Acute leukemia 62 Board reviewAcute leukemia ManitSae-teaw B.Pharm, BCP, BCOP Grad dip in...
Transcript of Acute leukemia 62 Board reviewAcute leukemia ManitSae-teaw B.Pharm, BCP, BCOP Grad dip in...
Acute leukemia
Manit Sae-teawB.Pharm, BCP, BCOP
Grad dip in pharmacotherapyFaculty of pharmaceutical sciences
Ubon Ratchathani University1
Outline Introduction to leukemia Acute Myeloid Leukemia (AML) AML non-M3 AML M3 (APL)
Acute Lymphoblastic Leukemia
2
Leukemia
3Ref : GLOBOCAN 2018 (IARC) Section of cancer information
Leukemia
4
No (thousands) World ThailandPopulation 7,632,819 69,183Number of new cases 437.03 4.72
Number of death 309.01 3.83
Ref : GLOBOCAN 2018 (IARC) Section of cancer information
Leukemia can divided in to Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Chronic myeloid leukemia (CML) Chronic lymphocytic leukemia (CLL)
Acute Myeloid Leukemia
In US : Estimated new cases (2014) 18,860 people Death 10,460 people
Median age of diagnosis 67 years AML can be de novo or secondary Alkylating agent/topoisomerase II inh Radiation Myelodysplastic syndrome (MDS)
5
Acute Myeloid Leukemia
Clinical presentation Bone marrow failure Leukostasis 2nd to high WBC Tumor lysis syndrome Extramedullary tissue invasion Gum and skin infiltration : leukemia cutis (M4,M5) CNS infiltration (M4,M5)
DIC (M3, may also M5)
6
Acute Myeloid Leukemia
AML is characterized by clonal expansion of myeloid blast
AML require ≥ 20% marrow myeloblast of bone marrow Additional cytogenetics abnormalities with
t(15;17), t(8;21), t(16;16) and inv(16) regardless of marrow blast
7
Morphologic classification
8
Molecular marker and risk stratification
Intermediate risk cytogenicity is most heterogenous group
2 most frequent molecular abnormalities NPM1 gene (18-35%) : mutation high CR FLT3 gene (37-46%) : FLT3-ITD poor prognosis FLT3-TKD inconclusive
Another mutation is CEBPA gene Double CEBPA mutation associated favorable
outcome9
Risk grouping of AMLRisk Cytogenetics Molecular mutations
Favorable risk
t(15;17)t(8;21)t(16;16)inv(16)
Normal karyotype with NPM1 mutation or double mutation of
CEBPA (w/o FLT3-ITD)
Intermediate risk
Normal karyotype+8 onlyt(9;11)
t(8;21), inv(16), t(16;16) with c-KIT mutation
Poor risk
Complex (>3 abnormalities)-5, -7, 5q-, 7q-
11q23 abnormalities excluding t(9;11)
Inversion 3t(3;3), t(6;9), t(9;22)
Normal karyotype with FLT3-ITD mutation
10
Management of Acute Myeloid Leukemia (Non-M3)
Induction therapy Age < 60 years Cytarabine + Anthracycline (7+3 regimen) Cytarabine 100-200 mg/m2
Idarubicin 12 mg/m2 or daunorubicin 90 mg/m2
Add oral midostaurin 50 mg q12h (day 8-21) (for FLT3-mutated AML)
Age ≥ 60 years Standard chemotherapy Low-intensity therapy
11
Anthracycline dose intensification in AML
Design : Phase 3, RCT Patients : 657 untreated AML patients Intervention : Daunorubicin 90 mg/m2 Comparator : Daunorubicin 45 mg/m2 Outcome : Overall survival (primary)
12Ref : Fernandez HF, et al. N Engl J Med 2009;361:1249.
13Ref : Fernandez HF, et al. N Engl J Med 2009;361:1249.
Idarubicin vs daunorubicin in AML patients
14
DNR : Daunorubicin 80 mg/m2 x 3 days IDA3 : Idarubicin 12 mg/m2 x 3 days IDA4 : Idarubicin 12 mg/m2 x 4 days
Ref : Pautas C, et al. J Clin Oncol 2010;28:808.
