1
Q
What is the modern classification of acute myeloid leukemia (AML) based on?
A
Cytogenetic and molecular genetic information
This reflects advancements in understanding AML’s biological basis.
2
Q
What are the most important prognostic indicators in AML?
A
Patient age, cytogenetics, and molecular genetics
3
Q
What should be obtained at diagnosis for AML?
A
A myeloid mutation panel including genes relevant to prognosis and treatment
Key genes include NPM1, CEPBA, TP53, FLT3, and IDH1/2.
4
Q
What is associated with poor clinical outcomes in AML?
A
Complex cytogenetic abnormalities and monosomal karyotypes
5
Q
Which cytogenetic abnormalities are associated with more favorable outcomes in AML?
A
t(15;17), t(8;21), and inv(16)
6
Q
What is the prognosis for patients with NPM1 or CEBPA b-zip mutations?
A
More favorable prognoses
7
Q
What mutations are associated with poor clinical outcomes in AML?
A
TP53 mutations and myelodysplasia-associated mutations, including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2
8
Q
What is the general treatment approach for AML?
A
Remission induction followed by postremission therapy
Some patients may benefit from maintenance therapy.
9
Q
What is the standard of care for intensive induction in most AML subtypes in adults?
A
Cytarabine combined with an anthracycline
10
Q
What is the new standard of care for medically less-fit adults with newly diagnosed AML?
A
Venetoclax and hypomethylating agent therapy
11
Q
What treatment should patients with IDH1 mutations receive?
A
Ivosidenib and hypomethylating agent
12
Q
What should be added to induction and consolidation therapy for patients with FLT3 mutations?
A
A FLT3 inhibitor, such as midostaurin or quizartinib
13
Q
What should be added during induction chemotherapy for patients with favorable-risk AML that is CD33 positive?
A
The CD33 antibody-drug conjugate gemtuzumab ozogamicin (GO)
14
Q
What is the benefit of high-dose Ara-C (HiDAC) consolidation chemotherapy?
A
Particularly beneficial for patients younger than 60 years with favorable cytogenetics involving core binding factor
Optimal number of cycles of postremission high-dose Ara-C remains to be defined.
15
Q
Who may benefit from allogeneic stem cell transplantation?
A
Patients with AML in first remission with intermediate- or poor-risk cytogenetics or those with favorable-risk NPM1 mutant or core binding factor AML with residual measurable residual disease
16
Q
What is unique about acute promyelocytic leukemia (APL)?
A
High cure rates and sensitivity to all-trans retinoic acid (ATRA), anthracyclines, arsenic trioxide, and gemtuzumab ozogamicin
17
Q
When should all-trans retinoic acid be started for suspected APL?
A
Immediately
18
Q
What complications may arise from APL?
A
Life-threatening coagulopathy or differentiation syndrome
19
Q
What is AML characterized as?
A
A heterogeneous clonal hematopoietic progenitor and/or stem cell malignancy
20
Q
What does AML result in regarding normal hematopoiesis?
A
Inhibition, manifesting as neutropenia, anemia, and thrombocytopenia
21
Q
What percentage of all acute leukemias in adults does AML account for?
A
90%
22
Q
What is the estimated number of new AML cases in the United States for 2023?
A
20,380 new cases
23
Q
What is the median age at diagnosis for AML?
A
Approximately 69 years
24
Q
What is the average overall survival rate for adults with AML from 2013 to 2019?
A
31.7% 5-year survival
25
What are the common causes of AML?
Most cases are de novo; can arise from preexisting myelodysplasia (MDS) or myeloproliferative neoplasm (MPN)
26
What is the most recognized risk factor for AML?
Previous exposure to radiation or chemotherapeutics
27
What environmental exposures are linked to secondary AML?
Benzene and ionizing radiation
28
What are common clinical manifestations of AML?
Signs related to infiltration of leukemic blasts, including infections, anemia, and thrombocytopenia
29
What symptoms are associated with AML?
Pallor, fatigue, bone pain, hepatosplenomegaly, fever, bruising, and bleeding
30
What complications may arise from leukocytosis with >50,000 leukemic blasts per microliter?
