1. When, How, and What Cell Source
for Transplantation in ALL CR1
Hillard M. Lazarus, MD, FACP
Professor of Medicine
Director of Novel Cell Therapies
University Hospitals Case Medical Center
Case Western Reserve University

2. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Definitions In This Presentation
Philadelphia chromosome t(9;22)(q34;q11) negativePhiladelphia chromosome t(9;22)(q34;q11) negative
““Adults” = ageAdults” = age >> 35 years35 years

3. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Background
• Pediatric ALL: 85% cure rate
• Adult ALL: Different biology and treatment results
• ~ 90% complete remission in age < 60 yr
• But despite arduous, long term therapy:
• 5-yr survival 30-40% in pts < age 60 yr
• 5-yr survival <15% in pts > age 60 yr
7% survival @ 5 years after relapse: few 2nd
chances

4. AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
MRC UKALL XII / ECOG 2993: N=1,929
JM Rowe, MRC & ECOG. Blood 106: 3760-3767, 2005
INDUCTION
RandomizeAssign
Sibling
Allograft
Autograft Consolidation/
Maintenance
HLA donor
< 50 (or 55) yr
No donor
High-dose
methotrexate x 3

5. Factors at Presentation Prognosis Association
Age Worse with increasing age
CNS involvement Slightly worse outcome
WBC count at
diagnosis
Adverse: B cell >30,000/μL; T cell >100,000/μL
Immunophenotype B-ALL: Adverse for CD20 and CD25
expression
T-ALL: Adverse for CD13; Favorable for CD1a
Cytogenetic
abnormalities
Adverse: t(9;22); t(4;11); t(1;19); complex (>5);
low hypodiploid; near tetraploid; BCR-ABL-like
Favorable: high hyperdiploid; del 9q
Molecular abnormalities Adverse: JAK2; IKFZ1; PAX5; TLX3; BAALC
Favorable: TLX1
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Clinical and Laboratory Risk Factors
JM Rowe. Br J Haematol 144: 468-483, 2009.
B Oran, DJ Weisdorf. Curr Opin Hematol 18: 395–400, 2011.
R Bassan, D Hoelzer. J Clin Oncol 29: 532-543, 2011.
J-M Ribera. Curr Opin Oncol 23: 692–699, 2011.

6. Factors After Therapy Prognosis Association
Time to initial response Adverse: no CR within 4 weeks
Minimal residual disease Adverse: detection at various
times
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Clinical and Laboratory Risk Factors (con’t)
JM Rowe. Br J Haematol 144: 468-483, 2009.
B Oran, DJ Weisdorf. Curr Opin Hematol 18: 395–400, 2011.
R Bassan, D Hoelzer. J Clin Oncol 29: 532-543, 2011.
J-M Ribera. Curr Opin Oncol 23: 692–699, 2011.

7. ACUTE LYMPHOBLASTIC LEUKEMIA
“BCR-ABL-Like”
JR Downing, CG Mullighan. Am Soc Hematol Educ Prog 118-22, 508,
2006.

8. PROSPECTIVE POST-REMISSION TRIALS
Chemotherapy vs Autograft vs Allograft
Design and Outcome

9. ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Autologous Transplant vs Chemotherapy
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
Autotransplants not efficacious (unlike Ph pos ALL)

10. ADULT ALL POST-REMISSIONADULT ALL POST-REMISSION
> 100 Patients/Trial: Age 15-64 Years> 100 Patients/Trial: Age 15-64 Years
Group/Yea
r
No.
Pts
Disease-Free Survival or Overall Survival
Donor No Donor
PETHEMA
2005
156 OS: 40% @ 5 yr 49% @ 5 yr
MRC-
ECOG
2008
1031 High-risk
OS: 41% @ 5 yr
Standard-risk
OS: 62% @ 5 yr
35% @ 5 yr
52% @ 5 yr
HOVON
2009
257 DFS: 60% @ 5 yr 42% @ 5 yr
JALSG
2011
649 High-risk
OS: 54% @ 10 yr
Standard-risk
OS: 38% @ 10 yr
40% @ 10 yr
25% @ 10 yr

11. TRANSPLANT INTENT-TO-TREAT TRIALS
Pitfalls Donor vs No Donor Studies
• Donor / no donor assigned @ different time points
• “Geography” of locating sibs affects search time
–If no sib, ? assign to “no donor” @ diagnosis
• Older studies: do not address unrelated donors
• “Relatively” less-intense induction
– CALGB AYA study 10403
• Not all “donor” assignments go to transplant
–Physician bias and patient refusal

