Naval Daver, MD, and Joseph D. Khoury, MD, FCAP, prepared useful practice aids pertaining to acute myeloid leukemia for this CME/MOC/CC activity titled "The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of Disease Subtypes." For the full presentation, complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/32hvh7Z. CME/MOC/CC credit will be available until October 14, 2022.
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The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of Disease Subtypes
1. Access the activity, “The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of
Disease Subtypes,” at PeerView.com/PDK40
A Snapshot of Innovative Therapies in AML
Current Status, Dosing, and Other Considerations
PRACTICE AID
STATUS DOSEDRUG TARGET
Approved
Plus chemotherapy in adults with newly diagnosed
FLT3-mutation–positive AML
50 mg orally twice daily with food on d 8-21 of each
induction cycle with cytarabine and daunorubicin and
on d 8-21 of each consolidation cycle with
high-dose cytarabine
Midostaurin4
FLT3
Approved
Adults with R/R IDH2-mutation–positive AML
100 mg orally daily
Enasidenib10
IDH2
Approved
Adults with IDH1-mutation–positive newly diagnosed
AML who are ≥75 years or who have comorbidities that
preclude the use of intensive induction chemotherapy
or R/R AML
500 mg orally daily
Ivosidenib11
IDH1
Phase 3 testing
Adults with newly diagnosed and R/R
FLT3-ITD–positive AML
60 mg used in phase 3 QuANTUM-R study
(30-mg lead-in)Quizartinib6-9
FLT3
Approved
Adults with newly diagnosed t-AML or AML-MRC
Induction: daunorubicin 44 mg/m2
and cytarabine
100 mg/m2
liposome IV over 90 min on d 1, 3, and 5a
CPX-3511-3
Cytotoxic therapy
(liposomal cytarabine +
daunorubicin 5:1 molar ratio)
Approved
Adults with FLT3-mutation–positive R/R AML
120 mg orally daily
Gilteritinib5
FLT3
Approved
In combination with azacitidine or decitabine or low-dose
cytarabine for newly diagnosed AML in adults ≥75 years
or who have comorbidities that preclude use of intensive
induction chemotherapy
Ramp-up phase: 100 mg orally on d 1, 200 mg on d 2,
400 mg on d 3; d 4 and beyond: 400 mg (with HMA)
or 600 mg (with low-dose cytarabine)
BCL-2
Venetoclax12
Accurate diagnosis (eg, of FLT3- or IDH-mutant AML, AML-MRC) has clear therapeutic implications for use of targeted agents and novel therapeutics
2. a
For additional induction, use d 1 and 3 for subsequent cycles, if needed; for consolidation: daunorubicin 29 mg/m2
and cytarabine 65 mg/m2
liposome IV over 90 min on d 1 and 3.
AML: acute myeloid leukemia; AML-MRC: AML with myelodysplasia-related changes; BCL-2: B cell lymphoma 2; BM: bone marrow; CD: cluster of differentiation; CR: complete remission; CRi: complete remission with incomplete blood count recovery; FLT3: fms-like tyrosine kinase 3; FN: febrile
neutropenia; HCT: hematopoietic cell transplantation; Hhp: hedgehog pathway; HMA: hypomethylating agent; IDH: isocitrate dehydrogenase; ITD: internal tandem duplication; mAb: monoclonal antibody; MDS: myelodysplastic syndrome; RFS: relapse-free survival; R/R: relapsed or refractory;
t-AML: therapy-related acute myeloid leukemia; TLS: tumor lysis syndrome; VOD: veno-occlusive disease.
1. Lancet JE et al. 52nd Annual Meeting of the American Society of Clinical Oncology (ASCO 2016). Abstract 7000. 2. Lancet JE et al. 2017 Annual BMT Tandem Meetings (BMT Tandem 2017). Abstract 19. 3. Vyxeos (daunorubicin and cytarabine) Prescribing Information. http://pp.jazzpharma.com/pi/
vyxeos.en.USPI.pdf. 4. Rydapt (midostaurin) Prescribing Information. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/rydapt.pdf. 5. Xospata (gilteritinib) Prescribing Information. https://astellas.us/docs/xospata.pdf. 6. https://clinicaltrials.gov/ct2/show/NCT02668653.
