Who, What and When: Transplant for Acute Lymphoblastic LeukemiaBrandon Hayes-LattinSeptember 13, 2013

Indications for Hematopoietic Stem Cell Transplants in the United States, 2010

(Inflation factor: Auto=1.25 (80%), Allo=1.05 (95%), All Transplants)

SUM12_28.pptSlide 8

Num

ber o

f Tra

nspl

ants

0

500

1,000

1,500

2,000

2,500

3,000

3,500

4,000

4,500

5,000

5,500

MultipleMyeloma

NHL AML ALL MDS/MPD HD CML AplasticAnemia

OtherLeuk

Non-Malig

Disease

OtherCancer

Allogeneic (Total N=8,860)Autogeneic (Total N=9,026)

ALL Survival

SEER AYA Monograph, 2006

Forman and Rowe, Blood 2013;121:1077-1082

“Myth of Second Remission”

Defining Role of Transplant in ALL

• Consolidation– 75-90% of patients achieve complete remission– Relapse risk remains high

• Potential benefit over chemotherapy– Myeloablative chemoradiotherapy– Graft-versus-Leukemia effect

• Balance of risks– Early treatment-related toxicity– Late effects (GVHD)

Predicting Risk

Cytogenetic Risk(2008 WHO Classification)

• Favorable– Hyperdiploidy (>50

chromosomes)– t(12;21)

• ETV6-RUNX1• Formerly TEL-AML

• Unfavorable– Hypodiploidy (<44

chromosomes)– t(9;22)

• BCR-ABL1• Philadelphia chromosome

– t(v;11q23)• MLL rearranged• t(4;11), t(9;11), t(11;19)

– t(5;14)• IL3-IGH

– t(1;19)• E2A-PBX1

ALL Cytogenetics by Age

Harrison CJ, Br J Haematol, 2008

Hyper-CVAD

Factor Score

Age: <40, 40-59, 60+ 0, 1, 2

KPS: 0-2, 3-4 0, 2

Hepatomegaly 0, 1

WBC: <50k, >50k 0, 2

Plt: >80, 20-80, <20 0, 1, 2

Philadelphia chromosome 0, 2

Hyper-CVAD

Good risk 0-15-year OS 62%

Intermed risk 2-35-year OS 34%

Poor risk 4-65-year OS 5%

Minimal Residual Disease (16 week, GMALL)

Overall survivalp<0.0001

Only significant factorin multivariate analysis

Novel Cytogenetic Abnormalities

• Christine Harrison: advances in cytogenetic technology– Intrachromosomal amplification of chromosome

21 (iAMP21)• Multiple copies of RUNX1• Older children/adolescents, present with low WBC, 5-

year EFS 26% vs 83%

Tricoli JV, JNCI, 2011. Harrison CJ, Br J Haematol, 2008

Integrated Genomic Analysis AYA ALL

• Charles Mullighan: B-cell precursors from patients in COG 9906, no known high-risk genetic alterations

• Deletions and point mutations in IKZF1 (lymphoid transcription factor)– Increased risk of relapse HR 2.4– Gene expression profiles similar to those of BCR-ABL1

patients– Resequencing found 11% with activating mutations in

JAK1, JAK2, or JAK3Tricoli JV, JNCI, 2011. Roberts, Cancer Cell,

2012

Gene Expression Profiling in ALL

• Cheryl Willman: 207 older children, high-risk (WBC >50), COG 9906

• 8 gene expression cluster groups– 2 associated with known cytogenetic abnormalites

• 11q23 rearrangements MLL• t(1;19)E2a-PBX1

– 6 novel

Zhang et al, Blood 2011

Somatic alteration profiles

Zhang et al, Blood, 2011

Regimens

Hyper CVAD

R-Hyper-CVAD (CD20+, age <60)

Rituximab3-year OS 75%

No rituximab3-year OS 47%

SURVIVAL: PEDIATRIC VS. ADULT REGIMENS

Stock BLOOD 2008, pre-published online

Years

Surv

ival HO 8899 (Adult)

Age 15-18 Years (N = 44)

DCOG 8599 (Pediatric)Age 15-18 Years (N = 47)

Age 19-20 Years (N = 29)

100%

75%

50%

25%

0%0 2 4 6 8 10

Netherlands United Kingdom

Surv

ival

100%

75%

50%

25%

0%0 1 2 3 4 5

UKALLXII / E2993 (Adult)

15-17 Years (N = 61)

15-17 Years (N = 67)

ALL97 (Pediatric)

Years

ALL age 15-21: Pediatric vs. Adult Therapy

North America

EFS CALGB 8811-9511 (Adult)

0 2 4 6 8 10

100%

80%

60%

40%

20%

0%

Age 16-20 Years (N = 103)

20-29 Years (N = 123)

Age 16-21 Years (N = 175)

Years

100%

80%

60%

40%

20%

0%

LALA 94 (Adult)

0 1 2 3 4 5 6

Surv

ival

France

Age 15-20 Years (N = 100)

FRALLE 93 (Pediatric) Age 15-20 Years (N = 77)

Years

CCG-1800 Series (Pediatric)

