87 Acute Myelogenous Leukemia Flashcards
4 environmental factors are established causal agents of AML
- high-dose radiation exposure
- chronic, high-dose benzene exposure (≥40 parts per million [ppm]-years)
- chronic tobacco smoking
- chemotherapeutic (DNA-damaging) agents
An endogenous factor that increases risk is obesity. Studies in North America show an increased risk of AML in men and women with elevated body mass index, and this is particularly notable for __________________
Acute promyelocytic leukemia (APL)
The precise mechanisms are still unclear but may be related, in part, to elevated leptin levels, decreased adiponectin levels, shortened telomeres, alterations in lipid metabolism, associated inflammation and as yet unknown factors in obese subjects
The most compelling data indicate that the bulk of AML cases arise from 1 of 2 predominant CD34+ cell populations:
CD34+CD45RA+CD38−CD90− (multipotential myeloid progenitor)
or
CD34+CD38+CD45RA+CD110+ (granulocyte–monocyte progenitor)
Chromosome changes involving CBF
t(8;21), inv(16), t(16;16), or t(15;17)
A more favorable outcome
Increased in frequency in patients over 60 years of age and in cases that develop after cytotoxic therapy
Deletions in chromosome 5 and 7 and complex cytogenetic abnormalities
Mutations with favorable outcomes
- t(8;21)(q22;q22.1); RUNX1-RUNX1T1
- inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFβ-MYH11
- Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
- Biallelic mutated CEBPa
Mutations with poor outcome
- t(6;9)(p23;q34.1); DEK-NUP214
- t(v;11q23.3); KMT2A rearranged
- t(9;22)(q34.1;q11.2); BCR-ABL1
- inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1)
- −5 or del(5q); −7; −17/abn(17p)
- Complex karyotype, monosomal karyotype
- Wild-type NPM1 and FLT3-ITDhigh
- Mutated RUNX1or ASXL1 without good risk karyotype
- Mutated TP53
TRUE OR FALSE
Patients with CBF leukemias expressing KIT have a good prognosis.
FALSE
Patients with CBF leukemias expressing KIT have a worse prognosis.
TRUE OR FALSE
A monosomal karyotype is associated with a decreased chance of achieving remission or survival, especially when combined with TP53 mutations.
TRUE
A monosomal karyotype is associated with a decreased chance of achieving remission or survival, especially when combined with TP53 mutations.
Approximately _______of AML cases have a normal karyotype
45%
Most frequently mutated gene in AML (50%)
Allogenic transplantation not needed in first
remission if this mutation occurs in absence
of mutated FLT3-ITD
NPM1
NPM1 mutation is not associated with better duration of complete remission in those treated with hypomethylating agents.
An ITD of FLT3 on chromosome 13 occurs in approximately ____ of adult AML cases
25%
FLT3-ITD expression is often higher at relapse.
Point mutations in the TKD of FLT3 mutations occur in approximately ____% of AML cases
6%
Have little impact on outcomes
The FLT3-ITD mutation confers a poor prognosis if the ratio of mutant to wild-type expression is (LOW/HIGH).
High (≥0.51)
A leucine zipper transcription factor involved in myeloid differentiation.
CEBPα
TRUE OR FALSE
CEBPα-double, but not CEBPα-single, mutation patients had a significantly better overall survival at 8 years than wild-type, CEBPα-single, or CEBPα-double and FLT3-ITDpositive patients.
TRUE
CEBPα-double, but not CEBPα-single, mutation patients had a significantly better overall survival at 8 years than wild-type, CEBPα-single, or CEBPα-double and FLT3-ITDpositive patients.
Catalyze oxidative decarboxylation of isocitrate into α-hemoglutarate
IDHs
Found to predict for the presence of IDH1/IDH2 mutations
Serum 2hydroxyglutarate
- A level of 700 ng/mL was found to discriminate mutated from nonmutated
- Those with levels greater than 20 ng/mL at the time of remission had shorter overall survival.
These mutations are highly enriched in therapy-related AML and in those with complex karyotype.
TP53 Mutations
The detection of persistent leukemia-associated mutations in at least ______% of marrow cells in day 30 remission marrow cell samples is associated with a high risk of relapse.
5%
Gene mutations associated with familial AML
- GATA2
- CEBPα and DDX41
- Telomerase RNA (TERC) or telomerase reverse transcriptase component (TERT)
AML is the predominant form of leukemia during the: (Neonatal OR childhood OR adolescence)period
Neonatal period
AML is more common in (males/females)
Males
The acute promyelocytic variant of AML is somewhat more common in __________ (race)
Latinos
Immunologic Phenotype
CD11b, CD13, CD15, CD33, CD117,
HLA-DR
Myeloblastic
Immunologic Phenotype
CD11b, CD13, CD14, CD15, CD32, CD33,
HLA-DR
Myelomonocytic
Immunologic Phenotype
Glycophorin, spectrin, ABH antigens,
carbonic anhydrase I, HLA-DR, CD71
(transferrin receptor)
Erythroid
Immunologic Phenotype
CD13, CD33
Promyelocytic
No CD34 and HLADR
Immunologic Phenotype
CD11b, 11c, CD13, CD14, CD33, CD65,
HLA-DR
Monocytic
Immunologic Phenotype
CD34, CD41, CD42, CD61, anti–von
Willebrand factor
Megakaryoblastic
Immunologic Phenotype
CD11b, CD13, CD33, CD123, CD203c
Basophilic
Immunologic Phenotype
CD13, CD33, CD117
Mast cell
Palpable splenomegaly or hepatomegaly occurs in approximately ______of patients.