7. https://clinicaltrials.gov/ct2/show/NCT02039726. 8. Cortez J et al. 23rd Congress of the European Hematology Association (EHA 2018). Abstract LB2600. 9. https://pharmaphorum.com/market-access-2/fda-grants-leukaemia-drug-breakthrough-status/. 10. Idhifa (enasidenib) Prescribing Information.
https://media.celgene.com/content/uploads/idhifa-pi.pdf. 11. Tibsovo (ivosidenib) Prescribing Information. https://www.tibsovo.com/pdf/prescribinginformation.pdf. 12. Venclexta (venetoclax) Prescribing Information. https://www.rxabbvie.com/pdf/venclexta.pdf. 13. Mylotarg (gemtuzumab
ozogamicin) Prescribing Information. http://labeling.pfizer.com/ShowLabeling.aspx?id=9548. 14. https://www.fda.gov/drugs/fda-approves-glasdegib-aml-adults-age-75-or-older-or-who-have-comorbidities. 15. Daurismo (glasdegib) Prescribing Information. http://labeling.pfizer.com/ShowLabeling.
aspx?id=11336. 16. Agura E et al. 60th American Society of Hematology Annual Meeting and Exposition (ASH 2018). Abstract 1017. 17. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-onureg-azacitidine-tablets-acute-myeloid-leukemia.
Access the activity, “The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of
Disease Subtypes,” at PeerView.com/PDK40
A Snapshot of Innovative Therapies in AML
Current Status, Dosing, and Other Considerations
PRACTICE AID
STATUS DOSEDRUG TARGET
Approved
In combination with low-dose cytarabine for newly
diagnosed AML in adults ≥75 years or who have
comorbidities that preclude use of intensive
induction chemotherapy
100 mg orally daily
Glasdegib14,15
Hhp
Approved
Patients with AML who achieved first CR or CRi
following intensive induction chemotherapy and
are not able to complete intensive curative therapy
300 mg orally daily for 14 d of 28-d
treatment cycles (QUAZAR study)Oral
azacitidine17
Epigenetic
modification
(novel oral formulation
of HMA)
Accurate diagnosis (eg, of FLT3- or IDH-mutant AML, AML-MRC) has clear therapeutic implications for use of targeted agents and novel therapeutics
Approved
Newly diagnosed CD33+ AML in adults, R/R CD33+
AML in adults, and in pediatric patients aged ≥2 years
Induction: 3 mg/m2
(up to one 4.5-mg vial) on d 1, 4,
and 7 in combination with daunorubicin and cytarabine
CD33Gemtuzumab
ozogamicin13
Phase 3 SIERRA study
Adults aged ≥55 years with active, R/R AML, adequate
organ function, and related/unrelated matched donor
Dosimetry directed
(SIERRA study)
CD45
(BC8 mAb linked to
radioisotope iodine-131)Iomab-B16
3. Access the activity, “The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of
Disease Subtypes,” at PeerView.com/PDK40
Tools for Characterizing and Diagnosing AML
and Higher-Risk Subtypes
PRACTICE AID
AML with recurrent genetic abnormalities
AML with t(8;21)(q22;q22.1);RUNX1-RUNX1T1
AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22);CBFB-MYH11
APL with PML-RARA
AML with t(9;11)(p21.3;q23.3);KMT2A-MLLT3
AML with t(6;9)(p23;q34.1);DEK-NUP214
AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM
AML (megakaryoblastic) with t(1;22)(p13.3;q13.3);RBM15-MKL1
Provisional entity: AML with BCR-ABL1
AML with mutated NPM1
AML with biallelic mutations of CEBPA
Provisional entity: AML with mutated RUNX1
AML with myelodysplasia-related changes
Therapy-related myeloid neoplasms
AML, NOS
AML with minimal differentiation
AML without maturation
AML with maturation
