update of aya acute lymphoblastic leukemia...

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Update of AYAAcute Lymphoblastic Leukemia (A.L.L.)

Stuart E. Siegel, M.D.

Archie Bleyer, M.D.

Annual Texas AYA Oncology Conference

San Antonio, Texas

February 20-22, 2020

12,095

12,069

10091

8,444

1,053

1,581

1,435

3,170

17,922

12,751

9,405

8,503

2,168

1,905

1,433

986

0 3,000 6,000 9,000 12,000 15,000 18,000

Suicide

Homicide

Neoplasms

Heart Disease

Chronic Liver Disease

Diabetes Mellitus

Cerebrovascular Dis.

HiV/AIDS

Deaths

2005

2017

Number of Deaths of Top 8 Most Common Causes in AYAs (Age 15‐39), excluding Accidents, U.S., 2005 and 2017

Cancer and HIV are the only causesof the top 8 non‐accidental causes that decreased during 2005‐2017. Suicide has dramatically increased.

Data Source: NCHS via SEER*Stat

1

2


Breast12%

CNS10%

Colorectum7%

Lung6%

NHL5%

AML5%

Soft Tissue Sarcoma

5%

Melanoma4%

Cervix Uteri4%

ALL4%

Bone Sarcoma4%

Stomach3%

Liver2%

Hodgkin Lymphoma

2%

Pancreas2%

Testis2%

Other Cancers23% 2005

Breast12%

CNS11%

Colorectum9%

Cervix Uteri6%

Soft Tissue Sarcoma

5%AML4%Lung

4%

NHL4%

Stomach4%

BoneSarcomas

4%

ALL3%

Melanoma3%

Pancreas2%

Ovary2%

Testis2%

Liver2%

Other Cancers23%

2017

Cancer Death Distribution, U.S. by Type

Data Source: NCHS via SEER*Stat

The Major Increases• Colorectal Cancer• Cervical Cancer• Gastric Cancer• Pancreas Cancer

Other Increases• CNS Tumors• Ovary Cancer

The Major Decreases• Lung• NHL• Melanoma

Other Reductions• ALL• AML

0

100

200

300

400

500

600

700

800

900

1,000

1,100

1,200

1975 1980 1985 1990 1995 2000 2005 2010 2015 2020

Number of

New Cases

Annual Number of New Cases of ALL in AYAs (Age 15‐39), 1975‐2016, U.S.Regressions are linear and 3o polynomial

R2 = 0.61 p < 10‐10

R2 = 0.69 p < 10‐8

3

4


0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2000 2002 2004 2006 2008 2010 2012 2014

All AYAs

Males

Females

Annual Incidence of ALL/LBL in AYAs, 2000‐2014, SEER18

Incidence per 100,000per Year

APC* p‐Value

1.82 0.000007

1.90 0.0003

1.77 0.006

ICD‐10 /3 Codes: 9805‐9, 9811‐18, 9820, 9827, 9831‐7

5

6


0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

2000 2002 2004 2006 2008 2010 2012 2014

Non‐Hispanic White

0.0

0.5

1.0

1.5

2.0

2.5

2000 2002 2004 2006 2008 2010 2012 2014

Hispanics

0

0.2

0.4

0.6

0.8

1

1.2

2000 2002 2004 2006 2008 2010 2012 2014

Black

0

0.2

0.4

0.6

0.8

1

1.2

1.4

2000 2002 2004 2006 2008 2010 2012 2014

Asian/Pacific Islander

ALL/LBL Inciden

ce per 100,000 per Yea

r By Ethnicity

All AYAs

Males

Females

All AYAs

Males

Females

All AYAs

Males

Females

All AYAs

Males

Females

0.6

1.6

1.8

2.8

2.2

1.6

0.9

0.4

‐1.0‐1.0

‐0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

<10 10‐19 20‐29 30‐39 40‐49 50‐59 60‐69 70‐79 80+

Age at Diagnosis (Years)

AAPC

Average Annual Percent Change (AAPC) in Incidence of ALL, 1992‐2016, SEER13, by 10‐Year Age Intervals

The cause of the increase is unknown, with obesity increase and diagnostic imaging (CT scans*) are under

consideration as potential factors.