25%
Lymphadenopathy is extremely uncommon, except in the ______________ variant of AML
Monocytic variant of AML
Extramedullary involvement is most common in____________________leukemia.
Monocytic or myelomonocytic leukemia
Skin involvement in AML may be of 3 types:
- Nonspecific lesions
- Leukemia cutis
- Granulocytic (myeloid) sarcoma of skin and subcutis
A necrotizing inflammatory lesion involving the terminal ileum, cecum, and ascending colon, can be a presenting syndrome or occur during treatment
Ileotyphlitis (enterocolitis)
A tumor composed of myeloblasts, monoblasts, or megakaryocyes
Myeloid sarcoma
Synonyms: granulocytic sarcoma, chloroma, myeloblastoma, monocytoma
The tumors originally were called chloromas because of the green color imparted by the high concentration of the enzyme myeloperoxidase present in myelogenous leukemic cells.
Most frequent cytogenetic disturbance in myeloid sarcomas
Abnormalities in chromosome 8
(Systemic chemotherapy or local therapy), should be used for treatment of myeloid sarcoma, although the long-term outcome in such cases usually is poor.
Systemic chemotherapy
Systemic chemotherapy, rather than local therapy, should be used for treatment, although the long-term outcome in such cases usually is poor.
Mutations with propensity to develop extramedullary leukemia
AML with t(8;21) or inv16
Principal cause of anemia in AML
Inadequate production of red cells
Mechanism of thrombocytopenia in AML
Inadequate production and decreased survival of platelets
Are elliptical cytoplasmic inclusions, approximately 1.0–1.5 μm long and 0.5 μm wide, that derive from azurophilic granules
Auer rods
APL: higher proportion of cells have Auer rods and some have multiple (bundles) of rods (so-called faggot cells).
Present in the blast cells of approximately 15% of cases
The WHO has invoked an arbitrary threshold of______of marrow nucleated cells being blast cells to distinguish polyblastic AML from oligoblastic myelogenous leukemia
20%
Relapse of AML can be identified as any increase in blast count greater than _______
2%
TRUE OR FALSE
Any distinctions between MDS and AML in survival are a function of age, cytogenetic risk category, and molecular features, and the blast count.
FALSE
Any distinctions between MDS and AML in survival are a function of age, cytogenetic risk category, and molecular features, not the blast count.
Myeloblasts are distinguished from lymphoblasts by any of 3 pathognomonic features:
- Reactivity with specific histochemical stains
- Auer rods in the cells
- Reactivity with a panel of monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117)
Leukemic myeloblasts give positive histochemical reactions for:
Myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate esterase
Blast cells may express :
Granulocytic surface antigens __________________ or
Monocytic surface antigens _____________
Granulocytic surface antigens (CD15, CD65) or
Monocytic surface antigens (CD11b, CD11c, CD14, CD64)
AML associated with intense fibrosis
Megakaryoblastic leukemia
Associated with marrow basophilia
t(6;9)
Associated with marrow eosinophilia
inv16 or t(16;16)
Associated with in cases of AML following chemotherapy or radiotherapy
Loss of part or all of chromosomes 5 and 7
Chromosome abnormality very common in acute myeloblastic leukemia
Trisomy 8
t(9;22) (q34; q22) in BCR-ABL1 gene is present in ______ of patients with AML
~2%
Often acute myelomonocytic phenotype; associated with increased marrow
eosinophils; predisposition to cervical lymphadenopathy, better response to
therapy
Inv(16) (p13.1;q22) or
t(16;16) (p13.1;q22)
~1% of cases of AML
Approximately 85% of cases with normal or increased platelet count
Marrow has increased dysmorphic, hypolobulated megakaryocytes.
Hepatosplenomegaly more frequent
Inv(3) (q21q26.2) /RPN1-EVI1
Approximately ______% of cases of AML contain cells that are cytogenetically normal.
45%
Serum uric acid and lactic dehydrogenase levels are higher in___________________AML than in other AML phenotypes
Myelomonocytic and monocytic AML
Are associated with hypofibrinogenemia and other indicators of activation of coagulation or fibrinolysis
APL and acute monocytic leukemia
Hyperleukocytosis is a markedly elevated blood blast cell count, usually greater than _____________
100 × 10 9 /L
Subsets of AML are associated with a greater likelihood of presenting with hyperleukocytosis
Myelomonocytic, acute monocytic, the microgranular variant of APL, and AML with inv16, 11q23 rearrangements, or FLT3-ITD
The circulations most sensitive to the effects of leukostasis
CNS, lungs, and penis
Approximately 10% of patients with AML present with a syndrome that includes pancytopenia, often with inapparent blood blast cells, and absence of hepatic, splenic, or lymph nodal enlargement
Hypoplastic Leukemia
Approximately 75% of these patients are men older than 50 years.
Marrow necrosis is uncommon but approximately _________ of cases are associated with lymphoid or myeloid malignancies and about ____________ of cases occur in patients with AML
two-thirds
one-fourth
Two most common symptoms or signs of marrow necrosis
Bone pain (approximately 80% of patients)
Fever (approximately 70% of patients)
Marrow findings in marrow necrosis
The marrow aspirate is often watery and serosanguineous.
