acute leukemias · trm and drug resistance estey eh. haematologica. 2011;96:795-798. risk of...

ACUTE LEUKEMIAS

Zaw Win Myint, MD

Jane Anne Nohl Division of Hematology &

Center for the Study of Blood Diseases

USC Norris Comprehensive Cancer Center

Keck Medical Center of USC

heterogeneous clonal stem cell malignancy in which immature hematopoietic cells proliferate and accumulate in bone marrow, peripheral blood, and other tissues.

results in inhibition of normal hematopoiesis, characterized by neutropenia, anemia, thrombocytopenia, and the clinical features of bone marrow failure.

AML AML AML AMLALL

MM

CLL

CML

differentiation proliferation

2015 US Leukemia Estimates

• ~ 54,270 new cases of leukemia were expected in the United States

• 24,450 leukemia-related deaths

Incidence of acute and chronic leukemias in

the United States.

Surveillance, Epidemiology, and End Results (SEER) Cancer Registry estimates of age-specific incidence rates of AML, ALL, CML, and CLL in the

U.S., SEER 18 areas, 2007-2011. Rates are given per 100,000 and are age-adjusted to the 2000 U.S. standard population.

ETIOLOGY

cause of leukemia is usually unknown

familial/genetic predisposition in some individuals

Genetic Predispositions:

– Single germline mutations in RUNX1, CEBPA, SRP72, and GATA2.

– defective DNA repair : Fanconi anemia, ataxia telangiectasia, Bloom syndrome

– ribosomal abnormalities : Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and dyskeratosis congenita.

– germline mutations in p53 and abnormalities in chromosome number: Klinefelter and Down syndromes.

ONCOGENIC VIRUSES: type I (HTLV-1) in adult T-cell leukemia/lymphoma. Epstein-Barr virus in endemic African form of Burkitt’s lymphoma/leukemia.

RADIATION: higher doses of radiation, particularly absorbed over a shorter period of time

CHEMICALS : benzene and benzene-containing compounds

DRUG- AND THERAPY-RELATED LEUKEMIAS :

– alkylating agents :typically 4 to 6 years after chemotherapy

– topoisomerase II inhibitors : 1 to 2 years, lacks a myelodysplasticphase, a monocytic morphology, 11q23 abnormalities; translocations of 21q22 are involved.

– autologous HCT : a cumulative incidence as high as 10%.

ETIOLOGY (Contd.)

Why is acute leukemia an emergency?

Tumor lysis

Leukostasis

Sepsis

DIC

TLS: Clinical Features

K+ uric acid PO4

Ca2+

CaPO4 Ca2+

arrhythmias

weakness

paralysis acute renal failure

tetany

AMS

K+

TLS: Prevention & Treatment

Prevention: Fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, fluids, allopurinol

Treatment: rasburicase or HD

purines/pyrimidines uric acidK+

allopurinol

What blood test should you get before administering rasburicase?

rasburicase

allantoin

Leukostasis

High blast count hyperviscosity tissue perfusion

Systems affected: CV (MI), pulm (ARDS), GI (bowel ischemia), CNS (CVA, retinal

hemorrhage)

CT head in pt with AML; Bx

showed leukocyte plugs

CXR in pt presenting with

AML;

CT + BAL Dx

Algharras et al. (2013) J Clin Diagn Res. 7(12): 3020–3022. Salloum et al. (1998) BMT 21:835-837. Vasquez (2012) FSFB-CIDER Case of the Month.

Retinal hemorrhage

Leukostasis: Diagnosis and Treatment

Leukostasis is a clinical diagnosis.

– There is no specific WBC cutoff to establish Dx or decide treatment

– Pathologic diagnosis is rarely available

– Rely on clinical judgment and investigation of appropriate DDx

– Ex: MI could be secondary to anemia, DIC, underlying CAD

• Medical management– Steroids, hydrea can rapidly decrease WBC count

– Risks: tumor lysis syndrome, hydrea can worsen other cytopenias

• Leukapheresis– Requires line placement, transfusion medicine consultation

– Contraindicated in APL

– Transfusion further increases viscosity (but hydration decreases it!)

hematology consultant

transfusion medicine

consultant

Sepsis

Patients with acute leukemia are immunodeficient

– Neutropenic

– Dysfunctional bone marrow dysfunctional immune system

Culture on admission, even if asymptomatic and afebrile

– Fast fever spikes are common, better to stay ahead of the curve!

Calculate the ANC even in the setting of elevated WBC count

– Low ANC may be “hiding”

Fever is an emergency in the neutropenic patient!

Sites of infection in neutropenic patients

Fungal infections in leukemia

DIC

Consumptive coagulopathy triggered by release of tissue factor from blasts

DVTCVAMI

ICHSDH

pulmonary hemorrhage

DIC

Occurs in ~10% of patients with acute leukemia

– At diagnosis

– After initiation of chemotherapy

Screen all patients by sending:

– Coags

– Fibrinogen

– D-dimer

How to manage:

– Monitor coags and fibrinogen even after initiation of chemotherapy!

– Keep plts > 20-30K (50K if bleeding)

– Keep fibrinogen > 150

Recognizing and treating DIC can save a patient’s life!Nur et al. (1995) Eur J Hem 55(2):78-82.

DIC in APL (AML M3)

APL has a unique molecular mechanism

– t(15;17) PML-RAR fusion protein

Nur et al. (1995) Eur J Hem 55(2):78-82.

ACUTE MYELOID LEUKEMIA

Age-Specific AML Incidence Rates

Juliusson G, et al. Blood. 2009;113:4179-4187.

Incid

en

ce

Pt Age (Yrs)

New cases per 1000 inhabitants of Sweden (1997-2005)

OS in AML Declines With Age

Data from Swedish Acute Leukemia Registry

Juliusson G, et al. Clin Lymphoma Myeloma Leuk. 2011;11(suppl 1):S54-S59.

Yrs

100

80

60

40

20

00 1 2 3 4 5 6 7

OS

(%

)

8 9 10 11 12 13

16-29 yrs, n = 76

30-39 yrs, n = 116

40-49 yrs, n = 200

50-59 yrs, n = 405

60-69 yrs, n = 642

70-79 yrs, n = 998

80-89 yrs, n = 682

90-99 yrs, n = 86

clinicaloptions.com/oncology

Current and Future Directions in the Treatment of Acute Myeloid Leukemia

Kantarjian H, et al. Cancer. 2010;21:4896-4901.

Survival in AML by Time Period

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al P

rob

ab

ilit

y

0 1 2 3 4 5 6 7

Yrs

1980-Present Age< 60≥ 60

Total19201769

Died12651519

Median, Mos17.5 6.2

5 Yrs, %308

P < .001

8




Survival in AML by Time Period

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

Pro

ba

bilit

y

0 1 2 3 4 5 6 7 8

Yrs

Age < 60 Yrs Treatment Era

< 197070-7980-8990-9900-09

Died68356375480410

Median, Mos2.7 11.8 14.0 18.0 22.8

5 Yrs,%313213038

Total69387446655819

P < .001

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al

Pro

bab

ilit

y

0 1 2 3 4 5 6 7 8

Yrs

Age ≥ 60 YrsTreatment

Era< 197070-7980-8990-9900-09z

Died4016927454170

Median,Mos0.91.6 3.7 5.5 7.4

5 Yrs,%0858

10

Total40170276572921

P < .001



Therapy-Related vs Secondary AML

Danish national population-based study (N = 3055 unselected patients with AML)

Granfeldt Østgård. J Clin. Oncol. 2015;33:3641.