Increased risk of pulmonary and CNS complications from microinfarction and hemorrhage
31
What laboratory derangements are associated with AML?
Coagulation abnormalities and metabolic abnormalities related to tumor lysis
32
What is included in the diagnostic workup for suspected AML?
Bone marrow examination, cytogenetics, FISH, and molecular testing for mutant genes
33
What is the purpose of a lumbar puncture in AML diagnosis?
To assess potential CNS involvement
34
What should be considered for asymptomatic patients with a high white blood cell count?
A lumbar puncture at the time of remission
35
What has the classification of AML moved towards in recent years?
More refined molecular and genomic classification frameworks
36
What significant change occurred in the diagnosis and classification of AML in 2022?
Release of the WHO 2022 and ICC 2022 classification schemas
37
What threshold blast count has been de-emphasized in the new AML classification systems?
Greater than or equal to 20%
38
Which genetic abnormalities are considered AML-defining according to WHO 2022?
* PML::RARA
* CBFB::MYH11
* RUNX1::RUNX1T1
39
What does ICC 2022 require for AML with certain genetic abnormalities?
A blast cutoff of 10%
40
What is the significance of having <20% blasts in patients with certain genetic abnormalities?
Similar clinical outcomes to patients with higher blast counts
41
What blast percentage is required for AML with BCR::ABL1 fusion?
20%
42
What new category was introduced in ICC 2022 for MDS/AML?
MDS/AML with certain MDS-associated genomic abnormalities
43
What are adverse clinical prognostic features in AML?
* Advanced age at diagnosis
* Therapy-related AML
* Presence of antecedent hematologic disorder
44
What age group has particularly poor long-term survival in AML?
Patients older than 60 years, especially those older than 75 years
45
What are the primary disease characteristics used to assign prognosis for newly diagnosed AML?
Chromosomal (cytogenetic) and molecular abnormalities
46
What is considered a complex karyotype in AML?
3 or more abnormalities
47
What cytogenetic finding is associated with excellent outcomes in AML?
t(15;17)(q22;q12-21)
48
Which cytogenetic abnormalities are associated with a relatively favorable prognosis?
* t(8;21)(q22;q22)
* inv(16)(p13.1 q22)
* t(16;16)(p13.1;q22)
49
What type of karyotypes are associated with poor outcomes in AML?
* Complex karyotype
* Monosomal karyotypes
50
What recent change was made regarding the FLT3-ITD allelic ratio in risk classification?
No longer considered in risk classification
51
What mutations are now categorized as adverse risk in the ELN classification?
* ASXL1
* BCOR
* EZH2
* RUNX1
* SF3B1
* SRSF2
* STAG2
* U2AF1
* ZRSR2
52
What mutation confers adverse risk if the variant allele fraction is at least 10%?
Mutated TP53
53
What type of mutations are categorized as favorable risk in AML?
CEBPA b-zip mutations
54
What is the impact of MRD assessment in AML prognosis?
Determining overall prognosis and directing postremission therapy
55
What treatment regimen began the modern era of AML therapy?
Combination chemotherapy with cytarabine for 7 days and an anthracycline for 3 days ('7 + 3')
56
What treatment is offered to medically fit patients with AML?
Intensive combination chemotherapy followed by further courses or HCT if CR is achieved
57
What is typically offered to medically less-fit patients with AML?
Less intensive, palliative chemotherapy
58
How many new agents were approved by the FDA for AML treatment between 2017 and 2024?
11 new agents
59
What is central to guide the choice of initial AML therapy?
Assessment of the medical fitness of the patient
## Footnote
Fitness determination involves evaluating comorbidities and performance status.
60
How can fitness determination be formally assessed?
Using instruments that assess burden of comorbidities, organ dysfunction, and/or frailty
## Footnote
Informal assessment is often done by clinician evaluation.
61
Is the time between diagnosis of AML and treatment initiation related to survival?
No, several larger studies have indicated it is not related
## Footnote
This suggests treatment can be delayed to gather genetic and molecular information.
62
What is the standard remission induction therapy for medically fit adults with AML?
7 + 3 regimen with cytarabine and either idarubicin or daunorubicin
## Footnote
Cytarabine is typically given at 100 to 200 mg/m2/d.