An amorphous extracellular eosinophilic background with disintegrating cells that have lost their staining characteristics with indistinct margins and varying degrees of pyknosis and karyorrhexis
Both technetium scanning and MRI can point to areas of intact marrow that may be used to make a diagnosis of the underlying disease, if it is unknown.
Four myeloproliferative syndromes related to AML have been identified in the neonate:
- Transient myeloproliferative disorder
- Transient leukemia
- Congenital leukemia
- Neonatal leukemia
Transient myeloproliferative disorder and transient leukemia are considered to represent the same phenomenon.
Can be present at birth, or occur shortly thereafter, in approximately 10% of infants with Down syndrome.
The blast cells usually have the immunophenotype of megakaryocytes.
Transient myeloproliferative disease (TMD)
In Transient myeloproliferative disease (TMD), the elevated white cell and blast cell counts disappear in most patients (approximately 80%) over a period of _____________
Weeks to months
Approximately _______of newborns with Down syndrome and transient leukemia develop______________________ in the first __________years of life.
25%
Acute megakaryocytic leukemia
First 4 years of life
Mutations that have been found in nearly all patients with TMD and in acute megakaryocytic leukemia in Down patients
GATA1 mutations
TMD
Treatment suggested for those patients with severe hepatic fibrosis, very high white cell counts, or hydrops fetalis
Very-low-dose cytarabine
TMD
Children with Down syndrome have either a ______-fold risk of AML or an approximately ________-fold of ALL by age 5 years
150x (AML)
40x (ALL)
Myelogenous leukemia in patients with Down syndrome often has what phenotype of leukemia
Megakaryoblastic or erythroid phenotype
A rare syndrome, occurs 10 times more often in newborns with Down syndrome than in newborns without trisomy 21
The disease has been diagnosed prenatally.
Congenital or neonatal leukemia
The most common phenotype and karyotype in congenital or neonatal leukemia
Monocytic leukemia and t(4;11)
The presence of a cytogenetic abnormality on band q23 of chromosome 11 is a very poor prognostic sign.
Cases of biphenotypic leukemia that are morphologically or cytochemically indicative of myelogenous leukemia
LY+AML
The WHO now classifies some of these disorders as mixed phenotype acute leukemia (MPAL).
Cases of biphenotypic leukemia that are more indicative of lymphocytic leukemia
MY+ALL
The WHO now classifies some of these disorders as mixed phenotype acute leukemia (MPAL).
2 notable syndromes are associated with hybrid leukemias:
(a) the myeloid leukemia and natural killer cell hybrid (CD56+, CD7+, CD13+, CD33+)
(b) the lymphoma, eosinophilia, and t(8;13) myeloid leukemia hybrid.
- The hybrids can appear de novo or after relapse of a lymphoma, T-cell leukemia, or blast crisis of CML.
- The hybrid leukemias usually have a poor prognosis.
Often simulates APL, with hypergranular cytoplasm present but an abnormality of chromosome 17 is absent
Myeloid–natural killer cell leukemia
Lymphoid and myeloid cells are present simultaneously but are derived from separate clones, or sequential myeloid and lymphoid leukemia are present, but the 2 lineages are derived from separate clones
Mixed Leukemias
An unusual but significant concordance has been reported between nonseminomatous mediastinal germ cell tumors and AML, especially the _________________ variant.
Megakaryoblastic
Most common in adults, and most frequent variety in infants.
Three morphologic– cytochemical types (M0, M1, M2).
Acute myeloblastic leukemia
The WHO has divided acute myeloblastic leukemia not otherwise specified, into 3 types: AML without differentiation, AML without maturation, and AML with maturation.
Approximately 15% of patients with AML
More likely to have extramedullary infiltrates in gingiva, skin, or CNS than are patients with acute myeloblastic leukemia
Acute Myelomonocytic Leukemia
FAB Classification of Acute Myelomonocytic Leukemia
Variant of myelomonocytic leukemia has increased numbers of marrow eosinophils (10–50%), Auer rods in blast cells, and inversion or rearrangement of chromosome 16
Has an increased risk of CNS involvement, it carries a more favorable prognosis
M4Eo
Translocations involving ______________ are associated with Acute Myelomonocytic Leukemia
Chromosome 3
Erythroid leukemia is arbitrarily divided into 3 degrees of severity:
(a) Erythroleukemia in which more than 50% of the marrow cells are dysmorphic
(b) Erythroblasts admixed with myeloblasts, the latter composing approximately 20% of nonerythroid cells or approximately 5% to 10% of total marrow cells
(c) Pure erythroid leukemia, in which more than 80% of marrow cells are dysmorphic erythroblasts with a trivial granulocytic proportion of cells and very few if any myeloblasts
Features of erythroblasts in Acute Erythroid leukemia
Glycophorin A, spectrin, carbonic anhydrase I, ABH blood group antigens, and other antigens that occur on early erythroid progenitors, such as the transferrin receptor (CD71)
Antihemoglobin antibody and antihuman erythroleukemic cell line antibody often are positive
TRUE OR FALSE
The more predominant the erythroid component and the lower the proportion of myeloblasts, the better the response to therapy.
TRUE
The more predominant the erythroid component and the lower the proportion of myeloblasts, the better the response to therapy.