Solid cancerLymphoproliferative disorderRheumatic diseaseMultiple myelomaAcute lymphoblastic leukemia

Myelodysplastic syndromeChronic myelomonocytic leukemiaPolycythemia veraMyelofibrosisEssential thrombocythemiasAML, miscellaneousMyeloproliferative neoplasms, unclassifiableMyeloproliferative neoplasms, other

51%

32%

10%

4%

3%

58%

4%

11%

11%

11%

2%

2%

1%

tAMLsAML



FAB Classification



Arber DA, et al. Blood. 2016 May 19;127(20):2391-405



Mrozek K, et al. J Clin Oncol. 2012;30:4515-4523.

N = 1550 pts younger than 60 yrs of age with de novo AML

European LeukemiaNet Genetic Risk Classification:

OS

Pro

bab

ility

of O

S

Yrs

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

P < .001

Favorable (n = 339)

Intermediate-I (n = 144)

Intermediate-II (n = 156)

Adverse (n = 179)



AML: Risk Status by Biologic Features

Morphologic examinationIdentifies changes in the number and morphology of bone marrow cells, particularly

blast cells and the presence of dysplasia

Immunophenotyping

Classifies leukemia cells based on the antigens present on their surfaces:

Flow cytometry

IHC

Cytogenetic evaluation

Required for classification of AML:

Karyotyping

FISH

Molecular genetic testing

Uses reverse transcriptase-PCR or direct PCR of DNA to detect molecular

abnormalities with prognostic significance:

Classifies AML into subtypes and stratifies pts into prognostic groups

Mutation-specific assays for FLT3 and IDH2 approved by FDA in 2017

(In most cases, treatment begins before cytogenetic and molecular genetic test results are available)

Arber DA, et al. Blood. 2016;127:2391-2405.



Smith ML, et al. Blood Rev. 2011;25:39-51.

Independent Prognostic Variables in AML

MRC/NCRI AML Trials: OS

100

80

40

20

00 1 2

Pati

en

ts A

live (

%)

3 4 5 6 7 8 9 10

t(15;17) (n = 330)t(8;21) (n = 247)inv(16)/t(16;16) (n = 154)CEBPα biallelic (n = 47)FLT3-ITD WT/NPM1 mut (n = 248)Other intermediate (n = 471)FLT3-ITD mut/NPM1 WT (n = 100)Other adverse (n = 130)

76%

58%52%51%

26%

11%

Yrs From Entry

60



AML Therapy Decisions by Probability of TRM and

Drug Resistance

Estey EH. Haematologica. 2011;96:795-798.

Risk of

Resistance

Risk of Therapy-Related Toxicity

HIGH

HIGH

LOW

LOWStandard

Investigational Tx, Investigational Tx,

Investigational Tx,

Low Intensity

Low Intensity

Intensity Tx

High Intensity



Current Approach to AML Therapy

Induction Goals:

- Stabilize patient

- Restore hematopoiesis

Consolidation Goals:

- CURE the patient

- Leukemia-free survival

Salvage Therapy Goals:

- Complete Remission

Formalize the assessment

of frailty in patients

- HCT-CI

- MD Anderson Risk Score

UNFIT for Intensive ChemoFIT for Intensive Chemotherapy

UnfavorableIntermediateFavorable

History = Secondary AML

Genetics = complex + TP53, FLT3,

Favorable (CBF)

Clinical Trials

vs

Hypomethylating agents

vs

Supportive care

vs

Hospice

Scheinberg et al. In: DeVita et al, eds. Cancer: Principles and Practice of Oncology. 5th ed. Lippincott-Raven; 1997:2293-2321.

Adult acute lymphocytic leukemia. Available at: https://medlineplus.gov/acutemyeloidleukemia.html



AML Therapy Decisions by Probability of

TRM and Drug Resistance

Estey EH. Haematologica. 2011;96:795-798.

Risk of

Resistance

Risk of Therapy-Related Toxicity

HIGH

HIGH

LOW

LOWStandard

Investigational Tx, Investigational Tx,

Investigational Tx,

Low Intensity

Low Intensity

Intensity Tx

High Intensity

Improve Induction

+ Consolidation



The 7+3 Regimen in AML

In 1973, Yates and colleagues[1] reported results from an AML regimen of 7 days of cytarabine and 3 days of daunorubicin, aka “7+3”

40 yrs later, 7+3 induction therapy continues to benefit pts with AML[2]:

– CR rate in younger pts: 60% to 75%

– CR rate in pts older than 60 yrs of age: 35% to 50%

– However, most will NOT be cured of their disease

1. Yates JW, et al. Cancer Chemother Rep. 1973;57:485-488.2. Lichtman MA, et al. Blood Cells Mol Dis. 2013;50:119-130.



Burden of Disease in AML



Mrozek K, et al. J Clin Oncol. 2012;30:4515-4523.

N = 1550 pts younger than 60 yrs of age with de novo AML

European LeukemiaNet Genetic Risk

Classification: OS

Pro

bab

ility

of O

S

Yrs

0

0.2

0.4

0.6

0.8

1.0

0 1 2 3 4 5

P < .001

Favorable (n = 339)

Intermediate-I (n = 144)

Intermediate-II (n = 156)

Adverse (n = 179)



Consolidation

Sawler D, Sanford D, Brandwein JM, et al. Abstract #464. Presented at the 2017 ASH Annual Meeting, December 10, 2017; Atlanta, GA.



Patel JP, et al. N Engl J Med. 2012;366:1079-1089.

Prognostic Relevance of Integrated Genomic Profiling

Gene Overall Frequency, %

FLT3 (ITD, TKD) 37 (30, 7)

NPM1 29

DNMT3A 23

NRAS 10

CEBPα 9

TET2 8

WT1 8

IDH2 8

IDH1 7

KIT 6

RUNX1 5

MLL-PTD 5

ASXL1 3

PHF6 3

KRAS 2

PTEN 2

TP53 2

HRAS 0

EZH2 0



Recurring Mutations in AML

April 2017: FDA approved FLT3 inhibitor midostaurin

(with 7 + 3) for pts with newly diagnosed FLT3-positive

AML as detected by FDA-approved companion

diagnostic test.

NPM1

CEBPA

FLT3-ITD (internal tandem duplication)

FLT3-TKD (point mutation in TK domain)

KIT

MLL-PTD (partial tandem duplication)

RAS

WT1

TP53

DNMT3A

TET2

IDH1, IDH2

ASXL1

Favorable


Induction Goals:

- Stabilize patient



- CURE the patient






- HCT-CI




“7+3” + midostaurin

Chemotherapy

vs

Supportive

Care

“HiDAC” + midostaurin

vs

Allogeneic BMT ±midostaurin



Favorable (CBF)

Clinical Trials

vs


vs

Supportive care

vs

Hospice



Induction Goals:

- Stabilize patient



- CURE the patient






- HCT-CI




“7+3” Clinical Trial

vs


vs

Supportive care

vs

Hospice

Chemotherapy

vs

Supportive

Care

“HiDAC”

vs

Allogeneic BMT



Favorable (CBF)




AML in Older Adults: A Major Challenge

SEER Program Populations. AML (1988-2012).SEER Program Populations. AML (2009-2013).