Acute myelomonocytic leukemia
Acute monoblastic/monocytic leukemia
AML and Related Neoplasms
Complex karyotype (≥3 abnormalities)
Balanced abnormalities
t(11;16)(q23.3;p13.3)
t(3;21)(q26.2;q22.1)
t(1;3)(p36.3;q21.2)
t(2;11)(p21;q23.3)
t(5;12)(q32;p13.2)
t(5;7)(q32;q11.2)
t(5;17)(q32;p13.2)
t(5;10)(q32;q21.2)
t(3;5)(q25.3;q35.1)
Cytogenetic Abnormalities
Note: these cytogenetic abnormalities
are sufficient to diagnose AML-MRC
when ≥20% PB or BM blasts are
present and prior therapy has
been excluded
The WHO released an updated classification of AML in 20161
Unbalanced abnormalities
–7/del(7q)
del(5q)/t(5q)
i(17q)/t(17p)
–13/del(13q)
del(11q)
del(12p)/t(12p)
idic(X)(q13)
Pure erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
4. AML: acute myeloid leukemia; AML-MRC: acute myeloid leukemia with myelodysplasia-related changes; APL: acute promyelocytic leukemia; BCR-ABL1: B-cell receptor–Abelson murine leukemia viral oncogene homolog 1; BM: bone marrow; CBFB: core-binding factor beta subunit; CD:
cluster of differentiation; CEBPA: CCAAT/enhancer binding protein alpha; FLT3-ITD: FLT3-internal tandem duplication; IDH1/2: isocitrate dehydrogenase 1/2; IHC: immunohistochemistry; KMT2A-MLLT3: lysine-specific methyltransferase 2A–myeloid/lymphoid or mixed-lineage leukemia;
MDS: myelodysplastic syndrome; MECOM: MDS1 and EVI1 complex locus; MPO: myeloperoxidase; MRD: minimal residual disease; MYH11: myosin heavy chain 11; NGS: next-generation sequencing; NOS: not otherwise specified; NPM1: nucleophosmin 1; PB: peripheral blood; PML-RARA:
promyelocytic leukemia/retinoic acid receptor alpha; PT: prothrombin time; PTT: partial thromboplastin time; RBM15-MKL1: RNA binding motif protein 15–megakaryoblastic leukemia (translocation) 1; RUNX1: runt related transcription factor 1; sAML: secondary acute myeloid leukemia; TKD:
tyrosine kinase domain; TP53: tumor protein 53.
1. Arber DA et al. Blood. 2016;127:2391. 2. NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2020. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. 3. Roloff GW, Griffiths EA. Blood Adv. 2018;2:3070-3080.
Access the activity, “The Pathology–Oncology Partnership in AML: Identifying and Treating the Diversity of
Disease Subtypes,” at PeerView.com/PDK40
Tools for Characterizing and Diagnosing AML
and Higher-Risk Subtypes
PRACTICE AID
Several tests should be considered to
accurately diagnose AML and its subtypes2
• Including assessment for c-KIT, FLT3-ITD, FLT3-TKD,
NPM1, CEBPA, IDH1/IDH2, and TP53
• Multiplex gene panels and NGS are recommended
for more comprehensive assessment
Although routine adoption of MRD assessment in all AML
settings is not yet recommended, efforts to standardize
assessment are underway. Methods include3
• Real-time PCR (dependent upon identification of a
suitable abnormality)
• NGS; potentially applicable to all leukemia-specific
gene combinations
Note: Some AML subtypes
may have a distinctive diagnosis
Example: AML-MRC can present with a
myeloblast phenotype and key markers such as
CD34 and CD117 and myeloid markers CD13, CD33,
and MPO
Consider ordering an MDS panel to ensure genetic
abnormalities related to sAML are identified
CBC, differential, platelets, chemistry profile
PT and PTT
BM core biopsy and aspirate analyses,
including IHC and cytochemistry
Cytogenetics and molecular analysis