APL occurs with greater frequency among (nationality)
Latinos from Europe and South and Central America
APL is also increased among persons with an (increased or decreased) body mass index.
Increased
Upregulation of polyunsaturated fatty acid metabolism genes has been noted, and in APL patients with obesity, FLT3 mutations are higher.
Promyelocytes with multiple Auer rods have been referred to as:
Faggot cells
Leukemic promyelocytes stain intensely with myeloperoxidase and Sudan black and express
CD9, CD13, and CD33
BUT NOT CD34 or HLA-DR
Microgranular cases represent approximately _____ of patients with promyelocytic leukemia.
The leukemic cells may mimic promonocytes with convoluted or lobulated nuclei.
20%
The total WBC often is highly elevated, and severe coagulopathy is prominent in microgranular cases.
The most frequent cytogenetic abnormality (>95%) in APL
t(15;17)(q22;q21)
Other variant translocations in APL
Chromosome 3, 5, or 11 and chromosome 17 or isochromosome 17
Rearrangement of the RARα gene that is retinoid responsive
t(15;17), PML–RARα fusion
t(5:17), NPM–RARα fusion
t(3;17), TBLR1–RARα fusion
Rearrangement of the RARα gene that is retinoid resistant
t(11;17), PLZF–RARα fusion
Mutation in APL where Auer rods are absent and CD56 expression usually is present
t(11;17)
The PML–RARα gene has 2 isoforms that produce a short-type and a long-type fusion mRNA, respectively.
Patients with the__________ isoform may have a worse outcome
Short
FLT3 mutations are frequently found in human disease, especially in the hypogranular variant.
APL
Approximately 5% to 10% of patients die during remission induction, most of
Hemorrhage
often into the brain
Have a higher prevalence (50%) of extramedullary tumors
Hepatomegaly, splenomegaly, and lymphadenopathy are more frequent
Acute Monocytic Leukemia
In Acute Monocytic Leukemia, monocytic cells react for nonspecific esterase stains, α-naphthyl acetate esterase, and naphthol AS-D-chloroacetate-esterase; in a cytochemical or chemoluminescence assay; or with monoclonal antibodies against monocyte surface antigens, especially ____
CD14
Immunoreactivity of cells for lysozyme is characteristic.
Results in the MOZ-CBP fusion gene, is characterized by mildly granular promonocytes (simulating hypogranular promyelocytes), intense phagocytosis of red cells, erythroblasts, and sometimes neutrophils and platelets in blood and marrow, simulating macrophagic hemophagocytic syndrome, intravascular coagulation or primary fibrinolysis, and a high frequency of extramedullary disease
Acute monoblastic leukemia with t(8;16)
TRUE OR FALSE
In acute monocytic leukemia, , examination of cerebrospinal fluid is often recommended, even in the absence of symptoms, when remission has been achieved
TRUE
In acute monocytic leukemia, examination of cerebrospinal fluid is often recommended, even in the absence of symptoms, when remission has been achieved
Greater incidence of CNS or meningeal disease
AML prevalent variant of AML that develops in patients with Down syndrome or in patients with mediastinal germ cell tumors and coincident AML
Has severe myelofibrosis
The serum lactic acid dehydrogenase level frequently is strikingly increased and has an isomorphic pattern unlike that seen with other acute leukemias.
Acute Megakaryoblastic (Megakaryocytic) Leukemia
Maturing megakaryocytes with agranular cytoplasm with cytoplasmic protrusions, clusters of platelet-like structures, or shedding of cytoplasmic blebs
Markers of Acute Megakaryoblastic (Megakaryocytic) Leukemia
Antibodies to von Willebrand factor or to platelet glycoprotein Ib (CD42), IIb/IIIa (CD41), or IIIa (CD61)
Confirmation of their megakaryoblastic maturation requires immunocytologic studies for the presence of von Willebrand factor and the immunoreactivity to CD41, CD42, or CD61.
Chromosal abnormalities associated with Acute megakaryocytic leukemia
chromosome 3
Infants with t(1;22)(p13;q13)
The eosinophilic cells are dysmorphic and the cytoplasm hypogranulated with smaller-than-normal eosinophilic granules.
Acute Eosinophilic Leukemia
Increased eosinophils in the marrow, but not in the blood, is a variant of acute myelomonocytic leukemia and inversion 16 or other abnormalities of chromosome 16, but is not considered an acute eosinophilic leukemia.
Acute eosinophilic leukemia
A specific histochemical reaction, _______________________, permits identification of leukemic cells with eosinophilic differentiation and diagnosis of acute eosinoblastic leukemia in some cases of AML with fewer identifiable eosinophils in blood or marrow.
Cyanide-resistant peroxidase
Proposed as a means of distinguishing acute eosinophilic leukemia from a polyclonal, reactive eosinophilia
Overexpression of WT gene expression
TRUE OR FALSE
Patients with acute eosinophilic leukemia do not usually develop bronchospastic signs, neurologic signs, and heart failure from endomyocardial fibrosis as is seen in chronic eosinophilic leukemia
TRUE
Patients with acute eosinophilic leukemia do not usually develop bronchospastic signs, neurologic signs, and heart failure from endomyocardial fibrosis as is seen in chronic eosinophilic leukemia
Probably because those tissue changes are the result of release of toxins in the granule crystalloid, absent in most eosinophils in acute eosinophilic leukemia and because of the shorter duration of survival in acute eosinophilic leukemia.
