to ALL include:

Answer 5

Ataxia-telangiectasia
Nijmegen breakage syndrome
Bloom syndrome

Question 6

These genes are key regulators of blood cell development, and acquired mutations of each are also detected in ALL cases

Consistently associated with childhood ALL

Answer 6

IKZF1, ARID5B, CEBPE, and CDKN2a

Question 7

The hypothesis that suggests that some susceptible individuals with a prenatally acquired preleukemic clone had low or no exposure to common infections early in life because they lived in affluent hygienic environments.

Such infectious insulation predisposes the immune system of these individuals to aberrant or pathologic responses after subsequent or delayed exposure to common infections at an age commensurate with increased lymphoid cell proliferation.

Answer 7

“Delayed infection” hypothesis

Question 8

The hypothesis that predicts that clusters of childhood ALL result from exposure of susceptible (nonimmune) individuals to common but fairly nonpathogenic infections after population mixing with carriers.

Answer 8

“Population-mixing” hypothesis

Question 9

The most frequent genetic (chromosomal) abnormality in ALL

Answer 9

Translocations

Question 10

Most common genetic abberations in childhood

Answer 10

Hyperdiploidy (>50 chromosomes)

23-29%

2nd: t(12;21)(p13;q22) [ETV6-RUNX1] 20–25%

Question 11

Most common genetic abberations in adults

Answer 11

t(9;22)(q34;q11.2) [BCR-ABL1]

25–30%

Question 12

Genetic abnormalities found in T-cell ALL

Answer 12

NOTCH1 mutations
HOX11L2 overexpression
LYL1 overexpression
TAL1 overexpression
HOX11 overexpression

Question 13

Encodes a paired-domain protein required for the pro–B-cell to pre–B-cell transition and B-lineage fidelity

Most frequent target gene in ALL

Answer 13

PAX5

Question 14

Second most frequently involved gene

Required for the earliest lymphoid differentiation

Answer 14

IKZF1

IKZF1 was deleted in the vast majority of cases of BCR-ABL1 ALL cases as well as chronic myeloid leukemia in lymphoid blast crisis (but not chronic phase).

Very poor outcome

Contributes to treatment resistance in ALL

Question 15

Intracranial hemorrhage occurs mainly in patients with an initial leukocyte count greater than

Answer 15

400 × 109/L

Question 16

Most common sites of extramedullary involvement, and the degree of organomegaly is more pronounced in children than in adults

Answer 16

Liver, spleen, and lymph nodes

Question 17

Overt testicular disease can be readily diagnosed by

Answer 17

Ultrasonography

Question 18

TRUE OR FALSE

Overt testicular disease is relatively rare, is generally seen in adults with B-cell leukemia and/or hyperleukocytosis, and does require radiation therapy.

Answer 18

FALSE

Overt testicular disease is relatively rare, is generally seen in infants or adolescents with T-cell leukemia and/or hyperleukocytosis, and does not require radiation therapy.

Question 19

Patients with hyperleukocytosis are more likely to have _______________ ALL

Answer 19

T-cell ALL

Hyperleukocytosis occurs more often in black children (23%) and in adults (16%)

Question 20

TRUE OR FALSE

Hypereosinophilia, generally reactive, may precede the diagnosis of ALL by several months.

Answer 20

TRUE

Hypereosinophilia, generally reactive, may precede the diagnosis of ALL by several months.

• Mostly male
• Have ALL with the t(5;14)(q31;q32) chromosomal abnormality and a hypereosinophilic syndrome (pulmonary infiltration, cardiomegaly, and congestive heart failure)

Question 21

Coagulopathy, usually mild, can be seen in 3% to 5% of patients, most of whom have ____ ALL, and is only rarely associated with clinical bleeding

Answer 21

T-cell ALL

Question 22

Translocation found in 0.5% of B-cell precursor ALL, is associated with adolescent age, disseminated coagulopathy, hypercalcemia, and dismal prognosis.