Idarubicin vs daunorubicin in AML patients
15Ref : Pautas C, et al. J Clin Oncol 2010;28:808.
Midostuarin
16
Midostuarin Mutitargeted kinase inhibitor (inh FLT3) Indication : AML w FLT3 mutation (ITD, TKD) Dose : oral 50 mg IV q12h for 14 days
(start at day 8 after CMT treatment) Toxicity : Common : edema, petechiae, febrile neutropenia Serious : QT prolongation, ILD (2-10%), febrile
neutropenia
17
RCT double blinded (RATIFY) 717 AML with FLT3 mutation (ITD, TKD) patients Compare midostaurin (50 mg q12h) 14 days (start at
day 8 after CMT treatment) vs placebo Endpoint : OS (primary)
18Ref : Stone RM, et al. N Engl J Med 2017;377:454.
19Ref : Stone RM, et al. N Engl J Med 2017;377:454.
Daunorubicin and cytarabineliposome for injection Combine cytarabine and daunorubicin as
encapsulated liposome at 5:1 ratio Dose : Admin via IV infusion over 90 min Induction: Liposomal daunorubicin 44 mg/m2 +
cytarabine 100 mg/m2 Day 1,3,5 (2nd induction day 1,3) Consolidation: Liposomal daunorubicin 29 mg/m2
+ cytarabine 65 mg/m2 Day 1,3
Toxicity : Hypersensitivity and copper overload (product
contain copper gluconate 5 mg/ml) Max exposure of copper 106 mg/m2 20
Gemtuzumab ozogamicin Humanized CD33 targeted monoclonal Ab Linked to calicheamicin
21
Gemtuzumab ozogamicin Internalized and
cleaved by lysosomes to release free calicheamicin
Calicheamicinenter nucleus causing double strand breaks initiating apoptosis
22
Gemtuzumab ozogamicin Indication : Newly diagnosed CD33 positive AML Relapse and refractory AML Adult and pediatric (≥ 2 years)
Dose : 3 mg/m2 IV over 2 hours Induction with 7+3 on days 1, 4, 7 Consolidation with infusion
cytarabine+duanorubicin + GEM day 1 Toxicity : Veno-occlusive disease (VOD), Hemorrhage, infection, N&V, constipation,
abnormal liver function, rash, allergic, mucositis 23
RCT open-label study, phase 3 278 aged 50-70 years untreated AML Compare : 3+7 regimen wiith Gemtuzumab ozogamicin 3 mg/m2 day 1, 4, 7 Placebo
Endpoint : Primary: EFS (not CR, relapse or death)
24Ref : Castaigne S, et al. Lancet 2012;379:1508.
25Ref : Castaigne S, et al. Lancet 2012;379:1508.
EFS Control 17.1% Gemtuzumab 40.8% HR 0.58 (0.43-0.78)
26Ref : NCCN 2019.
Low-intensity therapy
Low dose cytarabine1
20 mg SC BID for 10 days Azacitidine2
75 mg/m2 SC or IV daily for 7 days Decitabine3
20 mg/m2 IV daily for 5 days
27
1. Burnett AK, et al. Cancer 2007;109:1114.2. Fenaux P, et al. J Clin Oncol 2010;28:562.3. Kantarjian HM, et al. J Clin Oncol 2012;30:2670.