Appropriate choice for treatment for Acute eosinophilic leukemia
Cytarabine and an anthracycline
Most cases evolve from the chronic phase of CML
Characterized by presence of CD9, CD25, or both
Elevated blood and urine histamine and urinary methylhistamine levels
Acute basophilic leukemia
In some cases of acute myelomonocytic leukemia associated with t(6;9)(p23;q34), basophils may be increased in the marrow, but not in the blood.
Acute basophilic leukemia
The cells stain with ____________ and the basophilic granules can be most striking in myelocytes.
Toluidine blue or Astra blue
Related to a mutation of the KIT gene
Plasma tryptase is elevated
Naphthol AS-D-chloracetate-esterase–positive, CD11b-negative, CD117-positive, CD123-negative
Mast cell leukemia
The key laboratory distinctions between acute basophilic leukemia and acute mast cell leukemia
Basophilic leukemia: naphthol AS-Dchloracetate- esterase–negative, CD11b positive, CD117 negative or weakly positive, CD123 positive, have no increase in cell or plasma tryptase
Mast cell leukemia: naphthol AS-D-chloracetate-esterase–positive, CD11b-negative, CD117-positive, CD123-negative, have an increase in cell and plasma tryptase
Defined as elimination of the leukemic cell population in marrow as judged by microscopy and flow cytometry and the restitution of marrow hematopoiesis resulting in a normal or virtually normal white cell, hemoglobin, and platelet concentrations in the blood
Remission
Any suspicion of APL, however, should lead to urgent administration of ________________
ATRA
TRUE OR FALSE
Age is a contraindication to treatment, and septuagenarians and octogenarians who are fit cannot enter remissions.
FALSE
Age per se is not a contraindication to treatment, and septuagenarians and octogenarians who are fit can enter remissions.
More extensive evaluation of coagulation factors should be made if:
(a) clotting times are abnormal
(b) bleeding is exaggerated for the level of the platelet count
(c) APL or acute monocytic leukemia is the phenotype
Therapy for hyperuricemia is required if:
(a) the pretreatment uric acid level is greater than 7 mg/dL (0.4 mmol/L)
(b) the marrow is packed with blast cells, or
(c) the blood blast cell count is moderately or markedly elevated
Dose of Allopurinol
Allopurinol 300 mg/day
Allopurinol can cause allergic dermatitis and should not be used if the uric acid level is less than_________ and the total white cell count is less than approximately _______, as long as hydration is adequate and urine flow is high (>_______ mL/h)
less than 7 mg/dL
total white cell count is less than approximately 20 × 109/L
> 150 mL/h
Thus, allopurinol should be discontinued after the risk of acute hyperuricosuria or tumor lysis has passed (usually 4 to 7 days).
Reduce plasma urate levels by approximately 80% within 4 hours of the first drug dose.
Recommended dose is 0.2 mg/kg daily for 5–7 days IV
Recombinant urate oxidase (rasburicase)
The primary goal of induction therapy in AML
Complete remission
* <2% blasts in the marrow)
* A neutrophil count greater than 1 × 109/L
* Platelet count greater than 100 × 109/L
Current standard induction treatment for non-APL AML
Anthracycline or Anthraquinone and Cytarabine
The two most important variables in remission-induction therapy
- Age of the patients
- Proportion of patients with therapy-induced leukemia or an antecedent clonal myeloid disease (clonal evolution)
Anthracycline that does not induce P-glycoprotein expression -> drug resistance is reduced
Idarubicin
May be given during induction to reduce the risk of cardiotoxicity in patients at higher-than-usual risk because of a history of coronary artery disease or congestive heart failure
Dexrazoxane
TRUE OR FALSE
High-dose cytarabine does not increase complete remission rates and increases toxicity compared to conventional doses, especially in patients over 60 years of age
TRUE
High-dose cytarabine does not increase complete remission rates and increases toxicity compared to conventional doses, especially in patients over 60 years of age
The effect of induction chemotherapy is usually assessed by marrow aspirate and biopsy _______days after completion of chemotherapy.
7–10 days
“day 14 marrow”
Hypocellular marrow and no evidence of residual leukemic blasts: recovery of normal counts is awaited
Hypocellular marrow and a small number of residual blasts: additional therapy may be delayed until count recovery or until another marrow assessment often recommended at a 1 week interval after the “day 14 marrow” examination.
Sgnificant amounts of leukemic cells remaining: repeating the original induction therapy or use of a high-dose cytarabine regimen
TRUE OR FALSE
There are insufficient data to determine whether use of the same regimen or advancing to a high-dose cytarabine-containing regimen is the superior approach.
TRUE
There are insufficient data to determine whether use of the same regimen or advancing to a high-dose cytarabine-containing regimen is the superior approach.