Answer 22

t(17;19)(q22;p13.3) with E2A-HLF fusion

Question 23

TRUE OR FALSE

Examination of the cerebrospinal fluid (CSF) is an essential diagnostic procedure.

Answer 23

TRUE

Examination of the cerebrospinal fluid (CSF) is an essential diagnostic procedure.

Leukemic blasts can be identified in as many as one-third of pediatric patients and approximately 5% of adult patients at diagnosis of ALL; most of these patients lack neurologic symptoms.

Most protocols now require the procedure at diagnosis and instill the first dose of chemotherapy intrathecally.

Question 24

Morphologic characteristics of lymphoblasts

Answer 24

Small (ranging from the same size to twice the size of small lymphocytes), with scanty, often light-blue cytoplasm, a round or slightly indented nucleus, fine to slightly coarse and clumped chromatin, and inconspicuous nucleoli

Question 25

Are characterized by intensely basophilic cytoplasm, prominent nucleoli, and **cytoplasmic vacuolation**

Answer 25

B-cell blasts in Burkitt-type ALL

Question 26

Typical panels include antibodies to at least one highly sensitive marker and antibodies to a highly specific marker

Answer 26

*Highly sensitive markers:* **CD19** for B-cell lineage **CD7** for Tcell lineage, and **CD13 or CD33** for myeloid cells *Highly specific markers:* **cytoplasmic CD79a and CD22** for B-cell lineage, **cytoplasmic CD3** for T-cell lineage, and **cytoplasmic myeloperoxidase** for myeloid cells

Question 27

# Immunologic Subtype of ALL Infants and adult age group, high leukocyte count, initial CNS leukemia, pseudodiploidy, MLL rearrangement, unfavorable prognosis

Answer 27

Pro-B

Question 28

# Immunologic Subtype of ALL Favorable age group (1–9 years), low leukocyte count, hyperdiploidy (>50 chromosomes)

Answer 28

Early pre-B

Question 29

# Immunologic Subtype of ALL High leukocyte count, black race, pseudodiploidy

Answer 29

Pre-B

Question 30

# Immunologic Subtype of ALL Male predominance, initial CNS leukemia, abdominal masses, often renal involvement

Answer 30

Mature B cell (Burkitt)

Question 31

# Immunologic Subtype of ALL Male predominance, hyperleukocytosis, extramedullary disease

Answer 31

T Cell

Question 32

# Immunologic Subtype of ALL Male predominance, hyperleukocytosis, extramedullary disease, unfavorable prognosis

Answer 32

Pre-T

Question 33

**CD15, CD33, and CD65** are expressed in ALL cases with a rearranged ________ gene

Answer 33

MLL gene ## Footnote *The presence of myeloid-associated antigens lacks prognostic significance in contemporary treatment programs but can be useful in immunologic monitoring of patients for minimal residual leukemia.*

Question 34

**CD13 and CD33** are expressed in cases with the _________

Answer 34

ETV6-RUNX1 ## Footnote *The presence of myeloid-associated antigens lacks prognostic significance in contemporary treatment programs but can be useful in immunologic monitoring of patients for minimal residual leukemia.*

Question 35

# Prognosis: Hyperdiploidy (>50 chromosomes): Hypodiploidy (≤44 chromosomes):

Answer 35

**Hyperdiploidy (>50 chromosomes)**: favorable **Hypodiploidy (≤44 chromosomes)**: poor ## Footnote Near haploidy (25–29 chromosomes) is restricted largely to young children Low hypodiploidy (33–39 chromosomes) is characterized by structural abnormalities and older age High hypodiploidy (42–44 chromosomes) with complex karyotypes Low-hypodiploid ALL is also associated with mutations in the tumor suppressor gene TP53

Question 36

# TRUE OR FALSE Azoles should be avoided when vincristine is given.

Answer 36

TRUE Azoles should be avoided when vincristine is given.