100

80

60

40

0

20

0 1 2 43 5 6 7 98 10

Yrs

Surv

ival

(%)

Age, Yrs

< 5050-6465-74≥ 75

25

20

15

10

0

5

< 20 20-34 35-44 45-54 55-64 75-8465-74 > 84

Age (Yrs)

Ne

w C

ases

(%)

5.3 6.0 5.7

10.1

16.9

23.0 22.6

10.4

Percent of New AML Cases by Age Group

Survival in Elderly AML by Therapy (SEER–Medicare)

3317 elderly pts aged 65 yrs or older with AML

1193 (36%) received chemotherapy (younger, fewer comorbidities)

888 pts matched in both cohorts

Survival

Median, Mos 1 Yr, %

Overall 4.4

Chemotherapy 6.1 30

No treatment 1.7 10

Menzin J, et al. ASH 2006. Abstract 1973.

AML in Older Adults: Disease and Pt Factors Predict

Prognosis


Adverse prognostic factors

– Aged 75 yrs or older

– Unfavorable karyotype

– Treatment outside LAFR

– AHD ≥ 12 mos

– ECOG PS > 2

– LDH > 600 u/L

– Creatinine > 1.3 mg/dL

Risk group by number of factors

– Low: 0

– Intermediate: 0-2

– High: ≥ 3

Pro

port

ion o

f P

ts S

urv

ivin

g

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 12 24 36 60 84 9648 72

Mos

Survival Survival

Risk Group Total Dead Median,

% at

Mos 5

Yrs

Low 121 82 18 17

Intermediate 558 475 7 8

High 301 288 1 1

P < .001

Hypomethylating Agents: Structural Differences

RNA

DNA

Nucleic Acid

Incorporation

Azacitidine x 7 days, 28-day cycles

Decitabine x 5 days, 28-day cycles

Kuykendall JR. Ann Pharmacother. 2005;39:1700-1709.

Meletis J, et al. Med Sci Monit. 2006;12:RA194-206.

Phase II Study of Decitabine for Older Pts With

Untreated AML

N = 55 pts with ≥ 20% blasts

Median age: 74 yrs (range: 61-87)

Treatment: decitabine 20 mg/m2 IV daily x 5 Q4W

Median cycles: 3 (range: 1-25)

ORR: 25% (CR: 24%)

Responses included poor-risk

cytogenetics and in pts with prior MDS

Poor response in pts with high blast

count

Median OS: 7.7 mos

4-wk mortality rate: 7%

3-mo mortality rate: 25%

Cashen AF, et al. J Clin Oncol. 2010;28:556-561.

1.00

0.75

0.50

0

0.25

0 100 400 600 800

Days

Surv

ival

200 300 700500

Subjects, n55

Event82% (45)

Censored18% (10)

Median Survival (95% CI)231 (172.0-349.0)

Product-limit estimate curveCensored observations

CPX-351 Uses a Nano-Scale Delivery Complex

100-nm bilamellar liposomes

5:1 molar ratio of cytarabine to daunorubicin

1 unit = 1.0 mg cytarabineplus 0.44 mg daunorubicin

In August 2017, the FDA granted regular approval to CPX-351 for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC)

Lancet JE, et al. ASCO 2016. Abstract 7000.

First-Line CPX-351 in Pts Aged 60-75 with Untreated

Secondary AML: OS by Age

Medeiros BC, et al. ASH 2016. Abstract 902.

100

80

60

40

20

0

Surv

ival

(%)

Mos0 3 6 9 12 15 18 21 24 27 30 33 36

Events, n/N62/96

81/102

Median Survival, Mos (95% CI)

9.63 (6.24-12.62)6.37 (4.63-8.84)

CPX-3517+3

60-69 yrs

CPX-3517+3

96102

7973

5953

5141

4032

3124

2316

1310

86

73

42

10

100

80

60

40

20

0

Surv

ival

(%)

Mos0 3 6 9 12 15 18 21 24 27 30 33 36

Events, n/N42/5751/54

Median Survival, Mos (95% CI)

8.87 (4.73-12.19)5.62 (3.29-7.52)

CPX-3517+3

70-75 yrs

CPX-3517+3

5754

4337

3324

2815

2211

157

114

82

81

40

10

00


NPM1

CEBPA



KIT


RAS

WT1

TP53

DNMT3A

TET2

IDH1, IDH2

ASXL1

Favorable

TP53 Mutations: Frequency and Prognosis

TP53 mutations found in ~ 8% of AML pts[1]

‒ Incidence increases with age – Predominantly in pts with complex karyotype

Confers poor outcome to chemo, including lower CR rates, inferior RFS, OS[2]

OS by Karyotype Complexity[2]

All 21 pts

w/mutated

TP53

responded

1. Döhner H, et al. N Engl J Med. 2015;373:1136-1152. 2. Rucker FG, et al.

Blood. 2012;119:2114-2121. 3. Welch, et al. N Engl J Med. 2016;375:2023.

Response to Decitabine by Gene Mutation[3]

Pro

po

rtio

n o

f P

ts

OS

0.5

0.4

0.3

0.2

0.1

0

P < .001

P = .04

P = .05

Pts with a response

Pts without a response

100

75

50

25

00 12 24 36 48 60 72

Mos

TP53unaltered (n = 52)

TP53altered (n = 103)

P < .0001


NPM1

CEBPA



KIT


RAS

WT1

TP53

DNMT3A

TET2

IDH1, IDH2

ASXL1

Other Factors:

CD33 ExpressionFavorable

September 2017: FDA approved gemtuzumab

ozogamicin for patients with newly diagnosed or

relapsed/refractory CD33-positive AML.

Gemtuzumab Ozogamicin: MOA

1. Zein N, et al. Science. 1988;240:1198-1201. 2. Naito K, et al. Leukemia. 2000; 14:1436-1443. 3. Elmroth K, et al. DNA Repair (Amst). 2003;2:363-374.

Rosen DB, et al. PLoS One. 2013;8:e53518.

Monoclonal anti-CD33 antibody linked to calicheamicin-y1[1]

Internalized and cleaved in lysosomes to release free calicheamicin moiety[2]

Calicheamicin moiety enters nucleus and interacts with DNA causing double-strand breaks initiating apoptosis[1-3]

SurvivalSignaling

Drug TransporterActivityTarget

Levels

GO-InducedDNA Damage

GOInternalization/

Processing

GO-InducedApoptosis and

Cell Death

Growth Factors, Cytokines

Mitochondria

MDR-1/MRP-1

CD33GO

P13K/AKT

MEK/ERK

JAK/STAT

c-Casp3

γH2AX

p-CHk2

Cell Death

c-PARP

Gemtuzumab Ozogamicin: Efficacy in AML

3 open-label, single-arm phase II trails in CD33+ AML in first relapse

– N = 142 at interim analysis

– Remission: 32%

– High incidences of myelosuppression, hyperbilirubinemia, elevated hepatic transaminase levels

GO received accelerated approval in 2000 for pts 60 yrs of age or older with CD33+ AML in first relapse

Sievers EL, et al. J Clin Oncol. 2001;19:3244-3254.

