Acute Myeloid Leukemia Flashcards
Diagnosis of AML
> = 20% blasts (or blast equivalents)
OR
Any percentage of myeloid blasts w/ any of:
- t(8;21) or RUNX1::RUNX1T1 fusion
- Inversion (16) or t(16;16) or CBFB::MYH11 fusion
- t(15;17) or PML::RARA fusion
- DEK::NUP214 fusion
- RBM15::MRTFA fusion
- KMT2A rearrangement
- MECOM rearrangement
- NUP98 rearrangement
- NPM1 mutation
POOR Prognostic Factors of AML
- Age >= 60 years old
- Mutations:
- Karyotype
-Molecular Mutations:
- FMS-like tyrosine kinase (FLT)-3
- Nucleophosmin (NPM) 1
- CCAAT enhancer binding protein alpha (CEBPA)
- Isocitrate dehydrogenase (IDH) 1 and 2 - Lack of complete remission after first induction therapy
- < 6 mo remission
Treatment of AML
Phases
Induction
Consolidation
Maintenance
Treatment of AML
Remission induction chemotherapy
HOW SOON TO START
Remission induction chemotherapy should begin soon after definitive diagnosis is made
- NCCN guidelines: recommend expediting molecular and cytogenic analyses for immediately actionable mutations (CBF, FLT3, NPM1, IDH1, IDH2)
- For proliferative presentations:
- Hydroxyurea should be started or
- Cytarabine (1-2G) immediate dose prior to receiving results
Treatment of AML
Modifications based on Co-Morbidities
Cardiac dysfunction may either disqualify patient for intensive remission induction therapy or require a non-anthracycline containing regimen
INTENSIVE REGIMEN: Young/fit
LOW-INTENSIVE REGIMEN: Older/have significant comorbidities
Treat with curative intent for most patients unless significant comorbidities or elderly
Treatment of AML
INTENSIVE REMISSION INDUCTION TX
General Principles
- **Best outcomes **< 60 yo w/ ECOG performance status 0-2
- GOAL: induce complete remission (CR)
- **Bone Marrow Biopsy: **around day 14-21 counted from beginning of remission induction chemotherapy for chemo regimens for which this is indicated (ex 7+3)
- If evidence persists -> additional chemotherapy considered -
Screening lumbar puncture for CNS involvement and consideration of intrathecal chemotherapy should be considered in pts who present w/ CNS symptoms consistent with CNS involvement
- Pts w/ monocytic differentiation, mixed phenotype acute leukemia (MPAL), WBC count > 40,000 at diagnosis, high-risk APL, FLT3 mutation - **Consolidation therapy ** should begin within two weeks following:
- hematologic recovery after induction
- confirmed bone marrow evaluation demonstrating CR - Maintenance Therapy is considered for pts ot proceeding to allo-HCT and should begin after consolidation is complete and while pt is still in CR/CRi
Treatment of AML
INTENSIVE REMISSION INDUCTION TX
Bone Marrow Evaluation
Patients classified as high risk per ELN are recommended to receive consolidation with anallo-HCT
Patients classified as intermediate risk should be **considered **for an allo-HCT.
Patients with** favorable risk** AML do not require an allo-HCT in first remission (can consider if persistently MRD+)
1) Patients who are deemed appropriate for an allo-HCT can be prescribed consolidation chemotherapy as a bridge if logistics lead to a significant delay
Treatment of AML
Complete Remission Criteria
Must meet ALL criteria for CR
- ANC > 1
- PLT >100
- Patient independent of transfusions
- Bone marrow <5% blasts
- Absence of extramedullary disease
- Disappearance of Karyotype abnormality is NOT required
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
General Principles
Preferred in patients who are unfit for intensive induction therapy due to age and/or comorbidities
- Age is not a sole determinant for fitness but majority of low-intensity studies enrolled patients >70-75 years of age
Goal is mostly palliative and consists of regaining normal hematopoiesis, minimizing the need for transfusion, improving quality of life, and prolonging life.
Low-intensity therapy generally continues as long as tolerated, until progression of disease
Treatment of AML
INTENSIVE REMISSION INDUCTION TX
Standard induction therapy is based on the combination of cytarabine + anthracycline (idarubicin or daunorubicin are both appropriate).