Question 37

# TRUE OR FALSE If mercaptopurine and allopurinol are given together orally, the dosage of mercaptopurine must be reduced.

Answer 37

TRUE If mercaptopurine and allopurinol are given together orally, the dosage of mercaptopurine must be reduced.

Question 38

Extreme **leukocytosis** in ALL is defined as WBC >

Answer 38

>400 × 109/L

Question 39

Management of hyperleukocytosis

Answer 39

* Leukapheresis or exchange transfusion (in small children) * Glucocorticoids, with addition of vincristine and cyclophosphamide

Question 40

Alternative treatments for patients who cannot tolerate trimethoprim-sulfamethoxazole ## Footnote **Trimethoprim-sulfamethoxazole, 2–3 days per week**, as prophylactic therapy for Pneumocystis carinii (Pneumocystis jiroveci) pneumonia

Answer 40

Aerosolized pentamidine, dapsone, and atovaquone ## Footnote Prophylaxis is started after 2 weeks of remission induction and continues for several months after completion of all chemotherapy

Question 41

# TRUE OR FALSE Live-virus vaccines should be administered during immunosuppressive therapy.

Answer 41

FALSE Live-virus vaccines should **not** be administered during immunosuppressive therapy.

Question 42

Childhood ALL cases are divided into

Answer 42

* Standard-risk * High- (intermediate- or average-) risk * Very-high-risk ## Footnote Adult cases are generally divided into 2 risk groups.

Question 43

# TRUE OR FALSE In Burkit Leukemia, cranial irradiation does not appear to be necessary, even for patients presenting with CNS leukemia.

Answer 43

TRUE In Burkit Leukemia, cranial irradiation does not appear to be necessary, even for patients presenting with CNS leukemia.

Question 44

Treatment for leukemias affecting the precursor B-cell and T-cell lineages consists of three standard phases:

Answer 44

* Remission induction * Intensification (consolidation) * Prolonged continuation (maintenance)

Question 45

“Molecular” or “immunologic” remission, defined as leukemia less than

Answer 45

**0.01%** of nucleated marrow cells

Question 46

Steroid that provides better control of systemic and CNS disease

Answer 46

Dexamethasone

Question 47

Preparation and doses of asparaginase

Answer 47

* Pegaspargase : 2500 IU/m2 IV or intramuscularly every other week for 1–2 doses * Calaspargase: 2500 U/m2 IV every 3–4 weeks * Erwinia preparation: 20,000 IU/m2 IV or intramuscularly three times per week for 6–12 doses * E coli L-asparaginase: 5000–10,000 IU/m2 IV or intramuscularly administered 2–3 times per week for 6–12 doses ## Footnote Erwinia preparation has the shortest half-life

Question 48

# TRUE OR FALSE In terms of leukemic control, the dose intensity and duration of asparaginase treatment (ie, the amount of asparagine depletion) are far more important than the type of asparaginase used.

Answer 48

TRUE In terms of leukemic control, the **dose intensity and duration** of asparaginase treatment (ie, the amount of asparagine depletion) are far more important than the type of asparaginase used.

Question 49

# TRUE OR FALSE The addition of the monoclonal antibody rituximab improves the outcome for adult patients with CD20+ ALL.

Answer 49

TRUE The addition of the monoclonal antibody **rituximab** improves the outcome for **adult** patients with **CD20+ ALL**.

Question 50

Refers to treatment administered shortly after remission induction, refers to readministration of the induction regimen or to high doses of multiple agents not used during the induction phase

Answer 50

Intensification (Consolidation) Therapy

Question 51

Population that benefits from higher dose of methotrexate

Answer 51

* T-cell ALL * B-cell precursor ALL * ETV6-RUNX1 or TCF3-PBX1 gene fusion * Young adults? ## Footnote In adults, the methotrexate dose should probably be limited to **1.5–2.0 g/m2 IV** because higher doses may lead to excessive toxicities, delayed subsequent treatment, and reduced compliance.