Shao YH, Tsai K, Kim S, Wu YJ, Demissie K. Exposure to tomographic scans and cancer risks. JNCI Cancer Spectrum. In press

7

8


Why Increasing Incidence?

• Increasing obesity (Incidence BMI)• Race/Ethnicity Population Trends:

Blacks & Hispanics > Asians > Non-Hispanic Whites• ? CT Scans?

• Males > Females

• Race/Ethnicity Population Trends: Blacks & Hispanics > Asians > Non‐Hispanic Whites

Increasing Incidence:

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1990 1995 2000 2005 2010

Deaths per 100,000

Annual Age‐Adjusted Death Rate1991‐2010

p = 0.00005

p = 0.69

p = 0.000002Age <15

Age 15‐39

Age 40+

Linear regressionsF‐test p‐values

Number of Deaths

Age <15

Age 15‐39

0

100

200

300

400

500

600

700

800

900

1000

1970 1980 1990 2000 2010

1970‐2010Annual Deaths

Age 40+

ALL: U.S. Mortality

AYA is only age group without a statistically significant decrease in mortality rate.

By 2010, AYAs had 2x the number of deaths in children.

In 1970s, >2x as many children than AYAs died of ALL.

9

10


Annual 5-Year Survival, 1975-2005, SEER

20‐3920‐39

<10<10

10‐1910‐19

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1975 1980 1985 1990 1995 2000 2005

Survival

Stuck at 39% since 1991

1991‐2005 linear regressions

Age(Years)

p = 0.0003p = 0.0003

p = 0.0004p = 0.0004

p = 0.54p = 0.54

ALL: Survival

AYAs have not had a significant increase in their survival rate since 1991, in contrast to the highly significant improvement in younger patients

Molecular Abnormality in A.L.L.ALL

Inaba H, et al. Acute lymphoblastic leukaemia. Lancet 2013.

11

12


Table 1. Special features of cancers in adolescent and young adult (AYA) patients

Features of acute lymphocytic leukemia in AYA patients compared with children Higher incidence of poor prognostic cytogenetic features such as t(9;22) (PhiladelphiaChromosome) or hypodiploidy Lower incidence of favorable cytogenetic features associated with a favorable outcome such ashigh hyperdiploidy and t(12;21) ETV6‐RUNX1 translocation More likely to be associated with aberrant gene promoter methylationFeatures of breast cancer in AYA patients compared with adultsLower survival rate Worse outcome independent of stage, extent, or type Higher incidence of more aggressive triple‐negative form More likely to be higher grade, poorly differentiated, and less hormone‐sensitive More frequent spread to greater number lymph nodesFeatures of colorectal cancer in AYA patients compared with adults

More advanced disease and poorer prognosis at diagnosis Less responsive to treatment More mucinous histology and greater frequency of signet ring cells Greater frequency of microsatellite instability Lower frequency of loss of heterozygosity at 17p and 18q

��

13

14


Incidence of Ph‐Like

Leukemia (%)

Age (Years)

30

20

10

00 10 20 30 40 50 60 70

Comparison of the Incidence of All and Ph‐Like Subtype

Incidence of All per 100,000 per Year

1.0

10.0

Child‐hoodALL

AYA ALL

N = 12,372Log scale

0.1

Ph‐Like

15

16


0%

20%

40%

60%

80%

100%

0

50

100

150

200

250

300

350

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

AYA

Age (Years)

