90 Acute Lymphoblastic Leukemia Flashcards
TRUE OR FALSE
Most cases of ALL occur in children, but most deaths from ALL occur in adults.
TRUE
Most cases of ALL occur in children, but most deaths from ALL occur in adults.
Heritable cancer predisposition syndromes associated with increased ALL
Li Fraumeni syndrome with germline TP53 mutation
Approximately 61% of patients with ALL are diagnosed before the age of _________
before the age of 20 years
Only 20% of adult acute leukemias are ALL, but about one-third of ALL cases are in adults
Almost all ALL patients with Down syndrome have a deletion of
IKZF1.31
Genetic abnormalities more commonly associated with Down syndrome, such as +X, del(9), and CEBPD rearrangement
Autosomal recessive genetic diseases associated with increased chromosomal fragility and a predisposition to ALL include:
Ataxia-telangiectasia
Nijmegen breakage syndrome
Bloom syndrome
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
IKZF1, ARID5B, CEBPE, and CDKN2a
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.
“Delayed infection” hypothesis
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.
“Population-mixing” hypothesis
The most frequent genetic (chromosomal) abnormality in ALL
Translocations
Most common genetic abberations in childhood
Hyperdiploidy (>50 chromosomes)
23-29%
2nd: t(12;21)(p13;q22) [ETV6-RUNX1] 20–25%
Most common genetic abberations in adults
t(9;22)(q34;q11.2) [BCR-ABL1]
25–30%
Genetic abnormalities found in T-cell ALL
NOTCH1 mutations
HOX11L2 overexpression
LYL1 overexpression
TAL1 overexpression
HOX11 overexpression
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
PAX5
Second most frequently involved gene
Required for the earliest lymphoid differentiation
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
Intracranial hemorrhage occurs mainly in patients with an initial leukocyte count greater than
400 × 109/L
Most common sites of extramedullary involvement, and the degree of organomegaly is more pronounced in children than in adults
Liver, spleen, and lymph nodes
Overt testicular disease can be readily diagnosed by
Ultrasonography
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.
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.
Patients with hyperleukocytosis are more likely to have _______________ ALL
T-cell ALL
Hyperleukocytosis occurs more often in black children (23%) and in adults (16%)
TRUE OR FALSE
Hypereosinophilia, generally reactive, may precede the diagnosis of ALL by several months.
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)
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
T-cell ALL
Translocation found in 0.5% of B-cell precursor ALL, is associated with adolescent age, disseminated coagulopathy, hypercalcemia, and dismal prognosis.
t(17;19)(q22;p13.3) with E2A-HLF fusion
TRUE OR FALSE
Examination of the cerebrospinal fluid (CSF) is an essential diagnostic procedure.
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.
Morphologic characteristics of lymphoblasts
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
Are characterized by intensely basophilic cytoplasm, prominent nucleoli, and cytoplasmic vacuolation
B-cell blasts in Burkitt-type ALL
Typical panels include antibodies to at least one highly sensitive marker and antibodies to a highly specific marker
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
Immunologic Subtype of ALL
Infants and adult age group, high leukocyte count, initial CNS leukemia, pseudodiploidy, MLL rearrangement, unfavorable prognosis
Pro-B
Immunologic Subtype of ALL
Favorable age group (1–9 years), low leukocyte
count, hyperdiploidy (>50 chromosomes)
Early pre-B
Immunologic Subtype of ALL
High leukocyte count, black race, pseudodiploidy
Pre-B
Immunologic Subtype of ALL
Male predominance, initial CNS leukemia, abdominal masses, often renal involvement
Mature B cell (Burkitt)
Immunologic Subtype of ALL
Male predominance, hyperleukocytosis, extramedullary disease
T Cell
Immunologic Subtype of ALL
Male predominance, hyperleukocytosis, extramedullary disease, unfavorable prognosis
Pre-T
CD15, CD33, and CD65 are expressed in ALL cases with a rearranged ________ gene
MLL gene
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.
CD13 and CD33 are expressed in cases with the _________
ETV6-RUNX1
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.
Prognosis:
Hyperdiploidy (>50 chromosomes):
Hypodiploidy (≤44 chromosomes):
Hyperdiploidy (>50 chromosomes): favorable
Hypodiploidy (≤44 chromosomes): poor
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
TRUE OR FALSE
Azoles should be avoided when vincristine is given.
TRUE
Azoles should be avoided when vincristine is given.
TRUE OR FALSE
If mercaptopurine and allopurinol are given together orally, the dosage of mercaptopurine must be reduced.
TRUE
If mercaptopurine and allopurinol are given together orally, the dosage of mercaptopurine must be reduced.
Extreme leukocytosis in ALL is defined as WBC >
> 400 × 109/L
Management of hyperleukocytosis
- Leukapheresis or exchange transfusion (in small children)
- Glucocorticoids, with addition of vincristine and cyclophosphamide
Alternative treatments for patients who cannot tolerate trimethoprim-sulfamethoxazole
Trimethoprim-sulfamethoxazole, 2–3 days per week, as prophylactic therapy for Pneumocystis carinii (Pneumocystis jiroveci) pneumonia
Aerosolized pentamidine, dapsone, and atovaquone
Prophylaxis is started after 2 weeks of remission induction and continues for several months after completion of all chemotherapy
TRUE OR FALSE
Live-virus vaccines should be administered during immunosuppressive therapy.
FALSE
Live-virus vaccines should not be administered during immunosuppressive therapy.