63
What are the typical doses of daunorubicin used in AML treatment?
12 mg/m2/d or 90 mg/m2
## Footnote
The 90 mg/m2 dose was shown to be superior to 45 mg/m2 in older patients.
64
What is the expected CR rate for adults younger than 60 years using the 7 + 3 regimen?
70% to 80%
## Footnote
For fit adults older than 60 years, the CR rate is 40% to 60%.
65
What should be done if significant residual disease is present on day 14?
Reinduction chemotherapy should be administered
## Footnote
Choices vary from standard-dose cytarabine/anthracycline to high-dose Ara-C.
66
What is the significance of the RATIFY trial in AML treatment?
It showed that adding midostaurin decreased the risk of death by 22% in FLT3 mutation patients
## Footnote
Improvement in overall survival (OS) at 5 years was 7%.
67
What was the outcome of the QuANTUM-First trial?
Adding quizartinib improved OS in FLT3-ITD+ patients
## Footnote
This trial involved patients aged 18 to 75 years.
68
What does gemtuzumab ozogamicin (GO) do when added to intensive induction chemotherapy?
Improves outcomes in subsets of adults
## Footnote
The exact benefit varies by study.
69
What was indicated by the individual, patient-level meta-analysis regarding GO?
GO does not improve remission rates but decreases relapse rates
## Footnote
It prolongs event-free survival (EFS), relapse-free survival (RFS), and OS.
70
In which patients was OS benefit from GO especially apparent?
Patients with favorable cytogenetic characteristics
## Footnote
At 6 years, OS improvement was 20.7%.
71
What is the recommended treatment for adverse-risk patients with TP53 mutations?
Hypomethylating agent–based therapy may be preferable
## Footnote
TP53 mutations are associated with poor responsiveness to cytotoxic chemotherapy.
72
What treatment showed no difference in survival between TP53 mutant and wild-type patients?
Decitabine treatment
## Footnote
This suggests decitabine may negate the adverse effect of the TP53 mutation.
73
What was the outcome of CPX-351 treatment in patients aged 60 to 75 years with MDS-related cytogenetic abnormalities?
Led to higher remission rates and better OS than 7 + 3 induction
## Footnote
The benefit was greatest in patients who underwent allogeneic HCT.
74
How does CPX-351 compare to low-intensity therapy with azacitidine/venetoclax?
Higher transplant rate but no difference in OS
## Footnote
This comparison was based on real-world studies using retrospective observational data.
75
What is the purpose of postremission therapy?
To prevent relapse after achieving remission.
## Footnote
Postremission therapy options include consolidation chemotherapy or allogeneic HCT.
76
What factors influence the choice between postremission consolidation chemotherapy and allogeneic HCT?
Balancing risks of AML relapse with risks of transplant-related mortality.
## Footnote
Consolidation chemotherapy is recommended for favorable-risk disease, while HCT is for unfavorable-risk disease.
77
What is recommended for patients with favorable-risk disease after remission?
Consolidation chemotherapy unless induction chemotherapy is suboptimally effective.
## Footnote
Examples of suboptimal effectiveness include primary refractory or MRD+ disease.
78
What is the recommended therapy for patients with unfavorable-risk disease?
Allogeneic HCT at first remission.
## Footnote
This approach is intended to improve outcomes for patients with higher relapse risks.
79
What is the significance of HiDAC in consolidation chemotherapy?
It has been associated with improved disease-free survival in younger patients with favorable cytogenetics.
## Footnote
HiDAC stands for high-dose cytarabine.
80
What age group showed significant CNS toxicity in a pivotal trial of HiDAC?
Patients older than 60 years.
## Footnote
High-dose regimens are not recommended for older patients due to increased toxicity.
81
What is MRD in the context of AML?
Measurable residual disease denotes leukemia cells that survive remission induction therapy and may cause relapse.
## Footnote
MRD was previously called minimal residual disease.
82
What technologies are used to detect MRD in AML?
* Multiparameter flow cytometry
* Polymerase chain reaction (PCR)
* Next-generation sequencing
* Digital droplet PCR
## Footnote
These methods have evolved to improve sensitivity and specificity in detecting residual disease.
