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Acute Myeloid Leukemia in 2018:The Era of Individualized Therapy
Sila Shalhoub, PharmDPGY2 Oncology Pharmacy [email protected]
Pharmacy Grand Rounds February 6, 2018
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Objectives• Describe the impact of patient and disease characteristics on outcomes of acute myeloid leukemia (AML) with standard therapy
• Identify unique patient subtypes that may benefit from one of the four new medications approved for AML in 2017
• Integrate diagnostic information into the development of a personalized treatment approach to optimize AML outcomes
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Leukemia
NCCN. Acute Myeloid Leukemia. 3.2017American Cancer Society. Key Statistics for Acute Myeloid Leukemia. 2017
American Cancer Society. Cancer Facts & Figures. 2017
• Cancer of the bone marrow and blood
• 2018 estimates: • 60,300 new cases
• AML: 19,520 • 24,370 deaths
• AML: 10, 670
AML31%
CML10%ALL
10%
CLL37%
Others 12%
Types of Leukemia
AML: acute myeloid leukemia CML: chronic myeloid leukemia ALL: acute lymphoblastic leukemia CLL: chronic lymphocytic leukemia
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Acute Myeloid Leukemia
• Incidence: 3‐5 cases/100,000 individuals
• Median age 67 years
• Overall 5‐year survival • < 65 yo: 40%• ≥ 65 yo: 5%
Kouchkovsky ID, et al. Blood Cancer J. 2016 Jul; 6(7): e441Almeida AM, et al. Leuk Res Rep. 2016; 6: 1–7https://commons.wikimedia.org/wiki/File:0337_Hematopoiesis_new.jpg
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Risk Stratification
Prognostic Cytogenetics /Molecular abnormalities
FavorableInv(16), t(16;16), t(8;21), t(15;17)Normal karyotype with NPM1 mutation or CEBPA mutation
Intermediate +8 alone, t(9;11)KIT mutation
Poor Complex (≥3 clonal abnormalities) -5,5q-, -7, 7q-, 11q23, t(6;9)FLT3+, TP53 mutation
NCCN. Acute Myeloid Leukemia. 3.2017
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AML Treatment Paradigm
HypomethylatingAgents
Best Supportive
Care
Transplant Monitor
Fit
Induction
Unfit
Consolidation
Intermediate/High Risk Intermediate/Low Risk
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Standard Therapy Since the 1970’s • Induction with 7+3
• 7 days of cytarabine 100 or 200mg/m2 daily as a continuous IV infusion
• 3 days of either Idarubicin 12mg/m2 or daunorubicin 60mg/m2 as an IV push
• If complete remission (CR) achieved consolidation • High dose cytarabine
• 3000mg/m2 q12h day 1,3,5 for 3‐4 cycles
• High risk in CR Allogeneic stem cell transplant
Estey E, et al. Am J Hematol. 2016 Aug;91(8):824‐46Dombret H, et al. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017
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Outcomes of Standard Therapy
Prognostic CR rate RR w/ chemotherapy w/o allogeneic HCT
RR w/ chemotherapy w/ allogeneic HCT
Favorable > 80‐90% 35‐40% 15‐20%
Intermediate 50‐80% 50‐60% 20‐25%
Poor < 50% > 90% 40‐50%
Estey E, et al. Am J Hematol. 2016 Aug;91(8):824‐46Ossenkoppele GJ, et al. Haematologica. 2016 Jan; 101(1): 20–25
CR: complete remission, HCT: hematopoietic cell transplantation, RR: relapse rate
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Historically, what characteristics may affect induction treatment selection in AML patients ?