Childhood ALL cases are divided into
- Standard-risk
- High- (intermediate- or average-) risk
- Very-high-risk
Adult cases are generally divided into 2 risk groups.
TRUE OR FALSE
In Burkit Leukemia, cranial irradiation does not appear to be necessary, even for patients presenting with CNS leukemia.
TRUE
In Burkit Leukemia, cranial irradiation does not appear to be necessary, even for patients presenting with CNS leukemia.
Treatment for leukemias affecting the precursor B-cell and T-cell lineages consists of three standard phases:
- Remission induction
- Intensification (consolidation)
- Prolonged continuation (maintenance)
“Molecular” or “immunologic” remission, defined as leukemia less than
0.01% of nucleated marrow cells
Steroid that provides better control of systemic and CNS disease
Dexamethasone
Preparation and doses of asparaginase
- 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
Erwinia preparation has the shortest half-life
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.
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.
TRUE OR FALSE
The addition of the monoclonal antibody rituximab improves the outcome for adult patients with CD20+ ALL.
TRUE
The addition of the monoclonal antibody rituximab improves the outcome for adult patients with CD20+ ALL.
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
Intensification (Consolidation) Therapy
Population that benefits from higher dose of methotrexate
- T-cell ALL
- B-cell precursor ALL
- ETV6-RUNX1 or TCF3-PBX1 gene fusion
- Young adults?
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.
Considered as adolescents and young adults (AYA)
Ages of 16 and 39
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.
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.
Continuation therapy for______ years is an integral part of pediatric and adult ALL regimens.
2–3 years
TRUE OR FALSE
Early studies demonstrated that the third year of continuation therapy benefits girls but not boys.
FALSE
Early studies demonstrated that the third year of continuation therapy benefits boys but not girls.
Hence, most studies discontinue all therapy for girls after 2–2.5 years of treatment.
Mercaptopurine is better when the drug is administered in the_________
Evening
Mercaptopurine should not be given with milk or milk products containing xanthine oxidase, which can degrade the drug.
TRUE OR FALSE
Antimetabolite treatment should be withheld because of isolated increases of liver enzymes because such liver function abnormalities are intolerable and irreversible.
FALSE
Antimetabolite treatment should not be withheld because of isolated increases of liver enzymes because such liver function abnormalities are tolerable and reversible.
Thioguanine produced superior antileukemic responses to mercaptopurine but was associated with:
Profound thrombocytopenia
An increased risk of death, and
An unacceptable rate of hepatic venoocclusive disease
Mercaptopurine remains the drug of choice for ALL
Therapy of the Central Nervous System
- Triple intrathecal therapy with methotrexate, cytarabine, and hydrocortisone
- Systemic high-dose methotrexate and cytarabine
Treatment of CNS relapse
- Cranial irradiation
- Intrathecal chemotherapy (typically via an Ommaya shunt)
Plus reinduction and reconsolidation systemic therapy
Survival after CNS relapse is usually less than one year in adults.
Cases where hematopoietic stem cell transplantation is reccomended
- 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
Autologous T cells engineered to express a chimeric antigen receptor (CAR) that targets _____
Currently used only for patients with relapsed and refractory ALL
CD19
Efficacy is often accompanied by toxicity from cytokine release syndrome, which can be life threatening.
Treatment for Philadelphia chromosome–positive ALL
Tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, or ponatinib)
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.
TRUE OR FALSE
Surface expression of CD20 by leukemia cells is associated with an inferior outcome in adult, but not childhood, ALL.
TRUE
Surface expression of CD20 by leukemia cells is associated with an inferior outcome in adult, but not childhood, ALL.
Chemotherapy trials incorporating rituximab, an anti-CD20 antibody, have yielded promising results in adults with CD20+ B-cell precursor ALL.
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.
Blinatumomab
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.
An anti-CD22 antibody conjugated to calicheamicin that has yielded better outcomes in patients with relapsed or refractory ALL than standard chemotherapy.
Inotuzumab ozogamicin
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
Nelarabine
Most relapses occur during
During treatment or within the first two years after its completion
The most common site of relapse in ALL
Marrow
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.
Factors indicating an especially poor prognosis
- 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
Options for patients with ALL that has relapsed after allogeneic transplantation
A second transplant or donor T-lymphocyte infusion
TRUE OR FALSE
CNS relapses are associated with a lower level of MRD in the marrow than testicular relapses.
FALSE
CNS relapses are associated with a higher level of MRD in the marrow than testicular relapses.
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
Most deaths are caused by
Bacterial or fungal infections
Late sequelae of cranial irradiation
Second cancer, neurocognitive deficits, and endocrine abnormalities
The most devastating complication is the development of brain tumors and therapy-related myeloid leukemia.
Used for risk classification in almost every pediatric clinical trial involving precursor B-cell ALL.
Age and leukocyte count
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.
Adverse Prognostic Factors in Adult Acute Lymphoblastic Leukemia
Precursor B Cell
- 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
Adverse Prognostic Factors in Adult Acute Lymphoblastic Leukemia
Precursor T Cell
- Age >35
- Leukocyte count >100 ×109/L
- Pre-T
- HOX11L2 expression?
- ERG expression?
- Delayed remission (>4 weeks)
- Minimal residual disease >10–4 after induction
TRUE OR FALSE
Male sex has long been recognized as an adverse prognostic factor in childhood ALL but has less influence in adult ALL.
TRUE
Male sex has long been recognized as an adverse prognostic factor in childhood ALL but has less influence in adult ALL.
The most important prognostic factor
Measurement of MRD