83
What is the current sensitivity level of flow cytometry for MRD detection?
Can reach a level of 1:10^4.
## Footnote
This requires assays specifically designed to achieve this sensitivity.
84
What are some mutations that may not correlate with AML MRD?
* DNMT3A
* ASXL1
* TET2
## Footnote
These mutations may represent preleukemic founder mutations and persist after achieving complete remission.
85
What is the prognostic significance of MRD testing in patients with AML?
Patients with MRD have higher relapse rates and shorter survival than those without MRD.
## Footnote
The presence of MRD indicates a need for intensified postremission therapy.
86
What is the recommended postremission MRD testing schedule for NPM1 and CBF transcripts?
* After 2 cycles of chemotherapy in blood
* In bone marrow at the end of treatment
* In peripheral blood every 4 to 6 weeks thereafter
## Footnote
Reappearance or rise in these transcripts indicates impending relapse.
87
What is the most prevalent adult indication for allogeneic HCT?
AML.
## Footnote
Allogeneic HCT combines conditioning regimen efficacy with the graft-versus-leukemia effect.
88
What impact does allogeneic HCT have on 5-year overall survival in patients with intermediate-risk cytogenetics?
Improves from 45% to 52%.
## Footnote
This is based on a comprehensive meta-analysis of prospective clinical trials.
89
What is the survival rate after allogeneic HCT in CR1 compared to CR2?
Approximately 40% to 60% in CR1; ~25% to 30% in CR2.
## Footnote
Survival rates decrease significantly with higher CR stages or refractory disease.
90
What is CC-486 and its role in AML maintenance therapy?
An oral formulation of azacitidine approved for maintenance therapy.
## Footnote
It showed improved overall survival and relapse-free survival in a phase 3 trial.
91
What were the main side effects of CC-486 in the QUAZAR trial?
* Gastrointestinal toxicities
* Cytopenias
## Footnote
These were the most important side effects observed during the trial.
92
What is the role of FLT3 inhibitors in maintenance therapy for AML?
Gilteritinib improved relapse-free survival in patients with detectable MRD but had no overall benefit in the cohort.
## Footnote
Maintenance therapy with FLT3 inhibitors is still being evaluated.
93
What is the median age at diagnosis for AML?
68 years old
## Footnote
AML primarily affects older adults.
94
What is the estimated median survival for 66- to 75-year-olds diagnosed with AML?
4.5 to 6 months
## Footnote
Survival estimates vary based on age and treatment eligibility.
95
What percentage of individuals aged >65 years do not receive AML-directed therapy?
>50%
## Footnote
Many older patients are managed with supportive care only.
96
What is the primary treatment for older less-fit adults with AML?
Azacitidine/venetoclax
## Footnote
This combination has become the new standard of care.
97
In the VIALE-A trial, what was the composite complete remission rate for patients receiving venetoclax?
66.4%
## Footnote
This was significantly higher than the 28.3% for azacitidine alone.
98
What is the clinically most concerning adverse effect of venetoclax?
Profound myelosuppression
## Footnote
This effect necessitates careful patient management.
99
What are some reinduction regimens for relapsed AML?
* Mitoxantrone, etoposide, and cytarabine (MEC)
* Fludarabine, cytarabine, and G-CSF (FLAG)
* Clofarabine and cytarabine
* Cladribine, cytarabine, and G-CSF (CLAG)
## Footnote
These regimens typically use higher doses of cytarabine.
100
What is the prognosis for patients who relapse after allogeneic transplantation?
Dismal
## Footnote
Especially if relapse occurs early after allografting.
101
What is gilteritinib used for?
Relapsed FLT3-mutated AML
## Footnote
Gilteritinib is an oral FLT3 inhibitor approved by the FDA.
102
What were the CR rates for patients receiving gilteritinib compared to conventional salvage chemotherapy?
34.0% vs 15.3%
## Footnote
Gilteritinib showed a significant improvement in response rates.
103
What is the median overall survival for patients receiving gilteritinib?
9.3 months
## Footnote
This is longer than the 5.6 months for conventional salvage chemotherapy.