A. Molecular abnormalities (ex. FLT3 status) B. Disease features (ex. sAML)C. Performance status (ex. fit vs. unfit)D. B & C E. All of the above
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MidostaurinMidostaurin
Timeline of AML Therapies
7+3
Enasidenib
Gemtuzumab Ozogamicin*
Daunorubicin:Cytarabine liposomal
1960 1970 1980 1990 2000 2010 2017
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FLT3 Mutations • FLT3: cytokine receptor, regulate early myeloid and lymphoid stem and progenitor cells’ growth and survival
• Occur in 25‐30% of AML patients
• Two subtypes:• Internal tandem duplication (ITD) – 25%
• Poor prognosis, high relapse rate • Tyrosine kinase domain (TKD) – 5‐10%
• Prognosis uncertain
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017
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FLT3 inhibitor: MidostaurinMechanism of Action • Multi‐target tyrosine kinase receptor inhibitor
• Inhibit receptor signaling and cell proliferation
• Induces apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors
• Can also inhibit other signaling pathways• KIT, PDGFRα/β, VEGFR2, PKC
Rydapt® [package insert]. Novartis Pharmaceuticals Corporation, Inc., East Hanover, NJ. 2017
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CALGB 10603 – RATIFY Trial
7+3 plus midostaurin
7+3 plus placebo
Induction 1‐2 cycles (28days)
Consolidation 4 cycles (28days)
Midostaurin
Maintenance 12 cycles (28days)
Placebo
Primary Endpoint: Overall Survival
7+3 consisted of cytarabine IV 200mg/m2 + daunorubicin IV 60mg/m2
Midostaurin PO 50mg BID given on day 8‐21HiDAC: high dose cytatabine of 3000mg/m2 q12h on day 1,3,5
HiDAC plus placebo
CR
CR
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464
Transplant
De‐novo AML dx FLT3‐mutationAge 15‐59yo (n= 717)
HiDAC plus midostaurin
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Baseline Characteristics
Midostaurin(n= 360)
Placebo(n=357) p‐value
Age (median) 47.1 48.6 0.22
Female 186 (52%) 212 (59%) 0.04
Subtype of FLT3
mutation
TKD 81 (22%) 81 (23%) 1
ITD 279 (78%) 276 (77%) 1
WBC median 35,600 33,000 0.72
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464
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Results: Efficacy
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464
Midostaurin(n= 360)
Placebo(n= 357) p‐value
Median Overall Survival 74.7 months 25.6 months 0.009
4‐year Overall Survival Rate 51.4% 44.3% ‐‐‐
Complete Remission 212 (59%) 191 (54%) 0.15
Median Event‐Free Survival (months) 8.2 3 0.002
Transplantation 213 (59%) 196 (55%) ‐‐‐
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Results
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464
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Midostaurin(n= 360)
Placebo(n= 357) p‐value
Anemia 92.7% 87.8% 0.03
Rash 14.1% 7.6% 0.008
Nausea 9.6% 5.6% 0.05
Median Time for ANC Recovery 26 days 26 days ‐‐‐
Median Time forPlatelet Recovery 21 days 21 days ‐‐‐
Adverse Events
Stone RM, et al. N Engl J Med. 2017 Aug 3;377(5):454‐464
ANC: absolute neutrophil count
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Conclusion • First targeted therapy in high risk AML
• Midostaurin was associated with • 22% reduction in the hazard ratio for death • 7% increase of 4‐year overall survival• Cost: 14‐days course= $9000
• Unanswered questions:• Role of maintenance therapy• Role after transplant
• Future FLT3 inhibitors • Quizartinib, crenolanib , gilteritinib
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Daunorubicin:Cytarabine liposomal
Timeline of AML Therapies
7+3
Enasidenib
Gemtuzumab Ozogamicin*
1960 1970 1980 1990 2000 2010 2017
MidostaurinFLT3 positive MidostaurinFLT3 positive
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Daunorubicin:Cytarabine Liposomal
• Daunorubicin:Cytarabine Liposomal formulation in a 1:5 molar ratio
• Daunorubicin: anthracycline
• Cytarabine: antimetabolite
• Rational• Efficacy = maximum dose intensity • Synergy without antagonism • Peak effect vs. constant cytotoxic drug delivery
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CLTR0310‐301: Daunorubicin:Cytarabine Liposomal
tAML or AML‐MRCAge 60‐75yo (n= 309)
Daunorubicin:CytarabineLiposomal
7+3
Induction 1‐2 cycles (28days)
Daunorubicin:CytarabineLiposomal
Consolidation 1‐2 cycles (28days)
Primary Endpoint: Overall Survival
Liposomal induction: dauno 44mg/m2 + cytarabine 100mg/m2 on day 1,3,5 (day 1,3 in the second induction)Liposomal consolidation: dauno 29mg/m2 + cytarabine 65mg/m2 on day 1,37+3 1st induction: cytarabine IV 100mg/m2 day 1‐7+ daunorubicin IV 60mg/m2 day 1‐37+3 2nd induction & consolidation: cytarabine IV 100mg/m2 day 1‐5+ daunorubicin IV 60mg/m2 day 1‐2
CR
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
7+3CR
tAML: therapy related AMLAML‐MRC: AML with myelodysplasia‐related changes
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Baseline Characteristics All Patients (n= 309)