* Daunorubicin 60-90 mg/m2/day x 3 days
- High Dose Cytarabine (CONTROVERSIAL)
- Midostaurin (Type 1 FLT3 inhibitor for FLT3-ITD/FLT3-TKD mutation)
* midostaurin + cytarabine + daunorubicin - Improved OS - Quizartinib (highly potent, selective oral 2nd gen Type 2 FLT3 Inhibitor)
- Gemtuzumab Ozogamicin and standard 7+3 (withdrawn from market)
* Target CD33+
QUIZARTINIB
MOA: FLT3 Inhibitor
Indications: Newly diagnosed FLT3-ITD+ AML
Toxicities: Black Box QT Prolongation, torsades, cardiac arrest - REMS
Treatment of AML
INTENSIVE REMISSION INDUCTION TX
Summary of Preferred Tx
**Favorable Risk: **
- 7+3
- Preferred: 7+3 w/ GO (CD33+)
Intermediate Risk:
- Preferred: 7+3 (category 1)
Scondary AML (Therapy related, priod MDS/CMML or AML-MRC)
- 7+3 (category 1)
- Liposomal Daunorubicin/cytarabine (category 1 for > 60yo)
Poor-Risk
- 7+3 (category 1)
- HiDAC w/ etoposide and idarubicin or daunorubicin (category 1 < 45 YO)
FLT3 mutated
- 7+3 with midostaurin or quizartinib (ITD only)
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Advantages
- Benefits EFS and OS vs. Best Supportive Care
- Lower incidence of tx related adverse events that require hospitalization vs. intensive chemo
- Can be administered in ambulatory setting
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Disadvantages
- Responses may not be evident for several cycles, thus may have prolonged cytopenias
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Hypomethylating Agents
Azacitadine and Decitabine
- Have not been approved as single agents for AML however have been historical standards of care
Combination Therapy
- Has become the new standard:
- AZA w/ venetoclax
- AZA w/ ivosidenib
May require several cycles to see response
- generally low-intensity remission induction therapy continues until disease progression, blurring lines between “induction” and “post remission” (i.e consolidation and maintenance)
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Gemtuzumab Ozogamicin
AML-19 Study (CD33+ status)
- Median overall survival 4.9 mo (gem) vs. 3.6 (best supportive care)
- No benefit in those w/ adverse cytogenics
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Glasdegib
BRIGHT AML 1003 Study
- Glasdegib 100mg daily + cytarbine low dose (20mg BID) vs cytarabine mono
- CR: 17% vs. 2.3% in favor of glasdegib combination
- Median OS: 8.8 for gladegib + LDAC vs. 4.9 LDAC alone
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Venetoclax
FDA APPROVAL
VEN+AZA
- Mean OS: 14.7 mo VEN+AZA vs. 9.6 mo in PBO (placebo)+AZA
- CR/CRi 66% vs. 28%
- Significantly improved in de-novo AML, secondary AML, IDH1/2 mutation, FLT3 mutation, NPM1 mutation and TP53 mutation
- VEN+AZA also improved tranfusion independence
VEN+LDAC
- Mean OS: 7.2 mo vs. 4.1 mo PBO +LDAC
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Venetoclax
Clinical Pearls
Compared with HMA alone
- Responses are faster (CR in 1-2 cycles rather than 3-4+ cycles)
- Obtain a marrow at ~day 21-28
- If no morphologic evidence of leukemia, stop venetoclax, and give 7-14 day break of therapy. Can consider the use of G-CSF for patients with prolonged neutropenia to hasten count recovery
- Patients experience significant myelosuppression if no break in therapy is given
- Concern for treatment failure if no response after two cycles
Venetoclax requires significant dose reduction if given with concomitant moderate or strong CYP3A4 inhibitors, particularly anti-mold azole antifungals
- Stop antimicrobial prophylaxis when remission attained (and periods of neutropenia become shorter)
Consider shorter course of venetoclax (14-21 days) depending on cytopenias from previous cycles particularly in older patients where the goal of care is palliation and tolerability is paramount in the continuation of therapy
Treatment of AML
LOW-INTENSITY REMISSION INDUCTION TX
Ivosidenib
**FDA APPROVED: **
- 1st line IDH1 mutated AML as single agent for patients >75 OR
- Pts with comorbidities deemed unfit for intensive therapy
**Median OS: **24 mo IVO+AZA vs. 7.9 mo placebo+AZA
Treatment of AML
INDUCTION TX (LOW-INTENSITY)
Summary of Preferred Tx
No Actionable Mutations:
- Preferred: Venetoclax + AZA (catgory 1)
- Preferred: Venetoclax + decitabine
IDH1 Mutated:
- Preferred: Ivosidenib + AZA (category 1)
- Preferred: Ventoclax + AZA (category 1)
* decitabine can be used as alternative
IDH2 Mutated:
- Preferred: Enasidenib
- Preferred: Ventoclax + AZA (category 1)
FLT3 Mutated:
- Preferred: Venetoclax + AZA (category 1)