Response criteria
Complete remission (CR) ANC > 1,000/mcL Platelet > 100,000/mcL Transfusion independent Bone marrow < 5% blast Absence of blast with Auer rods Absence of extramedulary disease
Complete remission with incomplete hematologic recovery (CRi)
28
Management of Acute Myeloid Leukemia (Non-M3)
Post induction therapy Age < 60 years Favorable risk : HiDAC Intermediate risk : HiDAC or Allogeneic HCT Poor risk : Allogeneic HCT
Age ≥ 60 years Intermediate dose cytarabine Low-intensity regimen (Azacitidine, decitabine) Cytarabine + anthracycline (5+2 regimen)
29
Cytarabine regimen High dose cytarabine (HiDAC) Cytarabine 3 g/m2 over 3 hr q 12 hr
on day 1, 3, 5 X 3-4 cycles Intermediate dose cytarabine 1-1.5 g/m2/day x 4-6 doses x 1-2 cycles Clinical trial use 1 g/m2 q 12 hr x 6 days x 2 cycles
For better risk and good PFS S/E : cerebellum toxicity,
myelosuppression, rash, conjunctivitis
30
Management of Acute Myeloid Leukemia (Non-M3)
Relapse/refractory Early (< 12 mo) : new CMT + Allogeneic HCT Aggressive therapy
Low-intensity chemotherapy Late (≥ 12 mo) : repeat CMT + Allogeneic HCT 31
1. Cladribine + cytarabine + G-CSF ± mitoxanthrone or idarubicin
2. HiDAC ± anthracycline3. Fludarabine + cytarabine + G-CSF ± idarubicin4. Etoposide + cytarabine + mitoxanthrone5. Clofarabine ± cytarabine + G-CSF ± idarubicin
32
Relapse/refractory
Ref : NCCN 2019.
Enasidenib Selective inh of
mutant isocitratedehydrogenase (IDH) 2 enzymes Target mutant
R140Q, R172S, R172K
33Ref : Stein EM, et al. Future Oncol 2018;14:23. 21Ref : Dalle IA, et al. Ther Adv Hematol 2018;9:163. 34
35Ref : Stein EM, et al. Future Oncol 2018;14:23. 36Ref : Amaya ML, et al. Clin Cancer Res 2018;24:4931.
Phase 1/2 study 239 mutant IDH-2 relapsed/refractory AML Intervention: dose escalation Enasidenib Once daily: 5 level (30, 50, 75, 100, 150) Twice daily: 8 level
(50, 75, 100, 150, 200, 300, 450, 650) Endpoint : maximum tolerated dose (MTD), PK/PD,
Efficacy, safety37Ref : Stein EM, et al. Blood 2017;130:722. 38Ref : Stein EM, et al. Blood 2017;130:722.
39Ref : Stein EM, et al. Blood 2017;130:722. 40Ref : Stein EM, et al. Blood 2017;130:722.
Enasidenib IDH-2 enzyme inh Indication : IDH-2 mutation
relapsed/refractory AML Dose : Oral 100 mg OD until disease progression
Toxicity : Common : decrease appetite, N/V/D,
hyperbilirubinemia (inh UGT1A1) Serious : leukocytosis (hydroxyurea), pulmonary
edema, differentiation syndrome (dexamethasone)41
Evaluation and treatment of CNS leukemia Leptomeningeal involvement is less frequent (<3%) LP as part of routine diagnostic is not recommended
(only neurologic symptoms) CT/MRI for evaluation mass effect LP for CSF cytology Except: monocytic (M4, M5) histology or WBC > 40,000/mcL
Mass effect: biopsy then cranial RT then IT therapy IT or HiDAC should not use concurrent with RT
LP positive: IT twice weekly until CSF clear then weekly for 4-6 wk Liposomal ARA-C can given weekly HiDAC for induction therapy + dexamethasone
42
Management of Acute Promyelocytic Leukemia
APL is aggressive subtype (10% of AML) Associated with fatal coagulopathy Cytogenetic t(15;17) PML chromosome 15 to RARA on
chromosome 17 PML-RARA fusion gene (PCR) Interfere factors required for differentiation