Median Age 68
Male 61%
ECOG PS 0‐1 88%
t‐AML 20%
AML with antecedent hematologic disorder 54%
De‐novo AML with MDS 25%
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
ECOG: Eastern Cooperative Oncology GroupPS: performance status MDS: Myelodysplastic syndrome
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Results Daunorubicin:
Cytarabine Liposomal (n= 153)
7+3(n= 156)
Received at Least1 Induction Cycle 100% 97%
Received at Least1 Consolidation Cycle 32% 21%
Proceeded to Transplantin First CR 20% 12%
Overall Transplant 34% 25%
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
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Results
Daunorubicin:Cytarabine Liposomal
(n= 153)7+3
(n= 156)p‐value
Median overall survival 9.6 months 5.9 months 0.005
Complete Response 58 (38%) 41 (26%) 0.036
60‐day Mortality 13.7% 21.2% ‐‐‐
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
HR 0.69
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Daunorubicin:Cytarabine Liposomal
(n= 153)7+3
(n= 156)
Hemorrhage 74% 56%
Epistaxis 36% 18%
Grade ≥3 12% 8%
Fatal treatment‐emergent CNS hemorrhage 2% 0.7%
Prolonged thrombocytopeniarates past day 42 28% 12%
Prolonged neutropenia rates past day 42 17% 3%
Adverse Events
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
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Adverse Events • Infections (pneumonia, bacteremia)
• Gastrointestinal toxicity
• Rash, swelling, edema, mucositis
• Copper overload : 5mg/mL copper gluconate > 14% elemental copper
• Others:• Extravasation, cardiotoxicity, electrolytes abnormality, fatigue, musculoskeletal pain
Vyxeos® [package insert]. Jazz Pharmaceuticals, Inc., Palo Alto, CA. 2017Lancet JE, et al. Journal of Clinical Oncology34, no. 15_suppl (May 2016) 7000‐7000
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Conclusion • First therapy aimed at sAML
• Daunorubicin:Cytarabine Liposomal was associated with• Longer overall survival • Higher complete responses and transplant rate • Hemorrhage incidence and prolonged myelosuppression
• Cost of 1 induction course:• BSA ≤ 2m2= $46,500• BSA > 2m2 = $69,750
• Unanswered questions• Benefits of efficacy vs. risks of toxicity?
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How is Daunorubicin:CytarabineLiposomal formulation different than the conventional daunorubicin + cytarabine?
A. Less cardiotoxic on mg per mg basis of daunorubicin
B. More prolonged thrombocytopenia and neutropenia
C. Higher CR and OS rates across AML subtypes
D. Less healthcare resources utilized during induction
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Gemtuzumab Ozogamicin*
Timeline of AML Therapies
7+3
Enasidenib
1960 1970 1980 1990 2000 2010 2017
MidostaurinFLT3 positiveMidostaurinFLT3 positive
Daunorubicin:Cytarabine liposomalsAML
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CD33 Cell Surface Marker • Limited to myeloid progenitors
• Not present on normal hematopoietic stem cells
• Expressed on >90% of AML blasts
• Negative regulator of immunoreceptor signal transduction
• Gemtuzumab ozogamicin (GO) mechanism of action
Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017
CD33+Leukemia
Calicheamicin (antitumor antibiotic)
GO binds to CD33 Ab‐Ag complexinternalizes
Calicheamicinreleased
Cell death
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Gemtuzumab ozogamicin (GO) • Accelerated approval in 2000 for relapsed AML
• International, randomized, phase 3 (SWOG S0106) trial• GO at a dose of 6mg/m2 added to 7+3 in newly dx AML• <60 years of age • Interim analysis
• GO failed to improve CR and OS rate • Increase in induction mortality rate 5% vs 1.4% • Increase in grade 4 toxicities 21% vs 12%
• GO increase risk of VOD
• Voluntarily withdrawn from the market in 2010
Perl A. American Society of Hematology. 59th ASH Annual Meeting and Exposition. 2017
OS: overall survival VOD: veno‐occlusive disease
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Gemtuzumab ozogamicin
French ALFA‐0701 AML‐19 MyloFrance‐1
Population 278 newly dx AML Age 50‐70
237 newly dx AML Age ≥ 61, ECOG >2
57 R/R CD33 positive AML
Design Randomized, phase 37+3 ± GO
Randomized, phase 3GO vs. BSC
Phase 2single‐arm
Dosing 3mg/m2 on day 1,4,7 6mg/m2 on day 1 and 3mg/m2 on day 8
3mg/m2 on day 1,4,7 consolidation with Ara‐C
Outcomes EFS: 17.3 vs 9.5 monthsHR 0.56, p<0.001
OS: 4.9 vs 3.6 months HR 0.69, p=0.005
RFS: 11.6 months CR: 15 (26%)
Castaigne S, et al. Lancet. 2012 Apr 21;379(9825):1508‐16Amadori S, et al. J Clin Oncol. 2016 Mar 20;34(9):972‐9
Mylotarg® [package insert]. Wyeth Pharmaceuticals, Inc., Philadelphia, PA. 2017
EFS: event‐free survival RFS: relapse‐free survival
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Adverse Events • Veno‐occlusive disease (5%)
• Elevated AST/ALT, Tbili• Weight gain • Ascites
• Prolonged thrombocytopenia (3% ‐ 35%)• Hemorrhage
