acute myeloid leukemia refresher course...cytarabine 1.5 g/m² iv d1-4* idarubicin 12 mg /m² iv qd...
TRANSCRIPT
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Acute Myeloid Leukemia
Pimjai Niparuck
Division of Hematology, Department of Medicine
Ramathibodi Hospital, Mahidol University
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Outline
• Molecular biology
• Chemotherapy and Hypomethylating agent
• Novel Therapy
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Treatment
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Treatment for elderly patients with AML
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A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,
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A Randomized Phase II Trial of 5-Day Versus 10-Day Schedules of Decitabine for Older Patients with Previously Untreated Acute Myeloid Leukemia Nicholas J Short, MD1, Hagop M. Kantarjian, MD1, Guillermo Garcia-Manero, MD1, Gautam Borthakur, MD1, Tapan Kadia, MD1, Xuelin Huang, PhD2*, Naval Daver, MD1, Courtney D. DiNardo,
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Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (≥ 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III
Randomized Multicentre Study (EudraCT 2008-001290-15)
• 117 patients were randomly 1:1
1. observation (control group )
2. azacitidine maintenance (aza group), 50 mg/m2 (5 days) q 4 weeks, until relapse for a maximum of 12 cycles
• 52 patients received at least 1 cycle of aza
44, 40, 34 and 32 patients received at least 3, 6, 9 and 12 cycles respectively
• The 12 months DFS = 39% (control group), 63% (aza group)
Difference in OS between the two groups : not statistically significant in the cohort of patients in this pre-final analysis
• The 12 months OS (after censoring allo transplanted patients) = 64% (control group), 83% (aza group)
• Subgroup analysis (CR vs CRi at inclusion) revealed that patients with platelet count ≥ 100 x 109/L had a significant better OS in favor of aza maintenance treatment (logrank; p=0.01).
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Randomized Maintenance Therapy with Azacitidine (Vidaza) in Older Patients (≥ 60 years of age) with Acute Myeloid Leukemia (AML) and Refractory Anemia with Excess of Blasts (RAEB, RAEB-t). Results of the HOVON97 Phase III
Randomized Multicentre Study (EudraCT 2008-001290-15)
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Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics
• Adult pts with R/R AML or myelodysplastic syndromes (MDS) and preserved organ function
with a WBC<10,000/μL (hydroxyurea permitted) were eligible. The tx consisted of aza 75 mg/m2 d1-7, a bone marrow biopsy on cycle (C) 1 day 8, len 50 mg d8-28, and 2 weeks off tx, constituting a 42-day cycle.
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Sequential Azacitidine (Aza) and Lenalidomide (Len) for Patients (Pts) with Relapsed and Refractory (R/R) Acute Myeloid Leukemia (AML): Clinical Results and Predictive Modeling Using Computational Analysis and Serial Genomics
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Novel Therapy
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Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
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Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
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Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
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Phase II SORAML Trial of Sorafenib versus Placebo in Addition to Standard Therapy for Younger Patients with Newly Diagnosed AML
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Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years
• Venetoclax (VEN) is a small molecule inhibitor of BCL-2 that achieved remission rates of >60% combined with low-dose cytarabine (LDAC)
• Total= 71 pts, median age, 74 years [range, 66-87 years]
• cycle 1, VEN 50 mg/day PO and increased over a 5-day ramp-up to reach the designated cohort dose of 600 or 800 mg/day on day 6, which was continued through day 28
• In subsequent cycles, the desingated dose of VEN 600 or 800 mg/day was administered on days 1-28
• LDAC 20 mg/m2/day SQ was given on days 1-10 of each cycle
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Phase 1/2 Study of Venetoclax with Low-Dose Cytarabine in Treatment-Naive, Elderly Patients with AMLUnfit for Intensive Chemotherapy: 1-Year Outcomes; Age>65 years
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Phase II Study: Frontline Cytarabine and Idarubicin + Nivolumab in Newly
Diagnosed AML
Integrating New Hematology Findings Into Practice: Independent Conference Coverage of ASH 2017,* December 9-12, Atlanta, Georgia *CCO is an independent medical education company that provides state-of-
the-art medical information to healthcare professionals through conference
coverage and other educational programs.