Relapse-Free Survival

CRCRp

P = .624

Mos From Date of Remission

Pro

bab

ility

of

Rel

apse

-Fre

e S

urv

iva

l 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30

OR and 95% CI(GO: Control)

0.77 (67-0.90)2P = .0009

1.30 (1.04-1.63)2P = .02

0.93 (0.82-1.07)2P = .3; NS

0.46 (0.29-0.73)2P = .001

0.99 (0.69-1.40)2P = .9; NS

0.89 (0.78-1.00)2P = .06

1.00 (0.83-1.20)2P = 1.0; NS

0.90 (0.81-0.99)2P = .03

Gemtuzumab Ozogamicin in AML: Meta-analysis

Loke J, et al. Ann Hematol. 2015;94:361-373.

Trials

Resistant disease

Induction death

CR

Favorable

Favorable/intermediate

Intermediate

Adverse

Total

0 0.5 1.0 1.5 2.0

GO Better Control Better

Venetoclax: BCL-2 Selective Inhibitor

Konopleva M, et al. Cancer Discov. 2016;6:1106-1117.Lin T, et al. ASCO 2016. Abstract 7007.

BCL-2 overexpression allows cancer cells to evade apoptosis by sequestering proapoptotic proteins

Venetoclax binds to BCL-2, freeing proapoptotic proteins that initiate

apoptosis

BCL-XL MCL1

BIMBCL-2 BCL-2 BAX

Venetoclax

BCL-2

BCL-2

BIM

BAXBIM

BAX

BAXBAX

Cytochrome capoptosis

Minimal Residual Disease in AML

Detecting minimal residual disease (MRD) in morphologic CR provides an assessment of disease burden that may be used for guidance in therapy efficacy and relapse risk in patients with AML

MRD methodologies

– FISH

– Multicolor flow cytometry

– PCR assays, including real-time quantitative PCR, which has been used in clinical trials for markers including NPM1 and PML-RARA

– Next-generation sequencing

Minimal Residual Disease

Minimal Residual Disease in AML

Survival for Pts With Relapsed AML

0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

of

Surv

ival

0 26 52 78 104 130 156 182 208 234 260

Pts

436

175

Deaths

413

162

Pts Censoredat > 1, 2 Yrs

0, 0

2, 0

Wks of CR1

0-26

27-52

Wks

98

37

86

34

6, 3

1, 1

53-78

79-104

56 38 8, 7 104

Estey E. Leukemia. 1996;10:932-936.

Poor Risk Factors1.Duration CR1 < 6 mos2.Poor-risk karyotype3.KPS < 90%4.Circulating blasts5.Non-HLA identical donor

• Mismatch URD, 1 point• Related donor, but not HLA

identical sibling, 2 points

CIBMTR study (N = 2255): 1995-2004

Survival After Myeloablative AlloSCT for AML in Relapse

or Primary Induction Failure

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

01 2 3

Yrs

Pro

bab

ility

of

Surv

ival

42%

6%

28%

15%

0

Score = 0 Score = 1 Score = 2 Score = ≥ 3

Duval M, et al. J Clin Oncol. 2010;28:3730-3738.

Patel JP, et al. N Engl J Med. 2012;366:1079-1089.

Prognostic Relevance of Integrated Genomic

Profiling

Gene Overall Frequency, %

FLT3 (ITD, TKD) 37 (30, 7)

NPM1 29

DNMT3A 23

NRAS 10

CEBPα 9

TET2 8

WT1 8

IDH2 8

IDH1 7

KIT 6

RUNX1 5

MLL-PTD 5

ASXL1 3

PHF6 3

KRAS 2

PTEN 2

TP53 2

HRAS 0

EZH2 0


NPM1

CEBPA



KIT


RAS

WT1

TP53

DNMT3A

TET2

IDH1, IDH2

ASXL1

Other Factors:

CD33 ExpressionFavorable

August 2017: FDA approved IDH2 inhibitor

enasidenib for patients with relapsed/refractory

IDH2-positive AML as detected by FDA-approved

companion diagnostic test.

Mutant IDH enzymes convert a Krebs cycle intermediate, α-KG, into 2-HG.

Mark Levis Blood 2013;122:2770-2771

©2013 by American Society of Hematology

IDH1 and IDH2: Key Research Milestones

Cairns. Cancer Discov. 2013;3:730.

2008 2009 2010 2011 2012 2013

IDH1 mutations identified in glioblastoma

IDH1 and IDH2mutations identified in AML

Germline IDH2 mutations identified in D2HG aciduria

IDH mutations identified in chondrosarcomas

Initial characterization of mutant IDH1 knock-in mice

First small-molecule inhibitors of mutant IDH enzyme activity developed

IDH mutations identified in cholangiocarcinoma

IDH2 mutations identified in AITL

D2HG shown to inhibit many 2-OG-dependent dioxygenases

D2HG found to inhibit TET2 and affect DNA methylation

Production of D2HG by mutant IDH enzymes discovered


Induction Goals:

- Stabilize patient



- CURE the patient






- HCT-CI





Favorable (CBF)


“7 + 3”

Favorable = “7 + 3” + gemtuzumab

FLT3-mutation = “7+3” + midostaurin

Secondary = CPX-351

“HiDAC”

HiDAC + gemtuzumab

HiDAC + midostaurin

CPX-351

vs

Allogeneic BMT

Clinical Trial

vs

Hypomethylating Agents

vs

Supportive Care

vs

Hospice



Favorable (CBF)


ACUTE PROMYELOCYTIC LEUKEMIA

Pathogenesis

q22q12

#15 #17Chromosome

t(15,17)(q22,q12)

PML

RARa

PML

RARa

North American Intergroup Protocol I0129:

Maintenance

Tallman MS, et al. N Engl J Med. 1997;337:1021-1028.

ATRAObservation

Yr

Pro

bab

ilit

y o

f D

FS

0.5 4.01.0 1.5 2.0 2.5 3.0 3.5

1.0

0.8

0.6

0.4

0.2

00

Differentiation Syndrome (APL)

Mechanisms

– Cytokine release from differentiating APL blasts – “cytokine storm”

– Migration and tissue deposition of differentiating APL blasts

– Increased integrin expression endothelial adhesion capillaritis leak

Presentation

– Associated with WBC > 10K (especially > 30K)

– Symptoms: fever, hypoxia, pleural or pericardial effusion, renal failure, hypotension

Treatment

– Dexamethasone 10 mg BID x3-5 days with taper

– Consider holding ATRA

Call the hematology fellow with any concerning symptoms in an APL patient!

ACUTE LYMPHOBLASTIC LEUKEMIA

Incidence of Acute Lymphoblastic Leukemia by Age

.

SEER Cancer Statistics Factsheets. 2011-2015.