• QTc prolongation – due to calicheamicin
• Post marketing: • Neutropenic colitis, infections, hemorrhagic cystitis
Mylotarg® [package insert]. Wyeth Pharmaceuticals, Inc., Philadelphia, PA. 2017
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Conclusion • GO: CD33‐directed antibody‐drug conjugate
• Approved for • Newly diagnosed AML (monotherapy or combined therapy)• Relapsed/Refractory AML (monotherapy)
• At lower doses, GO was associated with• Longer event‐free, relapsed‐free, and overall survival • Veno‐occlusive disease
• Cost of 1 cycle= $32,800
• Place in therapy is not well defined
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Timeline of AML Therapies
7+3
Enasidenib
1960 1970 1980 1990 2000 2010 2017
MidostaurinFLT3 positiveMidostaurinFLT3 positive
Daunorubicin:Cytarabine liposomalsAML
Gemtuzumab Ozogamicin*CD33 positive
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Isocitrate Dehydrogenase 2 (IDH2) • Catalyze conversation of isocitrate to α‐ketoglutarate (αKG)
• Mutation reduction of αKG to R‐2‐hydroxyglutarate (R2‐HG)
• ↑R2‐HG levels differentiation arrest of hematopoietic cells
• Mutations occurs in ~12% of AML patients
• Enasidenib: First‐in‐class, oral selective inhibitor of isocitratedehydrogenase‐2 (IDH‐2) enzyme
Stein EM, et al. Blood. 2017 Aug 10;130(6):722‐731 IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
Citrate
Isocitrate
α‐KG
2‐HG
IDH3 IDH2
IDH2 mutation
MitochondriaTCA Cycle
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AG221‐C‐001: Enasidenib
≥18 yoMutant IDH2 R/R AML (n= 176)
Enasidenib100mg daily
Until disease progression
Stein EM, et al. Blood. 2017 Aug 10;130(6):722‐731 IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
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Results: Efficacy
Stein EM, et al. Blood. 2017 Aug 10;130(6):722‐731 IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
Enasidenib(n= 176)
Median Overall Survival 9.3 months
Overall Response Rate 71 (40%)
Complete Remission 34 (19%)
Complete Remission with Incomplete Hematologic Recovery 12 (9%)
Partial Remission 11 (6%)
Morphologic Leukemia‐Free State 14 (8%)
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Results: Response
Stein EM, et al. Blood. 2017 Aug 10;130(6):722‐731 IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
Enasidenib(n= 176)
Time to Response 1.9 months
Median Duration of Response 5.8 months
Median Duration of Response in CR patients 8.8 months
Proceeded to transplant 17 (10%)
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Adverse Events • Differentiation syndrome (14%)
• Non‐infectious leukocytosis (12%)
• Tumor lysis syndrome (6%)
• GI toxicities (50%)
• Decreased appetite (34%)
IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
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Case46 yo, 72kg, F, with relapsed (IDH2 mutated) AML, WBC 8.2 with 26% blasts.
Today is day 18 after enasidenib initiation. This morning patient developed a fever of 39.2°C, new onset dyspnea, O2 Sat 86% on room air, CXR showed diffuse bilateral interstitial infiltrates, WBC 36.4 with 3% blasts, weight 78kg.
What is the next step for managing this patient’s symptoms ?
IDHIFA® [package insert]. Agios Pharmaceuticals, Inc., Cambridge, MA. 2017
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CaseA. Obtain blood cultures and start treatment
with cefepime and vancomycin
B. O2 mask + bronchodilator
C. Stop enasidenib and give dexamethasone
D. Give furosemide 40mg IV x1
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Conclusion • Enasidenib was associated with
• 9.3 months median overall survival • Time to response was 1.9 months • 19% achieved CR lasting 8.8 months • Differentiation syndrome
• Cost: 30‐day supply= $24,870
• Phase 1/2 data, mature data outcomes?
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Summary • 1970 – 2017: no change in AML treatment
• Four novel therapies were approved in 2017 for the treatment of AML
• 2018: individualized AML treatment • Disease characteristics • Patient characteristics
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One Size Does Not Fit All
7+37+3
1960 1970 1980 1990 2000 2010 2017
Midostaurin
EnasidenibEnasidenib
Gemtuzumab OzogamicinGemtuzumab Ozogamicin
FLT3 positive Not as a single agent
Daunorubicin: Cytarabine liposomal
Single Agent in R/R AMLIDH2 mutation
Single Agent in tAML and AML‐MRC
Single Agent or in combination Newly dx or R/R CD33 positive
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What characteristics may affect induction treatment selection in AML patients ?
A. Molecular abnormalities (ex. FLT3 status) B. Disease features (ex. sAML)C. Performance status (ex. fit vs. unfit)D. B & C E. All of the above
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Questions & Discussion
Sila Shalhoub, PharmDPGY2 Oncology Pharmacy Resident
Acute Myeloid Leukemia in 2018:The Era of Individualized Therapy