Transcript Who, What and When: Transplant for Acute Lymphoblastic Leukemia Brandon Hayes-Lattin September 13, 2013

Who, What and When:
Transplant for Acute Lymphoblastic
Leukemia
Brandon Hayes-Lattin
September 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)
5,500
Allogeneic (Total N=8,860)
5,000
Autogeneic (Total N=9,026)
Number of Transplants
4,500
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
Multiple
Myeloma
NHL
AML
ALL
MDS/MPD
HD
CML
Aplastic
Anemia
Other
Leuk
NonMalig
Disease
Other
Cancer
Slide 8
SUM12_28.ppt
ALL Survival
SEER AYA Monograph, 2006
“Myth of Second Remission”
Forman and Rowe, Blood 2013;121:10771082
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 0-1
5-year OS 62%
Intermed risk 2-3
5-year OS 34%
Poor risk 4-6
5-year OS 5%
Minimal Residual Disease (16 week,
GMALL)
Overall survival
p<0.0001
Only significant factor
in 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, 5year 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 JAK3
Tricoli 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)
Rituximab
3-year OS 75%
No rituximab
3-year OS 47%
SURVIVAL: PEDIATRIC VS. ADULT REGIMENS
Stock BLOOD 2008, pre-published
online
ALL age 15-21: Pediatric vs. Adult Therapy
100%
100%
CCG-1800 Series (Pediatric)
80%
80%
CALGB 8811-9511 (Adult)
Survival
EFS
Age 16-21 Years (N = 175)
60%
FRALLE 93 (Pediatric)
Age 15-20 Years (N = 77)
Age 16-20 Years (N = 103)
40%
LALA 94 (Adult)
60%
Age 15-20 Years (N = 100)
40%
20-29 Years (N = 123)
20%
0%
20%
North America
France
0%
0
2
4
6
8
10
0
1
2
3
100%
DCOG 8599 (Pediatric)
15-17 Years (N = 61)
75%
75%
HO 8899 (Adult)
Survival
Survival
6
ALL97 (Pediatric)
Age 15-18 Years (N = 47)
Age 19-20 Years (N = 29)
50%
Age 15-18 Years (N = 44)
25%
0%
5
Years
Years
100%
4
2
4
6
Years
8
UKALLXII / E2993 (Adult)
15-17 Years (N = 67)
25%
Netherlands
0
50%
10
0%
United Kingdom
0
1
2
3
Years
4
5
ALL Survival: COG Chemotherapy
Hunger et al. JCO 2012:20;1663-1669
NCI Risk Classification at diagnosis
(0232)
Standard Risk
High Risk
Excluded (Very
High Risk)
Age
1-10
>10
>30
WBC
<50k
>50k
Other
Prior steroid
treatment or
testicular disease
t(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
iAMP21, MML
rearrangements
, hypodiploidy
t(9;22) BCRABL
Other
Prior steroid
treatment or
testicular
disease
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 -
Probability of Survival, %
100
100
90
90
80
80
Early (N=849)
70
70
60
60
50
50
Intermediate (N=1,203)
40
40
30
30
20
20
Advanced (N=210)
10
10
P < 0.0001
0
0
0
1
2
3
Years
4
5
6
Slide 30
SUM12_7.ppt
Survival after HLA-identical Sibling Donor
Transplants for ALL, Age  20 yrs, 2000-2010
- By Disease Status -
Probability of Survival, %
100
100
90
90
80
80
70
70
60
60
Early (N=2,214)
50
50
40
40
Intermediate (N=715)
30
30
20
20
Advanced (N=584)
10
10
P < 0.0001
0
0
0
1
2
3
Years
4
5
6
Slide 32
SUM12_9.ppt
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 2006
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
ASBMT 2012
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