80

70

60

50

40

30

20

10

0

New

Cas

es (

%)

Age (Yrs)

< 20 20-34 35-44 45-54 55-64 65-74 75-84 > 84

56.1

10.15.8 7.4 8.9

5.9 4.3 1.5

Clinical Presentation

Anemia

Thrombocytopenia

Neutropenia

Renal insufficiency

Peripheral blasts

Leukocytosis

Increased LDH

Increased uric acid

Bruising/bleeding

Ecchymoses/petechiae

Fatigue

Weight loss

Paul. Mayo Clin Proc. 2016;91:1645. Terwilliger. Blood Cancer J. 2017;7:e577. Luciano. Adv Chronic Kidney Dis. 2014;21:27. American Cancer Society. Signs and symptoms of acute lymphocytic leukemia. Kornberg. Blood. 1980;56:35.

Hepatomegaly/splenomegaly

Dyspnea

Dizziness

Headache

Infection

Diagnosis

Physical examination

Labs

– CBC

– CMP (LDH, uric acid, phos)

– Peripheral flow cytometry

Bone marrow

– Cytogenetics

– Flow cytometry

– Next generation sequencing

– Molecular analyses (BCR-ABL)

– Consider LDA card (Ph-like signature)

Lumbar puncture (if CNS disease suspected, must give with IT chemo)

Imaging: CT scan/PET-CT, if indicated

American Cancer Society. How is acute lymphocytic leukemia diagnosed? Terwilliger. Blood Cancer J. 2017;7:e577.

Prognostic Indices

Favorable Unfavorable

t(12;21) TEL-AML1– Incidence: pediatric, 20%; adult,

2% Hyperdiploidy

– Incidence: pediatric, 25%; adult, 5%

t(9;22) BCR-ABL (Ph+)– Incidence: pediatric, 3%; adult, 20% to

50% Older age (> 35 yrs) WBC: B-cell, > 30 x 109/L; T-cell, > 100 x 109/L Ph-like lesions Other cytogenetics

– t(4;11) MLL-AF4 ; t(8;14)– Complex karyotype (> 5 abnormalities)– Low hypodiploid/near triploidy

CNS involvement MRD positive (> 10-4 or 0.01%) after induction

Blasts ≥ 20%

Cytochemistry

MPOPos.

AML TdT

Neg. Pos. or Neg.

Flow Cytometry

CD19/CD79a

Pre-pre B-ALL

CD10

Common ALL

Cytoplasmic IgM

Pre B-ALL

Surface Ig

Mature B-ALL

T-cell Markers

T-ALL

ALL: Differentiating Subsets

Hoelzer. Ann Oncol. 2016;27(suppl 5):v69. Peters. Arch Pathol Lab Med. 2011;135:44.

16

%

44

%

28

%

Sasaki. ASH 2016. Abstr 3975.

OS in Ph-Negative ALL OS in Ph-Positive ALL

Survival in Ph-ALL by Regimen (Excluding Primary Refractory)

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168

Mos

0

0.2

0.4

0.6

0.8

1.0

Hyper-CVAD + imatinibHyper-CVAD

N No. Fail48 2150 45

P < .001

Median follow-up 77 mos (range, 27 to 101+ mos)

0 5 10 15 20 25 30 35Yrs

0

0.2

0.4

0.6

0.8

1.0

Median follow-up: 77 mos (range: 27-101+)

OS

Age15-3940-60> 60

Total185486301

Events142261193

Median4.5 yrs2.8 yrs1.3 yrs

P < .001P < .001

Ph-Like ALL Identified by Genomewide Classification Analysis

Ph-Like ALL

Den Boer ML, et al. Lancet Oncology. 2009;10:125-134.

CALGB 10403: Ph-Like Signature Is Associated With Poor EFS

28% of pts with Ph-like signature

– Median age: 24 yrs (range: 17-69)

Stock W, et al. ASH 2014. Abstract 796.

2-Yr EFS

100

80

60

40

20

0

Even

t-F

ree

Su

rviv

al

(%)

0 12 24 36 48 60 72

Mos

Not Ph-like

Ph-like

N = 58; events = 16

N = 23; events = 14 Log-rank P = .04

2 yr rate = 57%

2-yr rate: 81%

OS of 39,697 Children With ALL Treated on Sequential

CCG/COG Clinical Trials, 1968-2009

Hunger. NEJM. 2015;373:1541.

ALL: Age Distribution and Age-Based Differences in

Therapeutic Approaches

Care for ALL pts historically divided between 2 different clinical teams[1]

– No collaboration

– Different treatments

Estimated New ALL Cases

in 2016: 6590[2]

57.2%(< 20 yrs)

10.2%(20-34 yrs)

5.8%(35-44 yrs)

7.2%(45-54 yrs)

8.2%(55-64 yrs)

11.4%(≥ 65 yrs)

42.8%

of ALL

pts ≥ 20 yrs

of age

1. Sallan SE. Hematology Am Soc Hematol Educ Program. 2006;2006:128-132.

2. SEER Stat fact sheets: acute lymphocytic leukemia.

Adult ALL: No Standard Chemotherapy Approach

Fundamentally different regimens without common basic principles (except maintenance and CNS prophylaxis)[1]

No comparative trials between regimens or individual drugs

The role of HSCT is unclear[2]

1. NCCN. Clinical Practice Guidelines In Oncology (NCCN Guidelines) for Acute Lymphoblastic Leukemia. V2.2016.

2. Rowe JM. Biol Blood Marrow Transplant. 2011;17:S76-S83.

ALL: Treatment

Chemotherapy

– Backbone of treatment

– HyperCVAD, AYA therapy, 10403, Larson, FOA

Targeted therapies

– TKIs for Ph+ ALL

Immunotherapies

– Monoclonal antibodies, antibody–drug conjugates, and bispecific T-cell engager antibodies targeting CD19, CD20, CD22

– CAR T-cell therapy (patients ≤ 25 yrs of age)

Clinical trials

– For relapsed and refractory disease

– CAR T-cell therapy in patients > 25 yrs of age

Stem cell transplantation

Terwilliger. Blood Cancer J. 2017;7:e577.

Comparison Between the 2 Main Adult Regimens

Characteristic Asparaginase-Based BFM Models Hyper-CVAD

OriginModified from pediatrics[1] Pediatric Burkitt

leukemia[2]

Structure Complex

Each cycle has different drugs and

schedule[3]

Simple

A to B[1]

Asparaginase Yes

(much less than children)[1] None or limited*[1]

Myelosuppression Limited[4] Common[2]

Key toxicity Asparaginase related[4] Long cytopenias[5]

*Could include late 2 doses of pegaspargase 2500 U/m2 on Day 1 for Mos 9 and 12.