AccrualCliff

Number of

Accruals

The ALL AYA Clinical Trial Accrual Gap

2010‐2015

2000‐2009

AverageAnnual Accruals

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Accrual Proportion

EstimatedAccrual

Proportion

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

Age (Years)

p < 10‐9

p = 0.03

p <10‐27

p = 0.03

AYA

Survival Cliffp = 0.008

Accrual Cliffp = 0.003

0%

20%

40%

60%

80%

100%

0% 20% 40% 60% 80% 100%

Clinical Trial Accrual Proportion

R2 = 0.87F = 178p < 10‐12

5‐Year Leukemia‐Specific Survival

ALL Clinical Trial Accrual and Survival Cliffs

5‐Year Leukemia‐SpecificSurvival

Clinical Trial Accrual

Proportion

17

18


Blood consult: Therapeutic Strategy and complications in the adolescent and young adult with acute lymphoblastic leukemiaTaizo A. Nakano and Stephen P. Hunger

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

U.S.: CCG & CALGB

France

Netherlands

Sweden (EFS not OS)

Great Britain

Finland

Denmark

Italy

Japan

Turkey

Lebanon

Mexico

U.S.: M.D. Anderson Cancer Center

Overall Survivalexcept event‐free survival for Sweden

Pediatric Regimen Adult Regimen

Older Adolescent and Adult ALL: Overall Survival at 2‐12* Years after Diagnosis

*Follow‐Up (Years)7

6

5

5

5

5

5

5

5

2

10

12

3

Reports Comparing Pediatric and Adult Regimen Outcomes in AYAs after Same Follow‐Up Interval*

19

20


Age at Diagnosis (Years)

Relative Survival

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85

Age 1‐17F = 100.8p < 10 ‐7

Age 17‐68F = 169.6p < 10 ‐16

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70

18%

14%

11%

21%

Age 17‐20F = 29..5p = 0.03

Survival Cliff

Joinpoints17 20

The ALL Survival Gap: Switch from Pediatric to Adult Treatment Regimen

52 randomized trials in 20,235 patients

2 randomized regimens>3 randomized regimens

1955 1960 1965 1970 1975 1980 1985 1990 1995

Children’s Cancer Group (CCG) 1955-2000

134 treatment regimens

27 treatment regimens

8662

9404 (4)

9406 (4)

9605 (4)

97059806

908691079201

92029203

92959296

93989297

Pediatric Oncology Group (POG) 1986-2000

4 randomized11 single regimens

Acute Lymphoblastic Leukemia

vs. ~10 randomized trials in adult

patients

21

22


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1975 1980 1985 1990 1995 2000 2005 2010


Age <10

Age 10‐19

Age 20‐29

APC* = 2.25p < 0.0001

APC = 0.60p < 0.0001

APC = 7.17p < 0.0001

APC = 0.33p = 0.39

APC = 0.61p = 0,56

1989

1987

APC = 2.83p < 0.0001

APC = 2.44p < 0.001

1993 2000

ALL: Lack of Progress in 20‐29 Year‐Olds

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1975 1980 1985 1990 1995 2000 2005 2010


Age <15APC = 1.8 p < 0.0001

APC = 0.47 p = 0.0002

1992

Joinpoint/Average Annual Percent Change (APC) Analysis of Annual 5‐Year Cancer‐Specific Survival, 1975‐2011, SEER, Age <15, 15‐19 and 20‐29.


23

24


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1975 1980 1985 1990 1995 2000 2005 2010


Age <15

Age 15‐19APC = 1.8 p < 0.0001

APC = 0.47 p = 0.0002

APC = 2.2 p < 0.0001

1992



15‐19 year‐olds have had accelerated improvement and reached a survival rate similar to children younger than 15 by 2010.

Data Source: SEER*Stat

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1975 1980 1985 1990 1995 2000 2005 2010


Age 20‐29

Age <15

Age 15‐19APC = 1.8 p < 0.0001

APC = 0.47 p = 0.0002

APC = 4.8 p = 0.004 APC = 0.62 p = 0.17

APC = 2.2 p < 0.0001

1990

1992

20‐29 year‐olds have had <10% improvement since 1990 and >45% were still relapsing within 5 years as of 2011.