This activity is supported by educational grants from AbbVie; AstraZeneca;
Celgene Corporation; Genentech; Janssen Biotech, Inc administered by
Janssen Scientific Affairs, LLC; Jazz Pharmaceuticals; Novartis
Pharmaceuticals Corporation; Pharmacyclics Inc; Seattle Genetics; and
Takeda Oncology.
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Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design
Pts 18-60 yrs of age
(or > 60 if very fit)
with either AML by WHO
criteria or high-risk MDS
with ≥ 10% blast cells;
ECOG PS 0-2;
adequate cardiac, renal,
hepatic function (N = 35)
Cytarabine 1.5 g/m² IV D1-4*
Idarubicin 12 mg /m² IV QD x 3
Nivolumab† 3 mg/kg Q2W starting on D24 ± 2 days
Induction
Ravandi F, et al. ASH 2017. Abstract 815. ClinicalTrials.gov. NCT02464657.
Cytarabine 0.75 g/m² IV QD x 3
Idarubicin 8 mg /m² IV QD x 3
≤ 5 cycles
Nivolumab 3 mg/kg Q2W
≤ 1 yr
Consolidation Maintenance
*Cytarabine given over 24 hours; pts older than 60 yrs of age received 3 days instead of 4. †First 3 pts treated at run-in phase with nivolumab 1 mg/kg with no drug-related toxicity. The remaining 32 pts treated as noted in schema.
Slide credit: clinicaloptions.com
Allogeneic SCT for eligible pts at any time during or after consolidation
• Primary endpoint: MTD of nivolumab (phase I)
• Secondary endpoint: EFS (phase I/II)
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Characteristic IA + Nivolumab
(N = 35)
Median age, yrs (range) 54 (26-65)
Male, % 43
Median WBC x 109/L (range) 5 (0.4-46.1)
Median creatinine, mg/dL (range) 0.8 (0.51-1.31)
Median bilirubin, mg/dL (range) 0.7 (0.2-2.5)
Median BM blasts, % (range) 42 (15-96)
AML/MDS, %
De novo AML
Secondary AML
Therapy-related AML
High-risk MDS (≥ 10% blasts)
74
11
9
6
Previous therapy for MDS, %
None
Hypomethylating agents
89
11
Characteristic, % IA + Nivolumab (N =
35)
Cytogenetics
Diploid
Other
intermediate
-7/7q-/-
5/complex
23
23
40
ELN
Favorable
Intermediate
Adverse
14
46
40
Mutations
FLT3-ITD
FLT3-0835
NPM1
TP53
IDH1
IDH2
DNMT3A
KRAS/NRAS
9
9
17
23
6
23
17
14 Ravandi F, et al. ASH 2017. Abstract 815.
Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design
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0 3 6 9 12
15
18
Ravandi F, et al. ASH 2017. Abstract 815.
OS Event-Free Survival
Relapse-Free
Survival
Median OS: 15.8 mos (range: 0.5-21.1) N = 35; 12 died
Median EFS: 8.3 mos (range: 0.5-18.0) N = 35; 17 events
Median RFS: 17.3 mos (range: 0.6-17.3) N = 26 (CR/CRi/CRp); 9 relapses
Pro
bab
ility
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OS
Pro
bab
ility
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Even
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ee S
urv
ival
Pro
bab
ility
of
Rel
apse
-Fre
e Su
rviv
al
Mos
0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12
15
18
21
24
0
0.2
0.4
0.6
0.8
1.0
0
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0.4
0.6
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21 Mos Mos
Frontline Cytarabine, Idarubicin, Nivolumab for AML: Phase II Study Design