Approximately ____ of patients with persistent AML after 1 course of induction therapy have a complete remission after a second course, and disease-free survival at 5 years is approximately ___
40%
10%
A multitargeted kinase inhibitor, was approved by the FDA in 2017 for use in AML patients with FLT3 ITD or TKD point mutations
Midostaurin (ITD or TKD)
Sorafenib (ITD)
Second-generation FLT3 inhibitor
Gilteritinib and crenolanib
A humanized anti-CD33 monoclonal antibody conjugated to calicheamicin that has now been approved for addition to 7+3 chemotherapy
Gemtuzumab ozogamicin (GO)
3 mg/m2 on days 1, 4, and 7
The main toxicity of Gemtuzumab ozogamicin (GO)
Prolonged thrombocytopenia
A liposomal preparation of daunorubicin hydrochloride and cytarabine liposome in a fixed 1:5 molar ratio, was approved for use by the FDA in 2017 for patients over 60 years with AML and in those with secondary AML or MDS-related cytologic findings
CPX-351
Toxicity: longer duration of cytopenia
Use has been primarily in patients over 60 years deemed unfit for standard induction chemotherapy
Hypomethylating Agents
Decitabine
5-Azacytidine
Oral bioavailable small molecule inhibitor of BCL-2
Demonstrated synergistic activity with hypomethylating agents
Approved in the United States for use in previously untreated AML patients older than 75 years in combination with low-intensity chemotherapy,
Venetoclax
Mechanisms of resistance to venetoclax include overexpression of BCL-2A1, BCL-xL, and MCL-1,738 as well as through alterations in metabolic pathways.
A hedgehog pathway inhibitor approved by the FDA in 2018 for oral administration in combination with low-dose cytarabine for newly diagnosed AML patients 75 years old and older or who have comorbidities that preclude use of intensive induction chemotherapy
Glasdegib
Toxicity of Glasdegib
Muscle cramps, dysgeusia, and prolonged QT interval
Oral inhibitor of IDH2:
Oral inhibitor of IDH1:
Oral inhibitor of IDH2: Enasidenib
Oral inhibitor of IDH1: Ivosidenib
Only ivosidenib has been approved for initial therapy
Side effects of hypomethylating agents
Constipation
Side effect of Ivosidenib
Differentiation syndrome
Most serious complications of hyperleukocytosis:
Intracranial hemorrhage or pulmonary insufficiency
In management of hyperleukocytosis: - Hydration should be administered promptly to maintain urine flow greater than ____________
100 mL/h per m2
Hydroxyurea dose for Cytoreduction
Hydroxyurea 1.5–2.5 g orally every 6 hours (total dose 6–10 g/day) for approximately 36 hours
Appropriate remission-induction therapy should be initiated as soon as possible after the leukocyte count has been decreased significantly.
Simultaneous_____________________ can decrease blast cell concentration by approximately _______ within several hours without contributing to uric acid or cellular phosphate release.
Leukapheresis
30%
____________________ may improve the hypoxemia related to hyperleukocytosis
Inhaled nitric oxide
Granulocyte transfusion should not be used prophylactically for neutropenia but may be used in patients with :
- high fever, rigors, and bacteremia unresponsive to antibiotics
- with blood fungal infections
- with septic shock
TRUE OR FALSE
Patients with evidence of intravascular coagulation or exaggerated primary fibrinolysis should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started.
TRUE
Patients with evidence of intravascular coagulation or exaggerated primary fibrinolysis should be considered for platelet and fresh-frozen plasma administration before antileukemic therapy is started.
Infusion of cryoprecipitate can be used for fibrinogen levels less than approximately ____________
125 mg/dL
Intravascular coagulation or primary fibrinolysis may occur in patients with _____________
APL and acute monocytic leukemia
Management of CNS disease
Prophylactic therapy usually is not indicated, but examination of the spinal fluid after remission should be considered in:
(a) monocytic subtypes;
(b) cases with extramedullary disease;
(c) cases with inversion 16 and t(8;21) cytogenetics;
(d) CD7+ and CD56+ (neural cell adhesion molecule) immunophenotypes; and
(e) patients who present with very high blood blast cell counts
TRUE OR FALSE
Prophylactic intrathecal chemotherapy is not recommended if low-dose cytarabine is used for consolidation.
FALSE
Prophylactic intrathecal chemotherapy is NOT recommended if high-dose cytarabine is used for consolidation.
Treatment of meningeal leukemia
- High-dose IV cytarabine (which penetrates the blood–brain barrier)
- Intrathecal methotrexate
- Intrathecal cytarabine
- Cranial radiation
- Chemotherapy and radiation in combination
If CNS leukemia is present, intrathecal therapy is often given:
Twice per week until blasts are cleared, and then once per week for 4–6 weeks
This therapy can be accomplished via the lumbar puncture route or through placement of an Ommaya reservoir.
If there is a mass present treatment can be:
Radiation or high-dose cytarabine with glucocorticoids
TRUE OR FALSE
Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared.
TRUE
Unless the patient has neurologic symptoms, lumbar puncture generally is deferred until blood blast cells have cleared.
No consensus exists on a trigger for platelet transfusion in adults with AML undergoing lumbar puncture; a platelet count of less than 20 × 109/L has been proposed as such a trigger, but many therapists use a higher platelet count (eg, 50 × 109/L) as a safety threshold for lumbar puncture.
Myeloid sarcoma may be the presenting finding in approximately ____ of patients with AML.
1%
Patients with trisomy 8 have poorer survival rates.
Treatment for Nonleukemic Myeloid Sarcoma
Intensive AML induction therapy
Post remission therapy for patients with good risk cytogenetics and can also be considered in those with intermediate-risk cytogenetics
4 cycles of high-dose cytarabine
Post remission therapy for patients with poor-risk cytogenetics
Allogeneic HSC transplantation
Associated with benefit from high-dose cytarabine therapy:
A cycle is typically 3 g/m2 twice daily on days 1, 3, and 5, providing 6 doses per cycle
- RAS mutations
- CBF leukemias, such as t(8;21)
- Patients 60 years or younger, if they have adequate renal function
- NPM1 mutation without FLT3-ITD mutation
- Biallelic CEBPα mutations
KIT mutations in CBF AML are associated with a poorer prognosis.