1. NCCN. Clinical Practice Guidelines In Oncology (NCCN Guidelines) for Acute Lymphoblastic Leukemia. V2.2016.

2. Garcia-Manero G, et al. Hematol Oncol Clin North Am. 2000;14:1381-1396.

3. Larson RA, et al. Blood. 1995;85:2025-2037.

4. Patel B, et al. Leukemia. 2016;[Epub ahead of print].

5. Gill S, et al. Ann Hematol. 2008;87:727-734.

Pediatric vs Adult Regimens for ALL

4-8 wks 5-9 mos 2-3 yrs

Induction

AnthracyclineVincristine

Corticosteroid(Asparaginase)

(Cyclophosphamide)(TKI)

Induction 2or

extendedinduction

Consolidation

MethotrexateCytarabineVincristine

6-mercaptopurine6-thioguanine

CyclophosphamideAsparaginase

EtoposideTKI

Interimmaintenanc

e

Delayed Intensification

AnthracyclineVincristine

Corticosteroid(Asparaginase)

(Cyclophosphamide)(TKI)

Consolidation

Maintenance

MercaptopurineVincristine

MethotrexateCorticosteroid

(TKI)

Treatment for Ph-negative ALL

Treatment is long!

– 1-3 yrs[1]

Multi agent chemotherapy is a backbone of treatment for adults[1]

– CALGB 8811, GRAALL, Linker

– Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine

– 8 cycles total

– 4 of each cycle

– First cycle is induction; achieve remission

2 LPs given per cycle (for first 2-8 cycles) as CNS prophylaxis[2]

– Alternating methotrexate and cytarabine

– More given if at higher risk for CNS disease

Children and young adults[3,4]

– Augmented BFM

1. Terwilliger. Blood Cancer J. 2017;7:e577. 2. Kantarjian. J Clin Oncol. 2000;18:547. 3. Nachman. J Clin Oncol. 1997;15:2222. 4. Nachman. NEJM. 1998;338:1663.

Pediatric vs Adult Regimens for ALL: BFM

Regimen

Berlin-Frankfurt-Munster (BFM) Regimen for ALL Induction and Consolidation

Induction Consolidation CNS Prophylaxis Maintenance

Phase I

VCR 2 mg IV on D 1, 8, 15, 22

DNR 25 mg/m2 IV on D 1, 8, 15, 22

PSE 60 mg/m2 PO on D 1-28

L-Asp 5000 IU/m2 IV on D 1-14

Phase I (begin Wk 20)

VCR 2 mg IV on D 1, 8, 15, 22

Adria 25 mg/m2 IV on D 1, 8, 15, 22

DEX 10 mg/m2 IV on D 1-14

MTX 10 mg IT on D 31, 38, 45, 52

6-MP 60 mg/m2 PO on Wks 10-18 and 29-130

MTX 30 mg PO or IV QW on Wks 10-18 and

29-130

Phase II

CTX 650 mg/m2 IV on D 29, 43, 57 (max 1000 mg)

Ara-C 75 mg/m2 IV on D 31-34, 38-41, 45-48, 52-55

6-MP 60 mg/m2 IV on D 29-57

Phase II

CTX 650 mg/m2 IV on D 29

Ara-C 75 mg/m2 IV on D 31-34, 38-41

6-TG 60 mg/m2 PO on D 29-42

Cranial RT 2400 cGY* given with

Phase II induction

*Reduced to 1800 cGy if pt considered for allogeneic BMT while in first complete remission.

O’Donnell MR. Cancer Network. Cancer Management 2016.

Pediatric vs Adult Regimens for ALL: CALBG

Regimen

CALBG Regimen for ALL Induction and Consolidation

Wks 1-4Course 1: Induction (4 wks)CTX 1200 mg/m2 IV on D 1*DNR 45 mg/m2 IV on D 1-3*VCR 2 mg IV on D 1, 8, 15, 22PSE 60 mg/m2/d PO on D 1-21*L-Asp 6000 IU/m2 SC on D 5, 8, 11, 15, 18, 22, orPeg-Asp 2000 IU SC on D 15

Wks 13-25Course III: CNS Prophylaxis, Interim Maintenance (12 Wks)Cranial RT 2400 cGY on D 1-12MTX 15 mg IT on D 1, 8, 15, 22, 296-MP 60 mg/m2/d PO on D 1-70MTX 20 mg/m2 PO on D 36, 43, 50, 57, 64

Until 20 Mos from DiagnosisCourse V: Prolonged Maintenance VCR 2 mg IV on D 1 Q4WPSE 60 mg/m2/d PO on D 1-5 Q4WMTX 20 mg/m2 PO on D 1, 8, 15, 226-MP 60 mg/m2/d PO on D 1-28

Wks 5-12Course II: Early Intensification (4 wks, repeat 1x)MTX 15 mg IT on D 1CTX 1000 mg/m2 IV on D 16-MP 60 mg/m2/d PO on D 1-14Ara-C 75 mg/m2 SC on D 1-4, 8-11VCR 2 mg IV on D 15, 22L-Asp 6000 IU/m2 SC on D 5, 8, 11, 15, 18, 22, orPeg-Asp 2000 IU SC on D 15

Begin Wk 26Course IV: Late Intensification (8 Wks)DOX 30 mg/m2 on D 1, 8, 15VCR 2 mg IV on D 1, 8, 15DEX 10 mg/m2 PO on D 1-14CTX 1000 mg/m2 IV on D 296-TG 60 mg/m2/d PO on D 29-42Ara-C 75 mg/m2 SC on D 29, 32, 36-39

*For pts > 60 yrs of age, modify to CTX mg/m2 IV on D 1; DNR 30 mg/m2 IV on D 1-3; PSE 60 mg/m2/d PO on D 1-7.


Pediatric vs Adult Regimens for ALL:

MD Anderson Regimen (Hyper-CVAD)

MD Anderson (Hyper-CVAD) Regimen for ALL Induction and Consolidation

CTX 300 mg/m2 infused over 3 hrs Q12h X 6 doses (D 1-3)DOX 25 mg/m2/d continuous infusion over 24 hrs X 2 d; begins 12 hrs after last CTX dose (D 4-5)VCR 1.4 mg/m2 (maximum 2 mg) IV on D 4 and 11 DEX 40 mg/d on D 1-4 and 11-14

Alternate Q21d with MTX 1 g/m2 continuous infusion over 24 hrs on D 1Ara-C 3 g/m2 over 2 hrs Q12H X 4 doses (D 2-3)Leucovorin rescue 50 mg PO at end of MTX infusion; then 25 mg PO Q6h X 48 hrsMethylprednisolone 50 mg IV BID on D 1-3

All pts receive minimum of 4 doses of MTX IT for CNS prophylaxis. All pts receive maintenance therapy twice yearly with 6-MP 150 mg/d MTX 20 g/m2 PO QW VCR 2 mg IV QM PSE 200 mg PO for 5 days with VCR


ALL: Treatment

Maintenance of precursor B-ALL, Ph-negative ALL

– POMP x 24-30 mos following hyperCVAD

– Purinethol (6-mercaptopurine): orally every day

– Oncovin (vincristine): IV monthly on Day 1

– Methotrexate: orally once/wk

– Prednisone: orally x 5 days (Days 1-5 of each cycle)

Kantarjian. J Clin Oncol. 2000;18:547. Bassan. J Clin Oncol. 2011;29:532.

Reasons for Recent Success in Treatment of Adult

ALL

Addition of TKIs to various backbones in Ph-positive ALL

Addition of rituximab to chemotherapy in Burkitt and pre B-ALL (only if CD20-positive)

Addition of anti-CD19/CD3 bispecific T-cell engager blinatumomab to chemotherapy in salvage ALL therapies and in patients who are MRD+

Addition of CD22-directed antibody–drug conjugate inotuzumab ozogamicin to chemotherapy in salvage ALL therapies

Clinical trials combining chemotherapy with blinatumomab and inotuzumab in the upfront setting are ongoing

Papadantonakis. Ther Adv Hematol. 2016;7:252. Thomas. Hematol Oncol Clin North Am. 2009;23:949.