CR in >90% after treatment Coagulopathy can resolve within days
43
Management of Acute Promyelocytic Leukemia
44
APL classification based upon WBC and platelet
Risk WBC Platelet
Low < 10,000 > 40,000
Intermediate <10,000 ≤ 40,000
High ≥ 10,000 Any
Management of Acute Promyelocytic Leukemia
Initial management Presuming diagnosis APL with DIC should be
treated with ATRA If APL not confirm by FISH or PCR, stop ATRA
Prevent coagulopathy Maintain platelet > 50,000/mcL Maintain fibrinogen conc > 150 mcg/dL
Manage hyperleukocytosis (WBC > 100,000/mcL) Initiation CMT or leukapheresis
45
Management of Acute Promyelocytic Leukemia
46
Phase RiskHigh risk Intermediate/low risk
InductionATRA + Dauno + Ara-CATRA + IdaATRA + ATO + Ida
ATRA + ATOATRA + Dauno + Ara-CATRA + Ida
ConsolidationDauno + Ara-CATRA + Ida + Ara-CATRA + ATO(4-6 doses of IT CMT)
ATRA + ATODauno + Ara-CATRA + Ida
Maintenance (1-2 year) ATRA + 6MP + MTX ATRA + 6MP + MTX
(Low risk benefit unclear)
ATRA : All trans retinoic acid, Dauno : Daunorubicin, Ara-C : Cytarabine, Ida : Idarubicin, ATO : Arsenic trioxide, 6MP : 6-Mercaptopurine, MTX : Methotrexate
Management of Acute Promyelocytic Leukemia
Relapse/refractory PCR positive (2 consecutive 4 weeks) Bone marrow confirm relapse Early relapse (< 6 mo) Prior without anthracycline : ATRA + Ida + ATO Prior with anthracycline : ATRA + ATO
Late relapse (> 6 mo) ATRA + ATO
Allogeneic HCT should be applied after induction
47
All-Trans Retinoic Acid (ATRA)
Differentiation syndrome Symptoms include Rising WBC > 10,000/mcL with fever Fluid retention, dyspnea, hypoxia , episodic
hypotension, pulmonary infiltration, Pulmonary/pericardial effusion
Management (1st sign of respiratory) Dexamehtasone 10 mg bid for 3-5 day (taper 2 wk) Interrupting ATRA until hypoxia resolves
ATRA + ATO regimen Prophylaxis prednisolone 0.5 MKD
(day 1 through complete induction) 48
Arsenic trioxide (ATO)
Monitoring Prior to initiation therapy ECG for prolong QT interval Serum e’lyte (Ca, K, Mg) and creatinine
During therapy Differentiation syndrome (treat as ATRA) Reassess QT interval QT interval > 500 millisec should assess weekly
Maintain K > 4 mEq/L Maintain Mg > 1.8 mg/dL Maintain Ca > 9.0 mEq/L
49
Acute Lymphoblastic Leukemia
Estimated new cases (2014) 6,020 people Death 1,440 people
Median age of diagnosis 14 years 58.8% younger than 20 years of age
ALL improve survival and treatment response over the past several decades Understanding genetic and pathology Incorporation risk adaptive therapy Targeted agents
50
Acute Lymphoblastic Leukemia
Clinical presentation Constitutional symptoms: fever, night sweat,
weight loss Early bruising/bleeding Dyspnea Dizziness Infection CNS involvement (mature B-cell ALL) Mediastinal involvement (T-lineage)
51
Acute Lymphoblastic Leukemia
ALL characterized by proliferation of immature lymphoid cell
ALL require ≥ 20% marrow lymphoblast of bone marrow Lymphoblastic lymphoma is nodal/extranodal
site with < 20% marrow lymphoblast Treat as ALL like regimen
ALL classified into 3 subgroup Precursor B cell, mature B cell, T cell
52
Immunophenotyping
53
CD3
TdT
CD10 and Sureface Ig
T-cell
Mature B-cell
Pre B-cellEarly Pre B-cell
Common chromosomal and molecular abnormalities
54Ref : National Comprehensive Cancer Network (NCCN) 2018.