Data Source: SEER*Stat

25

26


0%

20%

40%

60%

80%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65

Joinpoint Analysis of ALL+LBL: 5‐Year Cancer‐Specific Survival, SEER18Age 2‐65 Years by Single Year of Age and Successive 5 Calendar Year Intervals

Leukemia Specific

Survival

Age (Years)

30%

23%

16%

Predominantly hyper‐CVAD

Increasingly more pediatric regimen

AYA Survival Cliff

AYA Survival Cliff

Decreasing AYA Survival Cliff

2000‐2004

2005‐2009

2010‐2014

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25 30 35 40 45 50 55 60 65

2010‐2005‐

2000‐

Joinpoint / Average Annual Percent Change (AAPC) Analysis of ALL+LBL: 5‐Year Cancer‐Specific Survival, SEER18

Age 2‐65 Years by Single Year of Age and Era

Leukemia Specific Survival

Age (Years)

30%16%

23%

The AYA survival cliff has progressively shortened, primarily due to increasing survival of 20+ year‐olds and likely due to increased utilization of pediatric regimens.

Age AAPC p‐Value Age AAPC p‐Value Age AAPC p‐Value Age

2000‐2004 2 ‐1.3 0.0000 14 ‐7.2 0.01 20 ‐2.0 0.0000 65

2005‐2009 2 ‐1.3 0.0000 17 ‐10.8 0.39 20 ‐1.3 0.0001 65

2010‐2014 6 ‐1.8 0.0000 17 ‐7.3 0.52 20 ‐1.2 0.0000 65

27

28


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20

Age <152010‐2016N = 1,429

2000‐2009N = 1,970

1990‐1999N = 1,911

1980‐1989N = 1,653

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20

Age 15‐39

2010‐2016N = 483

2000‐2009N = 715

1990‐1999N = 604

1980‐1989N = 581

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20

Age 40‐64

2010‐2016N = 451

2000‐2009N = 508

1990‐1999N = 408

1980‐1989N = 317

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 2 4 6 8 10 12 14 16 18 20

Age 65+

2010‐2016N = 223

2000‐2009N = 285

1990‐1999N = 312

1980‐1989N = 307

Years after Diagnosis

Relative Su

rvival

Relative Survival after Diagnosis of ALL/LBL,* by Age and Era, SEER

Survival Doubled !

2010‐20162000‐20091990‐19991980‐1989

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25

1980‐1989

Sasaki K, Jabbour E, O'Brien S, et al. ASH Annual Meeting – December 2016

Hyper‐Decade CVAD2010‐2016 672000‐2009 1451990‐1999 1551980‐1989 119

Since 1980, 15 to 39year‐old patients with Ph‐ ALL treated at MD Anderson with hyper‐CVAD have had no survival improvement.

Overall Survival

Years

Age 15‐39: Ph‐ ALL Treated with Hyper‐CVAD at MDACCA 35‐Year Single Institution Experience*

29

30


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 5 10 15 20 25

Sasaki K, Jabbour E, O'Brien S, et al. ASH Annual Meeting – December 2016Years

Hyper‐Decade CVAD SEER2010‐2016 67 5822000‐2009 145 8121990‐1999 155 6151980‐1989 119 581 15‐39 year‐olds with

ALL including Ph+ in SEER’s 9 regions have had progressive improvement since 1990 and a better survival than hyper‐CVAD at MDACC

Overall Survival

Age 15‐39: Ph‐ ALL Treated with Hyper‐CVAD at MDACC*and SEER9 Patients including Ph+ ALL

ALL Survival, Age 20‐29

Survival

Years

Province of Ontario* SEER9Canada USA

0%

20%

40%

60%

80%

100%

1986‐1991

1992‐1997

1998‐2003

2004‐2009

1986‐1991

1992‐19971998‐2003

2004‐2009

Ontario used the pediatric regimen from Dana Farber

Hyper‐CVAD was the predominant regimen

*Pole JD, et at. Leuk Res. 37;1258‐64:2013

31

32


Weeks from Start of Therapy

1st 8 months

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

6MP

Maintenance

ASNase

6MP

IVMTX

IVMTX

IVMTX

IVMTX

IVMTX

ITMTX

ITMTX

ITMTX

ITMTX

6TG

AraC AraC

ITAraC

ITMTX

ITMTX

ITMTX

ITMTX

Induction Consolidation Interim Maintenance

Delayed Intensification

ITMTX

ITMTX

ITMTX

VCR

CPMCPMPDN DXM

DNM DOX

Pediatric Regimen C10403

ITMTX

MTX

VCRPDN

MTXAraC

LV

ITAraC

ITMTX

Ritux

ITAraC

ITMTX

ITAraC

ITMTX

DXMDOX

ITAraC

ITMTX

VCRCPM

if CD20+

MaintenanceConsolidationInduction

6MP

MTX

VCRPDN

Hyper‐CVAD

[Cranial RT]