Pediatric vs Adult Regimens for ALL

1. Alacacioglu I, et al. Chemotherapy 2014; 60:219-223. 2. Buyukasik et al. Acta Haematologica 2013; 130:199-205.

Cu

mu

lati

ve S

urv

ival

1.0

0.8

0.6

0.4

0.2

0

RFS Functions

TherapyHyper-CVADBFM-like

P = .009

0 20 40 60 80 100

Mos

Cu

mu

lati

ve S

urv

ival

1.0

0.8

0.6

0.4

0.2

0

OS Functions

TherapyHyper-CVADBFM-like

P = .012

0 20 40 60 80 100

Mos

Dis

eas

e-f

ree

Su

rviv

al

1.0

0.8

0.6

0.4

0.2

0

TherapyHyper-CVADCALGB-8811

P = .001

0 25 50 75 100 125Mos

Ove

rall

Surv

ival

1.0

0.8

0.6

0.4

0.2

0

TherapyHyper-CVADCALGB-8811

P = .05

0 25 50 75 100 125Mos

“AML-Like” Myelosuppression: Is Prolonged and Profound

Marrow Aplasia Necessary in AML?

No added benefit from anthracycline dose intensification[1-3]

Steroids + vincristine = CR 50%

3 out of 4 or 5 drugs used in BFM inductions are nonmyelosuppressive: asparaginase, prednisone, vincristine[1,4-7]

Long, low-dose maintenance

Pediatric regimens typically use nonmyelosuppressivedrugs[10]

1. Stock W, et al. Cancer. 2013;119:90-98. 2. Thomas D, et al. Cancer. 2010;116:4580-4589. 3. Lamanna N, et al. Cancer.

2013;119:1186-1194. 4. Stock W, et al. Leuk Lymphoma. 2011;52:2237-2253. 5. Teuffel O, et al. Leukemia. 2011;25:1232-1238.

6. Egbelakin A, et al. Pediatr Blood Cancer. 2011;56:361-367. 7. Shaw PJ, et al. Med Pediatr Oncol. 1995;24:18-22. 8. Gökbuget

N, et al. Hematology Am Soc Hematol Educ Program. 2006;2006:133-141. 9. Kung FH, et al. Cancer. 1978;41:428-434.

10. Ribera JM, et al. Mediterr J Hematol Infect Dis. 2014;6:e2014052.

Retrospective Comparison in Adolescents and

Young Adults Pre-2008: Pediatric vs Adult Protocols

Study Age Range,

Yrs

N EFS,* % P Value

Pediatric

Protocol

Adult

Protocol

United States[1] 16-20 321 63 34 < .0001

France[2] 15-20 177 67 41 < .0001

The Netherlands[3] 15-18 91 69 34 .0001

Sweden[4] 15-20 59 74 39 < .01

United Kingdom[5] 15-17 128 65 49 .01

Italy[6] 14-17 242 83 55 NR

*7-yr EFS for US study; 5-yr EFS for France, The Netherlands, Sweden, and UK studies; 2-yr EFS for Italy study.

1. Stock W, et al. Blood. 2008;112:1646-1654. 2. Boissel N, et al. J Clin Oncol. 2003;21:774-780. 3. de Bont JM,

et al. Leukemia. 2004;18:2032-2035. 4. Hallböök H, et al. Cancer. 2006;107:1551-1561. 5. Ramanujachar R, et

al. Pediatr Blood Cancer. 2007;48:254-261. 6. Testi AM, et al. Blood. 2004;104:1954a.

Treatments for ALL: Pediatric vs AYA vs Adult Pts

Katz AJ, et al. Cancer Causes Control. 2015;11:1627-1642.

Age at Diagnosis (Yrs)

39

15-21

60-65+ ?

Employing a different treatment

9

8

6

4

2

0

Rate

pe

r 10

0,0

00

20%

46%

7

5

3

1

Pediatricians Adult Oncology Specialists

Asparagine

Glutamine Glutamic acid

Asparagine synthetase

Asparagine

circulating in blood

Aspartic acid

Diet

synthesis in liver

L-Asparaginase Mechanism of Action

ALL tumor cell

Asparaginase

Multiple Cycles of Asparaginase in Pediatric/Pediatric-

Inspired Regimens: Adult ALL Trials 2007-2014

Regimen Study Asparaginase Form Asparaginase Dose, IU/m2

Pediatric DFCI[1] Pegaspargase2500 Q2W or

2000 Q3W x 8-15 doses

Pediatric CALGB 10403[2] Pegaspargase[3] 2500 x 7 cycles

Pediatric inspired PETHEMA[4] E coli 10,000 x 3 cycles

20,000 Q4W x 12 mos

Pediatric inspired GRAALL-2003[5] E coli 10,000 x 9 cycles

Pediatric inspired USC[6] Pegaspargase 2000 x 6 cycles

1. DeAngelo DJ, et al. ASH 2015. Abstract 80. 2. Stock W, et al. ASH 2014. Abstract 796.

3. Larsen EC, et al. J Clin Oncol. 2016;34:2380-2388. 4. Ribera JM, et al. J Clin Oncol.

2008;26:1843-1849. 5. Huguet F, et al. J Clin Oncol. 2009;27:911-918. 6. Douer D, et al.

J Clin Oncol. 2014;32:905-911.

RCTs of E coli Asparaginase Addition to Frontline

Pediatric ALL

Consolidation ± 25,000 IU/m2 E coli asparaginase weekly x 30

1. Amylon MD, et al. Leukemia. 1999;13:335-342. 2. Sallan SE, et al. Cancer Res. 1983;43:5601-5607. (Updated

courtesy of Dr. DeAngelo. 3. Salzer WL, et al. Leukemia. 2010;24:355-370. 4. Salzer WL, et al. Ann N Y Acad Sci.

2014;1329:81-92.

POG 8704: 7 drugs

T-cell ALL[1]

DFCI 77-01: 8 drugs

Non–T-cell ALL[2-4]

P < .001

100

80

60

40

20

00

2 4 6 8

Continuous C

R (

%)

Yrs

20%

38%P =

.04

10

08

0

6

0

4

0

2

0

00

2 4 6 8

Surv

ival (

%)

Yr

s

+ Asparaginase

No asparaginase

20

%

46

%

1

0

1

2

1

4

1

6

1

8

2

0

Number of Cycles With Asparaginase in Newly

Diagnosed Adult ALL, 1988-2000

ProtocolAsparaginase

Form

Induction Dosing,

IU/m2

Consolidation Dosing, IU/m2

Doses/Cycle Cycles

Pre-1988[1,2] E coli 5000-6000 x 9-14 d None None

CALGB 8811[3]

and 19802[4] E coli 6000 x 6 6000 x 4 (BIW) 2

CALGB 9511[5] Pegaspargase 2000 x 2 2000 x 2 1

MRC/ECOG

UKALLXII/E2993[6] E coli 10,000 x 14 d 10,000 x 3 None

UCSF 8707[7] E coli 6000 x 14 d 12,000 x 6 (TIW) 1

1. Hoelzer D, et al. Blood. 1988;71:123-31. 2. Annino L, et al. Blood. 2002;99:863-871. 3.

Larson RA, et al. Blood. 1995;85:2025-2037. 4. Stock W, et al. Cancer. 2013;119:90-98. 5.