High-dose cytarabine frequently causes conjunctivitis and photophobia hence this should be given
Glucocorticoid eyedrops are usually used every 6 hours for 24–72 hours after the last dose of the drug
May decrease the likelihood of severe cerebellar toxicity associated with Cytarabine
1-hour duration infusion of high-dose or reduced-dose (eg, 2 g/m2) cytarabine
Patients over age 60 years and patients with renal insufficiency require dose attenuation (ie, to 1–2 g/m2).
Can be used for AML who achieve a remission, do not have a compatible stem cell donor, and are into the eighth decade of life
Autologous marrow or blood stem cell rescue
An adoptive immunotherapy with donor mononuclear cell infusions is sometimes used to treat relapse of leukemia after allografting
Donor Leukocyte Infusion
Most effective in early relapses and in the absence of extensive of chronic GVHD.
The major complications of Donor Leukocyte Infusion
GVHD and marrow aplasia
After patients complete consolidation therapy, they are generally followed with blood counts every _______________
Every 3 months for 2 years, and then every 3–6 months for 5 years
A predictive factor for relapse
Time taken to enter complete remission after induction
TRUE OR FALSE
In patients who relapse more than 1 year after the first remission, the original remission-induction regimen can be readministered or a combination salvage chemotherapy regimen can be administered.
TRUE
In patients who relapse more than 1 year after the first remission, the original remission-induction regimen can be readministered or a combination salvage chemotherapy regimen can be administered.
Defined as leukemia that does not respond to 2 initial induction chemotherapy treatments with cytarabine and an anthracycline or anthraquinone.
Refractory leukemia
TRUE OR FALSE
A retrospective study suggested that clofarabine-based versus fludarabine-based regimens had a higher complete remission rate and a longer survival
TRUE
A retrospective study suggested that clofarabine-based versus fludarabine-based regimens had a higher complete remission rate and a longer survival
Leukemia that reoccurs following a remission
Relapsed leukemia
The probability of a second remission is approximately _% in younger (ages 15–60 years) patients, and approximately _% in older (ages 60–80 years) patients, but the duration of remission is nearly always much shorter than the first remission.
40%
25%
Second-generation DNA methylation inhibitors
Guadecitabine
Can promote histone acetylation and gene transcription in RUNX1/ETO-positive leukemic cells
Depsipeptide
An aminonucleoside inhibitor of DOT1L histone methyltransferase activity is under clinical investigation in MLL-rearranged leukemias.
Pinometostat
Are small molecule inhibitors of MDM2 (Murine Double Minute 2), a negative regulator of p53
Nutlins / Idasanutlin
An oral exportin-1 inhibitor
Selinexor
A CDK6 inhibitor has activity in MLL-rearranged leukemias
Palbociclib
A CDK9 inhibitor, is being examined as an MCL-1 inhibitor
Alvocidib
Has been studied in CBF leukemias with a KIT mutation in conjunction with chemotherapy
Dasatinib (Sprycel)
Inhibitor of oxidative phosphorylation
Metformin
Mubritinib
An oral iron chelator, inhibits leukemic CD34+CD38− cells through NF-κB inhibition and reactive oxygen species generation
Deferasirox (Exjade)
TRUE OR FALSE
Patients who are suspected APL based on morphology and presence of coagulopathy should begin ATRA without waiting for definitive FISH or molecular confirmation.
TRUE
Patients who are suspected APL based on morphology and presence of coagulopathy should begin ATRA without waiting for definitive FISH or molecular confirmation.
In APL, those with WBC of ________________ or higher are considered to have high-risk disease
10 × 109/L
Used alone, ATRA can induce a short-term remission in at least _______ of patients.
80%
Leukocytosis during ATRA–arsenic trioxide therapy in patients with white cell counts higher than 10 × 109/L can be treated with _____________.
Hydroxyurea or idarubicin
Chemotherapy for APL
Low-risk disease:
High-risk patients:
Chemotherapy for APL
Low-risk disease: A combination of ATRA plus arsenic trioxide, ATRA plus idarubicin alone, or ATRA plus daunorubicin plus cytarabine
High-risk patients: ATRA plus daunorubicin and cytarabine, ATRA plus idarubicin, or ATRA and arsenic trioxide with idarubicin (dose-adjusted based on age)
Cause of mortality for APL despite treatment with ATRA
Fatal intracranial hemorrhage
5%
High white count has been found to be a predictor of early hemorrhagic death.
Variant of APL, in which the promyelocytic leukemia zinc finger (PLZF) gene is fused to RARα, DOES NOT respond to ATRA.
t(11;17)
With ATRA, leukemic promyelocytes disappear from the blood in ______weeks, and a normal marrow aspirate maybe obtained in ______ weeks.
2–4 weeks
4–10 weeks
A rapid increase in the total blood leukocyte count to as high as 80 × 109/L in the first several weeks of therapy of APL
Differentiation syndrome
(previously called the retinoic acid syndrome)
Key feature or symptom of Differentiation Syndrome
Respiratory distress
The syndrome consists of fever, weight gain, dependent edema, pleural or pericardial effusion, and bouts of hypotension.