Question 52

Considered as adolescents and young adults (AYA)

Answer 52

Ages of 16 and 39

Question 53

# TRUE OR FALSE Several retrospective comparative analyses have reported that adolescents and young adults with ALL treated on pediatric protocols have had superior EFS and overall survival rates when compared with similar patients enrolled on adult ALL trials.

Answer 53

TRUE Several retrospective comparative analyses have reported that **adolescents and young adults with ALL treated on pediatric protocols have had superior EFS and overall survival rates** when compared with similar patients enrolled on adult ALL trials.

Question 54

Continuation therapy for______ years is an integral part of pediatric and adult ALL regimens.

Answer 54

2–3 years

Question 55

# TRUE OR FALSE Early studies demonstrated that the third year of continuation therapy benefits girls but not boys.

Answer 55

FALSE Early studies demonstrated that the **third year** of continuation therapy **benefits boys but not girls**. ## Footnote Hence, most studies discontinue all therapy for girls after 2–2.5 years of treatment.

Question 56

**Mercaptopurine** is better when the drug is administered in the_________

Answer 56

Evening ## Footnote Mercaptopurine **should not be given with milk or milk products containing xanthine oxidase**, which can degrade the drug.

Question 57

# TRUE OR FALSE Antimetabolite treatment should be withheld because of isolated increases of liver enzymes because such liver function abnormalities are intolerable and irreversible.

Answer 57

FALSE Antimetabolite treatment **should not be withheld** because of isolated increases of liver enzymes because such liver function abnormalities are **tolerable and reversible**.

Question 58

**Thioguanine** produced superior antileukemic responses to mercaptopurine but was associated with:

Answer 58

Profound thrombocytopenia An increased risk of death, and An unacceptable rate of hepatic venoocclusive disease ## Footnote Mercaptopurine remains the drug of choice for ALL

Question 59

Therapy of the Central Nervous System

Answer 59

* Triple intrathecal therapy with methotrexate, cytarabine, and hydrocortisone * Systemic high-dose methotrexate and cytarabine

Question 60

Treatment of CNS relapse

Answer 60

* Cranial irradiation * Intrathecal chemotherapy (typically via an Ommaya shunt) Plus reinduction and reconsolidation systemic therapy ## Footnote Survival after CNS relapse is usually less than one year in adults.

Question 61

Cases where **hematopoietic stem cell transplantation** is reccomended

Answer 61

* Philadelphia chromosome–positive ALL * Those with a poor initial response to induction therapy * Ph-like ALL and early T-precursor phenotype * Adults with the t(4;11) ALL

Question 62

**Autologous T cells** engineered to express a chimeric antigen receptor (CAR) that targets _____ Currently used only for patients with **relapsed and refractory ALL**

Answer 62

CD19 ## Footnote Efficacy is often accompanied by toxicity from **cytokine release syndrome**, which can be life threatening.

Question 63

Treatment for Philadelphia chromosome–positive ALL

Answer 63

Tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, or ponatinib) ## Footnote In combination with steroids or chemotherapy In combination with chemotherapy, they induce not only a higher complete remission rate but also a high rate of molecular remission in children and adults **It is uncertain whether and when to discontinue imatinib or dasatinib after the patient is treated with chemotherapy or transplantation.**

Question 64

# TRUE OR FALSE Surface expression of CD20 by leukemia cells is associated with an inferior outcome in adult, but not childhood, ALL.

Answer 64

TRUE Surface expression of **CD20** by leukemia cells is associated with an **inferior outcome in adult, but not childhood**, ALL. ## Footnote Chemotherapy trials incorporating rituximab, an anti-CD20 antibody, have yielded promising results in adults with CD20+ B-cell precursor ALL.

Question 65

A **bispecific T-cell engaging (BiTE)** monoclonal antibody that binds **both CD3+ T cells and CD19+ ALL cells** and has been approved for patients with **relapsed or refractory B-cell precursor ALL**.