Prognosis factor and risk classification
AYA and childhood patient (15-39 YO) with ALL Age < 1 YO or > 10 YO WBC > 30,000 (B-cell) and 100,000 (T-cell)
cells/mm3 T-cell ALL Present Minimal Residual Disease (MRD) Cytogenetic Poor : t(9;22), hypoploidy, MLL rearrangement Good : hyperploidy, ETV6-RUNX1 subtype
55
Prognosis factor and risk classification
Adult patient with ALL Age > 35 YO WBC > 30,000 (B-cell) and 100,000 (T-cell)
cells/mm3 (esp < 65 YO) T-cell ALL Present Minimal Residual Disease (MRD) Cytogenetic Poor : t(9;22), hypoploidy, MLL rearrangement Good : hyperploidy, ETV6-RUNX1 subtype
56
Treatment of ALL
Treatment phases are include Induction phase Consolidation/intensification phase Maintenance phase CNS prophylaxis (during treatment)
Multiagent chemotherapy developed by Berlin-Frankfurt-Munster (BFM) :
COG and CALGB MD Anderson Cancer Center (MDACC) :
HyperCVAD57
Induction phase To reduce tumor burden from bone marrow Typical backbone chemotherapy include Vincristine Anthracycline Corticosteroid ± L-asparaginase and cyclophosphamide
COG, Linker (4-drug induction) CALGB, Larson regimen (5-drug regimen) MDACC developed hyperCVAD A regimen (CTX, VCR, Doxorubicin, Dexa) B regimen (MTX, ARA-C) 58
Dexamethsone vs prednisolone in ALL
59Ref : Teuffel O, et al. Leukemia 2011;25:1232.
Dexamethsone vs prednisolone in ALL
60Ref : Teuffel O, et al. Leukemia 2011;25:1232.RR<1 prefer Dexamethasone
Minimal Residual Disease (MRD)
Presence of leukemia cell below detection by conventional morphologic methods
Increase risk of relapse Measurement method for MRD include Multicolor flow cytometry (1 x 106 MNCs) Real-time quantitative PCR (RQ-PCR) (1 x 107) Sensitivity threshold of <1x10-4 (0.01%) bone
marrow mononuclear cell (MNCs) Assess after induction therapy
61
Consolidation/Intensification To eliminate any leukemic cells remaining after
induction therapy MRD monitoring should be performed Combination chemotherapy are preferred Duration of treatment vary among studies High-dose MTX, Cytarabine, 6-MP and L-
asparaginase are incorperated into regimen
62
Maintenance To prevent disease relapse Chemotherapy backbone include 6-MP (daily) Methotrexate (weekly) Vincristine and corticosteroid (periodic)
Duration of treatment for 2 year in adult and 2-3 year for children Maintenance can be omitted in mature B-cell ALL
Chemotherapy dose (6-MP) can be adjusted (25%) if ANC > 1,500 cells/mm3 6 weeks
63
CNS prophylaxis and treatment Prevent CNS disease or relapse Most chemotherapy can not cross blood brain
barrier CNS directed therapy include Cranial irradiation Intrathecal chemotherapy High dose chemotherapy
CNS prophylaxis is given entire course of ALL treatment
64
Treatment of ALL
65
Philadelphia chromosomePositive Negative
AgeAYA (15-39) Adult (>40)
RiskStandard High
Treatment ALL
66
ALL
High risk
Induction + TKIAllo HCT
Maintenance +TKI
InductionAllo HCT
Maintenance
InductionConsolidationMaintenance
Standard risk
Philadelphia (-)Philadelphia (+)
Treatment for Ph+ ALL Tyrosine Kinase inhibitors (TKI) have shown
benefit in Ph+ ALL ALL induction therapy would combined with TKI Include adequate CNS for all patients
Complete remission after induction should be treated with allogeneic HCT If matched donor available
Maintenance therapy would combined with TKI Less than CR after induction or relapse should
be managed as relapse/refractory disease
67
Tyrosine Kinase Inhibitors (TKI) Targeted to BCR-ABL gene tyrosine kinase
enzyme (Imatinib, Nilotinib, Dasatinib, Bosutinib, Ponatinib) Create by philadelphia chromosome Well evidence support in CML
68
Treatment for Ph+ ALL (Relapse/refractory) Mutation testing for ABL gene should be done Treatment options based on ABL mutation
status of CML (European LeukemiaNet)1
Complete remission after induction should be treated with allogeneic HCT
691. Soverini S, et al. Blood 2011;118:1208.
Treatment for Ph- ALL For AYA should be used regimen as pediatric For adult can selected Larson regimen, Linker or
hyperCVAD Complete remission after induction Standard risk : Consolidation and maintenance High risk or MRD+ : Allogeneic HCT
Less than CR after induction or relapse should be managed as relapse/refractory disease
70
Treatment for Ph+ ALL (Relapse/refractory)
71
TKI MutationDasatinib Y253H, E255K/V, F359V/C/INilotinib V299L, T315A, F317L/V/I/C
Bosutinib E255K/V, F317L/V/I/C, F359V/C/I, T315A, Y253H
Ponatinib T315I
Ref : Soverini S, et al. Blood 2011;118:1208.