Treatment of differentiation syndrome
Early use of cytotoxic chemotherapy and glucocorticoid administration
Dexamethasone 10 mg IV every 12 hours
Prophylactic glucocorticoids should be given to those:
- With a WBC higher than 10 × 109/L or
- Those receiving both ATRA and arsenic trioxide
APL
Targeted levels for
Platelet counts:
Fibrinogen:
Platelet counts: 30–50 × 109/L
Fibrinogen: 1.5 g/L or higher
TRUE OR FALSE
Arsenic trioxide can trigger apoptosis of APL cells at low concentrations and maturation at high concentrations.
FALSE
Arsenic trioxide can trigger apoptosis of APL cells at high concentrations and maturation at low concentrations.
Consolidation therapy for APL
Arsenic trioxide plus ATRA or an anthracycline plus ATRA
High Risk: the addition of cytarabine or use of arsenic trioxide can be used to diminish the rate of relapse
High-risk patients may require intrathecal chemotherapy during consolidation to prevent central nervous system relapse.
At the end of consolidation, molecular remission in the marrow should be assessed by
Reverse transcriptase–polymerase chain reaction (RT-PCR)
TRUE OR FALSE
In those patients treated with ATRA plus arsenic trioxide, and white cell count lower than 10 × 109/L at diagnosis, no maintenance is required.
TRUE
In those patients treated with ATRA plus arsenic trioxide, and white cell count lower than 10 × 109/L at diagnosis, no maintenance is required.
For others, ATRA maintenance with chemotherapy is recommended
Best results were achieved when ATRA was combined with 6-mercaptopurine and methotrexate.
APL maintenance is usually recommended for ______ years.
2 years
During maintenance, PCR monitoring on blood samples is recommended.
If the PCR is positive in blood, a marrow examination should be done.
APL High Risk
MRD monitoring should be performed every ___ months in high-risk patients up to ___ years after completion of consolidation therapy.
3 months
3 years
TRUE OR FALSE
Secondary AML responds more poorly to chemotherapy and allogeneic HSC transplantation than does de novo AML.
TRUE
‘
Secondary AML responds more poorly to chemotherapy and allogeneic HSC transplantation than does de novo AML.
Exposure to wha drugs can lead to AML with MLL gene rearrangements on chromosome 11q32.
Topoisomerase II inhibitors (eg, etoposide, mitoxantrone, amsacrine)
Latency period for development of AML after:
Topoisomerase II Inhibitors :
Alkylating Agents and Cisplatin :
Topoisomerase II Inhibitors : 2 years
Alkylating Agents and Cisplatin : 6 years
Topoisomerase II Inhibitors : No relationship with higher cumulative dose has been identified.
Alkylating Agents and Cisplatin : The risk is related to cumulative alkylating agent dose.
The most common cytogenetic changes in secondary AML from Alkylating Agents and Cisplatin
Deletions of all or part of chromosome 5 or 7
Other drugs that may increase the risk of secondary leukemias:
- Low-dose weekly methotrexate for rheumatoid arthritis
- Etanercept therapy
- Temozolamide
- Growth hormone administration
- G-CSF given to patients with congenital, but not idiopathic or cyclic neutropenia
Characteristics of AML older than 60 years old
- More frequent CD34 expression
- High frequency of unfavorable cytogenetic findings (32%)
- Higher MDR1 expression (71%)
- Functional drug efflux (58%)
Leukemia (AML, ALL, CML) is the _________ most common malignancy of women in the childbearing age group
Second
AML in Pregnancy
If the pregnancy is not terminated,_______________ might be useful in the__________________ trimester, when chemotherapy poses a high risk to the embryo.
Leukapheresis
First
The preferred anthracycline to treat pregnant women as it has lower transplacental transfer
Doxorubicin
TRUE OR FALSE
Leukemic infiltrates can be found on both the maternal side of the placenta and the villi.
FALSE
Leukemic infiltrates can be found on the maternal side of the placenta, but usually not in the villi.
The risk of serious cardiac effects is correlated with
- Increasing dose of anthracycline
- Increasing patient age
- Presence of underlying heart disease.
The incidence of congestive heart failure is dose related and ranges from approximately:
5% at ____mg/m2
Greater than 30% at ____ mg/m2
5% at 550 mg/m2
Greater than 30% at 600 mg/m2
Diagnosis of Neutropenic Enterocolitis is confirmed by
Sonography or CT scanning
Mucosal thickening and polypoid appearance
Management of Neutropenic Enterocolitis
Bowel rest, nasogastric suction, fluids, and antibiotics
- Parenteral alimentation is sometimes used but is generally not helpful.
- Right hemicolectomy is usually done only in the absence of resolution and if hemodynamic stability is lost
Definition of Remission
- Neutrophil count greater than 1 × 109/L
- Platelet count greater than 100 × 109/L
- Less than 5% blasts in the marrow by microscopy
- Absence of extramedullary AML
Remission with incomplete platelet recovery CRplatelets (CRp) has all these requirements, but the platelet count does not reach 100 × 109/L.
Early death can occur during induction chemotherapy, and ____________and ___________are the most important predictors of treatment-related mortality.
Performance status and age
The two most compelling determinants of a poor outcome in AML
Older age and less-favorable cytogenetic risk