Wetzler M, et al. Blood. 2007;109:4164-4167. 6. Rowe JM, et al. Blood. 2005;106:3760-3767.

7. Linker C, et al. J Clin Oncol. 2002;20:2464-2471.

USC Trial: Modification of Augmented CCG

Pediatric BFM Protocol in Adult ALL

DNR

VCR

Peg-Asp

Cyclo

DEX

Ara-C

6-TG

IT-MTX

Maintenance

therapy continues

for 2 yrs

Induction 1

DNR

VCR

PRED

Peg-

Asp

IT-MTX

Cyclo

VCR

PRED

Peg-

Asp

Ara-C

6MP

IT-MTX

HD-MTX

VCR

Peg-Asp

PRED

IT-MTX

Pegaspargase (2000 IU/m2 IV x 6 doses) in adults with ALL

x 2

Induction 2 Consolidation 1 Consolidation 2Delayed

Reinduction 1

ARA-

C

VM 26

Douer D, et al. J Clin Oncol. 2014;32:905-911.

XX

Rituximab Improves Outcome for CD20+ ALL

Thomas DA, et al. J Clin Oncol. 2010;28:3880-3889.

Rituximab + Hyper-CVAD

Hyper-CVAD ± Imatinib in Ph+ ALL: OS

Thomas DA, et al. ASCO 2010. Abstract 6506.

Pro

bab

ilit

y o

f

Su

rviv

al

1.0

0.8

0.6

0.4

0.2

0

0 1

2

2

4

3

6

4

8

6

0

7

2

8

4

9

6

108 120 132 144 156 168

Mos

Survival in Ph-Positive ALL by Regimen*

*Excluding primary

refractory.

Hyper-CVAD + imatinib

Hyper-CVAD

n

4

8

5

0

Fail, n

21

45

P < .001

Median follow-up: 77 mos (range: 27-101+ mos)

Measurable (Minimal) Residual Disease (MRD)

Cancer Cell Burden

Campana D. Hematology Am Soc Hematol Educ Program. 2010;2010:7-12. Curran EK, et al. Trends Immunol. 2017;38:513-525.

Ideal

Ce

ll N

um

ber

Time

Cancer Cell Eradication

Actual

Ce

ll N

um

be

r

Time

Measurable Residual Disease

MRD

Clinical relapse

Dis

ease

bu

rden

1011

10-1

10-7

10-2

10-3

10-4

10-5

10-6

100

1⁰ Treatment Response

Consolidation/Maintenance Therapy

Immunologic Effects

High-Risk Genetics

Niche Effects

Immune Evasion

MRD Strongly Predicts Outcome in ALL

Brüggemann M, et al. Blood. 2006;107:1116-1123.

Probability of DFS According to MRD

100

80

60

40

20

0

DFS

(%

)

0 1 2 3 4 5Yrs

Day +24P = .003

100

80

60

40

20

0D

FS (

%)

0 1 2 3 4 5Yrs

Wk +22P < .001

10080

6040

20

0

DFS

(%

)

0 1 2 3 4 5Yrs

Wk +52P < .001

MRDNegative/< 10-4

> 10-4

n7582

3-Yr DFS (95% CI)68.6 (55.0-82.2)37.8 (24.5-51.1)

MRDNegative/< 10-4

> 10-4

n10125

3-Yr DFS (95% CI)65.4 (54.1-76.7)11.8 (0-31.6)

MRDNegative/< 10-4

> 10-4

n11311

3-Yr DFS (95% CI)67.9 (56.9-80.6)14.6 (0.0-40.0)

Methods for MRD Quantification in ALL

Parameter Flow Cytometry ASO-PCR NGS

Sensitivity 10-4 (to 10-5) 10-4 to 10-5 10-6

Samples Fresh Fresh or Frozen Fresh or Frozen

Availability Widely available* Not widely availableUniversally via centralized

reference lab

Customization Not required† Patient-specific probes and primers

Not required

Cost Expensive Expensive Expensive

*Conventional analysis may not be adequate for MRD quantification. †Phenotype of cancer cells must be different from normal cells.

MRD Status Before and After HCT Predicts RFS and OS

N = 43, 18-63 yrs of ageMAC alloHCT in CR1

MRD quantification: TCR/Ig ASO-PCR or BCR/ABL or MLL/AF4 Q-PCR

OS by MRD Status pre-HCT

CIR by MRD Status Pre-HCT

CIR by MRD Status at Day 100

Spinelli O, et al. Haematologica. 2007; 92:612-618.

1.00

0.75

0.50

0.25

0

Mos

1440 12 24 36 48 60 72 84 96 108 120 132

P = .17

n = 120.80 (0.40-0.95)

n = 250.49 (0.20-0.67)

MRD+

MRD-

1.00

0.75

0.50

0.25

0

Mos1440 12 24 36 48 60 72 84 96 108 120 132

P = .027

n = 250.46 (0.27-0.71)

n = 120

MRD-

MRD+

1.00

0.75

0.50

0.25

01440 12 24 36 48 60 72 84 96 108 120 132

Mos

n = 140.8 (0.46-0.98)

n = 170.07 (0.01-0.39)

MRD+

MRD-

P = .0006

Treatment of older patients

Low-Intensity Chemotherapy + Dasatinib in Ph+

ALL Pts 55 Yrs of Age or Older

Phase II EWALL-PH-01 study (2007-2010)

– Induction: dasatinib 100-140 mg/day; vincristine 1-2 mg/wk; dexamethasone 20-40 mg/day twice weekly

– Consolidation: dasatinib 100 mg/day; MTX-Asp C1,3,5; cytarabine C2,4,6

– Maintenance: dasatinib + POMP

Rousselot P, et al. Blood. 2016;774-782.

Parameter Pts (N = 71)

Median age, yrs

(range)69 (59-83)

CR, % 96

MMR, % 60

CMR, % 20

5-yr OS, % 36

5-yr EFS, % 27

Relapses, n

T315I, n/n (%)

36

18/24 (75)

GIMEMA 1509: Chemotherapy-Free Induction in

Ph+ ALL

Steroids x 35 days; dasatinib140 mg/day x 85 days

If no CMR, clofarabine + cyclophosphamide and/or alloHSCT

Median follow-up: 28 mos

Parameter Pts (N = 60)

Median age, yrs (range) 42 (19-59)

CHR, % 97

CMR, % 19

Deaths in CMR, n 12

No CMR, n

Total relapses, n

p210+ relapses, n

46

14

8

36-mo OS, % 58

30-mo DFS, %

85-day CMR, %

p190+, % (n)

p210+, % (n)

49

79

59

40

Chiaretti S, et al. ASH 2015. Abstract 81.

Take Home Messages

Questions / Comments ?

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