Acute leukemia 62 Board reviewAcute leukemia ManitSae-teaw B.Pharm, BCP, BCOP Grad dip in pharmacotherapy Faculty of pharmaceutical sciences UbonRatchathaniUniversity 1 Outline Introduction

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)

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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)

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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

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Morphologic classification

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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

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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

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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

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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

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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

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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

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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

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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)

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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)

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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

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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

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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

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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

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APL classification based upon WBC and platelet

Risk WBC Platelet

Low < 10,000 > 40,000

Intermediate <10,000 ≤ 40,000

High ≥ 10,000 Any


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

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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


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

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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

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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

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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)

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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

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Immunophenotyping

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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

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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

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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

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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

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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

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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

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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

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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

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Treatment for Ph+ ALL (Relapse/refractory)

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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

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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)

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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


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)


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Acute leukemia 62 Board reviewAcute leukemia ManitSae-teaw B.Pharm, BCP, BCOP Grad dip in pharmacotherapy Faculty of pharmaceutical sciences UbonRatchathaniUniversity 1 Outline Introduction