Answer 65

Blinatumomab ## Footnote For children and AYA patients with intermediate- or high-risk relapsed B-ALL, **blinatumomab as a single agent is superior to standard chemotherapy** as post-reinduction chemotherapy before transplantation, resulting in fewer and less severe toxicities, high rates of minimal residual disease response, and improved disease-free and overall survival.

Question 66

An **anti-CD22 antibody** conjugated to calicheamicin that has yielded better outcomes in patients with **relapsed or refractory ALL** than standard chemotherapy.

Answer 66

Inotuzumab ozogamicin

Question 67

A soluble **pro-drug of 9-β-D-arabinofuranosylguanine (ara-G)**, a deoxyguanosine derivative shown considerable activity in **T-cell ALL**, both alone and in combination with other chemotherapy

Answer 67

Nelarabine

Question 68

Most relapses occur during

Answer 68

During treatment or within the first two years after its completion

Question 69

The most common site of relapse in ALL

Answer 69

Marrow ## Footnote Although some individuals can be rescued with additional chemotherapy alone, in general, **only allogeneic hematopoietic stem cell transplantation offers a reasonable chance for cure and long-term survival**.

Question 70

Factors indicating an especially poor prognosis

Answer 70

* Relapse while on therapy or after a short initial remission * T-cell immunophenotype * The presence of the Philadelphia chromosome or Ph-like ALL * Isolated hematologic relapse * Persistence of minimal residual disease after reinduction treatment

Question 71

Options for patients with ALL that has relapsed after allogeneic transplantation

Answer 71

A second transplant or donor T-lymphocyte infusion

Question 72

# TRUE OR FALSE CNS relapses are associated with a lower level of MRD in the marrow than testicular relapses.

Answer 72

FALSE **CNS relapses** are associated with a **higher level of MRD** in the marrow than testicular relapses. ## Footnote Hence, patients with extramedullary relapse and undetectable disease in marrow require intensive systemic treatment to prevent subsequent hematologic relapse. The recommended treatment strategy remains the same: combining **CNS-directed treatment with additional systemic chemotherapy**

Question 73

Most deaths are caused by

Answer 73

Bacterial or fungal infections

Question 74

Late sequelae of cranial irradiation

Answer 74

Second cancer, neurocognitive deficits, and endocrine abnormalities ## Footnote The most devastating complication is the development of **brain tumors and therapy-related myeloid leukemia.**

Question 75

Used for risk classification in almost every pediatric clinical trial involving precursor B-cell ALL.

Answer 75

Age and leukocyte count ## Footnote Age **younger than 35 years** and leukocyte count **less than 30 × 109/L** are considered favorable prognostic indicators In general, **age younger than 60 years** is considered a practical guide for selecting candidates who might benefit from intensive therapy, including allogeneic transplantation.

Question 76

Adverse Prognostic Factors in Adult Acute Lymphoblastic Leukemia **Precursor B Cell**

Answer 76

* Age >35 * Leukocyte count >30 ×109/L * Pro-B (CD10–) * t(9;22) [BCR-ABL1] * t(4;11) [MLL-AF4] * Hypodiploidy? * Delayed remission (>4 weeks) * Minimal residual disease >10–4 after induction

Question 77

Adverse Prognostic Factors in Adult Acute Lymphoblastic Leukemia **Precursor T Cell**

Answer 77

* Age >35 * Leukocyte count >100 ×109/L * Pre-T * HOX11L2 expression? * ERG expression? * Delayed remission (>4 weeks) * Minimal residual disease >10–4 after induction

Question 78

# TRUE OR FALSE Male sex has long been recognized as an adverse prognostic factor in childhood ALL but has less influence in adult ALL.

Answer 78

TRUE **Male sex** has long been recognized as an *adverse prognostic factor in childhood ALL but has less influence in adult ALL.*

Question 79

The most important prognostic factor

Answer 79

Measurement of MRD