Treatment for Ph- ALL (Relapse/refractory) 2nd line therapy depend on duration of response Late relapse (≥ 36 months) : retreat same induction Early relapse (< 36 months) : Induction regimen not previous use Chemotherapy with agents include Clofarabine, Nelarabine (T-cell ALL), Vincristine sulfate
liposome injection (VSLI), Cytarabine or alkylating Allogeneic HCT Inotuzumab ozogamicin (precursor B-cell) Blinatumomab (precursor B-cell) CAR-T cell
72
Treatment extramedullary disease
Comprehensive neuropsychologic testing Risk factor in adult include mature B-cell, T-cell,
High WBC and elevated LDH Classification CNS status (LP as protocol) CNS-1 : no lymphoblast in CNS CNS-2 : WBC<5/mcL in CSF presence of lymphoblast CNS-3 : WBC≥5/mcL in CSF presence of lymphoblast
Steinherz-Bleyer algorithm can be applied If WBC/RBC ratio in CSF ≥ 2-fold in blood : CNS-3 If WBC/RBC ratio in CSF < 2-fold in blood : CNS-2
73
Treatment extramedullary disease
Combination systemic chemotherapy and IT regimen should be used for prophylaxis Cranial irradiation can be avoided
Patient with CNS involvement should receive 18 Gy cranial irradiation
Testicular examination should be performed in all male patient T-cell ALL is most common Radiation is performed with 1st cycle of maintenance
(total dose 24 Gy) for treatment
74
Asparaginase
3 formulations in clinical use Pegaspagase (E Coli) Asparaginase (Erwinia) Asparaginase (E Coli)
All agent can be given IM or IV Hypersensitivity reaction Associated to neutralizing antibodies Cross reactivity btw E Coli product No cross reactivity btw E Coli and Erwinia
75
Asparaginase
Reaction not associated with neutrlizingactivities (not indicate to switch to Erwinia) Local injection site reaction after IM Grade 1 IV infusion-related allergic reaction Grade 1 urticaria
Pancreatitis Monitor serum amylase Discontinue for grade 3-4
Others : hypofibrinogenemia, hyperglycemia, elevated LFT
76
Chimeric Antigen Receptor Therapy (CAR)
Genetically engineered protein constructs Incorporated into a patient’s own T cells to
help them to recognize and fight cancer cells Infusing large quantities of modified
T-cells is aimed at Making T-cells recognize and target cancer
cells Making T-cells can thrive in a very hostile
tumor environment Restoring a number of good quality T-cells
77
Chimeric Antigen Receptor Therapy (CAR)
78
79
Tisagenlecleucel (Kymriah®) Anti-CD19 chimeric antigen receptor FDA approval history Accelerated approval in July 2017 Fully approval in August 2017
Treatment of patient up to age 25 years with relapse or refractory ALL
Pretreatment lymphodepleting CMT 2-14 days prior (Fludarabine 4 days + CTX 2 days)
Premedication (Acetaminophen + H1) Corticosteroid should be avoided
80
Phase 2, single cohort 75 CD19+ relapse or refractory B-cell ALL Outcome (primary) Overall remission rate (CR/CRi) within 3 months
81Ref: Maude SL, et al. N Engl J Med 2018;378:439.
At 3 months ORR 81% (CR 60%, CRi 21%) All have negative MRD
82Ref: Maude SL, et al. N Engl J Med 2018;378:439.
CRS manage with toclizumab (IL-6 receptor inh) BW < 30 kg 12 mg/kg q8h (Max 3 doses) BW ≥ 30 kg 8 mg/kg q8h (Max 3 doses)
83Ref: Maude SL, et al. N Engl J Med 2018;378:439.
g{tÇ~ çÉâ yÉÜ çÉâÜ tààxÇà|ÉÇ
84