Hunger et al. JCO 2012:20;1663-1669

ALL Survival: COG Chemotherapy

NCI Risk Classification at diagnosis (0232)

Standard Risk High Risk

Excluded (Very High

Risk)

Age 1-10 >10 >30

WBC <50k >50k

OtherPrior steroid treatment or

testicular diseaset(9;22) BCR-ABL,

hypodiploid

High-Risk Therapy Based on AALL0232 (“PH” arm)

• Induction– Prednisone x 28 days, age >10 (increased osteonecrosis with

dexamethasone)• Consolidation • Interim Maintenance #1

– High-dose methotrexate (5-year EFS 82% vs 75.4% with Capizzi methotrexate)

• Delayed Intensification #1• Slow Early Responders

– Interim Maintenance #2– Delayed Intensification #2

• Maintenance

C10403: Intergroup ALL• Intergroup (CALGB, SWOG & ECOG) Phase II

Clinical Trial for Adolescents and Young Adults With Untreated Acute Lymphoblastic Leukemia (ALL)– Ages 16-39 years– Specific Aims

• Improve outcome of AYAs with ALL• Evaluate efficacy and toxicity of this regimen in patients up to

age 39 years• Evaluate adherence of medical oncologists to a “pediatric” ALL

regimen

• Assessment of Drug Delivery– vincristine, peg-asparaginase and methotrexate

COG Risk Classification at diagnosis (1131)

Standard Risk High Risk Very

High Excluded

Age 1-10 >10 >13 >30

WBC <50k >50k

OtherPrior steroid treatment or

testicular disease

iAMP21, MML rearrangemen

ts, hypodiploidy

t(9;22) BCR-ABL

AALL1131: Very High-Risk• Induction• Consolidation

– Control, OR– Arm 1: fractionated cyclophosphamide, etoposide, OR– Arm 2: clofarabine, fractionated cyclophosphamide, etoposide– MRD Flow: hypodiploidy or induction failure - option of SCT

• Interim Maintenance #1• Delayed Intensification

– Control, OR– Arm 1: fractionated cyclophosphamide, etoposide, OR– Arm 2: clofarabine, fractionated cyclophosphamide, etoposide

• Interim Maintenance #2• Maintenance

Allogeneic Transplant

Allo Transplant Conditioning Regimen

• Cyclophosphamide + 1200 cGy TBI• Children and Adolescents, Tracey et al. BBMT

2013;19:255-259– Neither TBI >1200 cGy nor addition of etoposide

improves survival

Survival after HLA-identical Sibling Donor Transplants for ALL, Age < 20 yrs, 2000-2010

- by Disease Status -

SUM12_7.pptSlide 30

Years0 2 61 3 4 5

0

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Prob

abilit

y of

Sur

viva

l, %

P < 0.0001

Early (N=849)

Intermediate (N=1,203)

Advanced (N=210)

Survival after HLA-identical Sibling Donor Transplants for ALL, Age ³ 20 yrs, 2000-2010

- By Disease Status -

Slide 32Years

0 2 61 3 4 50

20

40

60

80

100

10

30

50

70

90

0

20

40

60

80

100

10

30

50

70

90

Prob

abilit

y of

Sur

viva

l, %

P < 0.0001

Intermediate (N=715)

Advanced (N=584)

Early (N=2,214)

SUM12_9.ppt

ASBMT 2006

ASBMT Evidence-Based Review: Children

• Matched related Allo– In CR1 for very high risk Ph+ patients– Equivalent to or better than chemo in remission beyond

CR1• MUD

– Insufficient evidence• Auto

– Insufficient evidence• Regimens

– TBI-containing regimens are recommended

ASBMT 2012

ASBMT Evidence-Based Review: Adult ALL, updated 2012

• Changed– Myeloablative allo age <35 in CR1 (all risk groups)– RIC allo may produce similar results

• Unchanged– Allo over chemotherapy in CR2– Allo over Auto– Related similar to unrelated donor

• New– In absence of suitable donor, auto may be appropriate– In absence of suitable donor, cord blood by me appropriate– Imatinib before and/or after SCT for Ph+ ALL yields significantly

superior survival

Allo in CR1?

• Gupta et al. Blood 2013;121:339-350– Available sibling, or randomized auto vs chemo– 13 studies, N=2962, excluding Ph+– Age <35 having matched sibling OR 0.79 (p=0.0003)– Age 35+ having matched sibling OR 1.01– Auto vs chemo OR 1.18 (CI 0.99-1.41)

OHSU Adult Regimen Guidelines• Age <30

– per COG AALL 0232 (PH) - no transplant– If unable to complete 0232 or other high risk features (Ph+, persistent

diasease) move to allo transplant– Open COG AALL 1131

• Age 30-60– hyper-CVAD - CR1 allogeneic SCT– R-hyper-CVAD - consider no CR1 allogeneic SCT

• Age 60+– hyper-CVAD (reduced cytarabine) - consider CR1 reduced intensity

allogeneic SCT– R-hyper-CVAD (reduced cytarabine) - consider CR1 reduced intensity

allogeneic SCT– EWALL