104
What is the approval status of quizartinib?
Not approved for relapsed AML
## Footnote
It is approved in the up-front setting in combination with chemotherapy.
105
What are the oral inhibitors of mutant IDH1 and IDH2 approved for?
Relapsed/refractory IDH-mutant AML
## Footnote
Ivosidenib and enasidenib are the specific inhibitors.
106
What is the approximate CR/CRh rate for IDH inhibitors in nonrandomized studies?
25% to 40%
## Footnote
The median duration of response is around 9 months.
107
True or False: No standard of care exists for patients with relapsed/refractory AML.
True
## Footnote
Best treatment for these patients is through clinical trials.
108
What is acute promyelocytic leukemia (APL)?
A subtype of AML characterized by a balanced reciprocal translocation resulting in the fusion of the PML gene on chromosome 15 with the RARA gene on chromosome 17.
109
What are the two forms of APL?
Hypergranular (typical) and microgranular.
110
What is a characteristic cell found in hypergranular APL?
Faggot cells containing bundles of Auer rods.
111
How is APL categorized based on WBC count at presentation?
Low (or low-intermediate) risk: ≤10,000/µL; High risk: >10,000/µL.
112
What has contributed to the high cure rate in APL patients?
The incorporation of anthracyclines and all-trans retinoic acid (ATRA), leading to a CR rate over 90% and cures in 80% of patients.
113
What is the preferred treatment for low-risk APL?
ATRA/ATO without additional chemotherapy.
114
What is the role of anthracyclines in treating high-risk APL?
They lower the WBC count and minimize the risk of differentiation syndrome.
115
What is molecular remission in APL?
Undetectable levels of the PML-RARA fusion gene transcript.
116
What should be done for patients with suspected initial diagnosis of APL?
Hospitalize immediately and manage as a medical emergency.
117
What are the common causes of death before and early after treatment initiation in APL?
Intracerebral and pulmonary hemorrhages due to complex coagulopathy.
118
What is differentiation syndrome (DS) in APL?
A complication during induction caused by differentiating agents leading to a systemic inflammatory response-syndrome-like process.
119
What is the recommended strategy to decrease the risk of severe DS?
Use of prophylactic steroids in an ATO- and ATRA-based induction approach.
120
What is the primary treatment for pediatric AML?
Intensive cycles of anthracycline- and cytarabine-based chemotherapy.
121
What is a significant molecular feature of pediatric AML?
KMT2A gene rearrangements are identified in 25% of childhood AML cases.
122
What is the only targeted agent approved for children with relapsed AML?
Gemtuzumab ozogamicin (GO).
123
What are some constitutional predispositions to AML?
Autosomal dominant and recessive syndromes, including aberrations in copy number and transcription factors.
124
What mutation is especially prevalent in adults with germline predisposition to AML?
DDX41 mutations, accounting for ∼80% of known germline predisposition.
125
What is the significance of identifying individuals with AML predisposition?
Understanding prognosis, therapeutic vulnerabilities, donor considerations, long-term follow-up, and family planning.
126
Fill in the blank: APL is characterized by low expression or absence of _______.
HLA-DR, CD34, CD117, and CD11b.
127
True or False: Hydroxyurea is recommended when WBC count exceeds 10 × 10^9/L in APL treatment.
True.
128
What are the most common features of differentiation syndrome?
Acute respiratory distress, weight gain, edema, fevers, acute renal failure.
129
What is the recommended treatment for patients in second complete molecular remission of APL?
Autologous stem cell transplantation.
ASH SAP 9 ED
flashcards
Decks in class (17)
# Cards
-
2 Outpatient Hematology104
-
15 Intro VTE228
-
23 ITP151
-
27 Laboratory Hematology243
-
30 Basics of SCT104
-
31 Auto Transplant149
-
32 Allo Transplant151
-
33 Adoptive Cellular Therapy83
-
37 MPNs190
-
39 Acquired BMF178
-
40 MDS and CHIP252
-
41 AML129
-
42 ALL104
-
43 Hodkgin Lymphoma131
-
47 CLL224
-
48 MGUS and Myeloma346
-
49 AL Amyloid, Waldenstrom, POEMS152