A

Months from Start of Maintenance Therapy

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34

2nd 8 months

Maintenance

Intensification

Maintenance

DoxDXM

CPM

VCR

Rituxif CD20+

MTXASNase

Maintenance

Intensification

6MPMTX

VCRPDN

Hyper‐CVAD

DoxDXM

CPM

VCR

Rituxif CD20+

MTXASNase

6MP

Maintenance

MTX

VCR

PDN

ITMTX

ITMTX

ITMTX

ITMTX

C10403

B

33

34


Chemotherapy AgentDoseUnit

Pediatric(C10403)

Hyper‐CVAD 2,36

Total Dose

Cyclophosphamide mg/m2 3,000 7,200

Anthracycline (Dox Equiv) mg/m2 158 200

Prednisone mg 5,400 36,000

Dexamethasone mg 70 1,280

Methylprednisolone mg 0 1,200

Vincristine mg 68 88

Cytarabine mg/m2 1,800 48,000

6‐Mercaptopurine mg/m2 58,380 109,500

Methotrexate IV mg/m2 500 5,800

Methotrexate IT mg 132 48‐192^

Cytarabine IT mg 70 400‐1600^

Hydrocortisone IT mg 0 240

Cranial radiation Gy 0‐12^ 0‐30^

Rituximab (CD20+) mg/m2 0 3,000

17,500 0* ‐ 20,000

840

2,160

0

0

6‐Thioguanine mg/m2

mg/m2Methotrexate PO

Asparaginase (Pegylated) IU/m2

^depending on CNS status at diagnosis *No asparaginase for LBL patients

CNS Toxicity

in Pediatric

in Hyper‐CVAD

35

36


0 2 4 6 8

0.0

0.2

0.4

0.6

0.8

1.0

AALL0031 (n=44)Historical Controls (n=56)

P = 0.0062

Event‐Free Survival by Cohort 1/2, 3/4 vs. 5

0 1 2 3

0.0

0.2

0.4

0.6

0.8

1.0

Years

Even

t‐Free

Survival Probab

ility

Cohort 1/2 (n=17)Cohort 3/4 (n=22)Cohort 5 (n=44)

P = 0.0178 Even

t‐Free

Survival Probab

ility

Imatinib with Chemotherapy Improves Early OutcomeFor Childhood Ph+ ALL (AALL0031)

AALL0031 Cohort 5 vs. Historical Control

Kirk Schultz, JCO

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4 5

Age <15 Age 15‐39

Relative Survival

Years after Diagnosis

Survival during 2000‐2016 of All A.L.L. Patients and Those Registered in SEER as Ph+

All A.L.L. Patients Ph+ Patients

N = 5,110

N = 2,140N = 48

N = 94

• Ph+ patients began to be registered in SEER in 2010 but only a fraction of them have been registered.• As of 2016, only 4% of the ALL AYA patients in SEER18 were identified as Ph+.• Thus, there are too few Ph+ patients to expect their exclusion to significantly change the overall ALL survival curve.• The inclusion of Ph+ patients inflates the 5‐year all‐patient survival rate in comparison to rates that exclude Ph+ patients.• Hence, the survival rates for SEER data would be higher if Ph+ patients were excluded.

37

38


39

40


Newer Additions to AYA Acute Lymphoblastic Leukemia Therapy

• RITUXIMAB• BLINATUMOMAB• INOTUZUMAB• CAR‐T CELLS

41

update of aya acute lymphoblastic leukemia...

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