12. ALTERNATIVE DONORS
Graft Source Considerations
Time-censoring bias may improves URD outcome:
correction required
J Mehta. Blood 112: 447-448, 2008

13. ACUTE LYMPHOBLASTIC LEUKEMIA
Matched-Related vs Matched-Unrelated Donor
O Ringden, CIBMTR. Blood 113: 3110-3118,
N=483
N=189
Leukemia-FreeSurvival

14. ALTERNATIVE GRAFT SOURCES IN ALL
UCB vs Matched Unrelated Donor: Retrospective
Author/
Group
No. Pts TRM/NRM Relapse DFS/LFS/OS
Eapen:
CIBMTR,
EBMT
165 UCB
1360 MUD
33% @ 2 yr
40% @ 2 yr
-
-
44% @ 2 yr
50% @ 2 yr
Atsuta:
Japan
114 UCB
222 MUD
24% @ 2 yr
25% @ 2 yr
31% @ 2 yr
24% @ 2 yr
49% @ 2 yr
57% @ 2 yr
Ferra:
GETH,
PETHEMA
87 UCB
62 MUD
31% @ 1 yr
48% @ 1 yr
29% @ 5 yr
29% @ 5 yr
33% @ 5 yr
22% @ 5 yr

15. GRAFT SOURCES IN ALL CR1 Ph-
UCB vs Matched Related & Unrelated Donor
S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract
95 UCB, ‘CB’
388 related, ‘RD’
434 unrelated, ‘URD’
Overall Survival
Cumulative incidence relapse

16. REDUCED INTENSITY CONDITIONING
Relying On “Allogeneic Effect”

17. Evidence For GVL Effect In Adult ALL?Evidence For GVL Effect In Adult ALL?
YesYes
PL Weiden, FHCRC. NEJM 300: 1068-1073, 1979
• 163 allografts without GVHD vs 79 allografts with GVHD
• Relative relapse rate 2.5 times lower with GVHD (p<0.01)
• Anti-leukemia effect more marked in ALL than AML
AH Goldstone, UK MRC & ECOG. Blood 111: 1827-1833, 2008
• 239 pts: relapse rate 24% for donor vs 49% no donor (p<0.00005)
• High-risk: 37% relapse rate donor vs 63% no donor (p<0.00005)

18. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Reduced Intensity ConditioningReduced Intensity Conditioning
Author/Center No. Pts (CR1) Relapse DFS/LFS/OS
Stein:
City of Hope
24 (11) 21% @ 2 yr 62% @ 2 yr
Bachanova:
U Minnesota
22 (12) 36% @ 3 yr 50% @ 3 yr
Cho:
Korea
37 (30) 20% @ 3 yr 64% @ 3 yr
Nishiwaki:
Japan
26 (21) 26% @ 2 yr 63% @ 2 yr
Mohty:
EBMTR
127 (105) 47% @ 2 yr 32% @ 2 yr
Marks:
CIBMTR
93 (55) 35% @ 3 yr 45% @ 3 yr

19. 0
25
50
75
100
0 2 4 6 8 10
ACUTE LYMPHOBLASTIC LEUKEMIA Ph-
RIC vs Full-Intensity in CR1/CR2: Survival
Survival(%)
Years
Full-intensity conditioning
(n=1,428)
Reduced-intensity conditioning
(n=93)
DI Marks, CIBMTR. Blood 116: 366-374, 2010.

20. Remission Induction/Consolidation; start donor search
Randomize (stratify by):
Intent: chemotherapy vs HCT after Blinatumumab; MRD status
Blinatumomab No Blinatumomab
Chemotherapy ± Blinatumomab versus HCT (optional)
Intensification
MRD Assessment
E1910 INTERGROUP
New diagnosis Ph-, Age 35-70 Yr
CR
Bispecific anti-CD3,
anti-CD19 antibody

21. MINIMAL RESIDUAL DISEASE

22. Theoretic Time Course Leukemia
Minimal Residual Disease (MRD) Assessment
M Brüggemann, et al. Blood 2012
100
10-1
10-2
10-5
10-4
10-3
Complete remission Hematologic relapse
MRD relapse
MRD persistence
Complete MRD response
Detection limit
Morphology
Lower limit
MRD assay
Sensitivity limit
MRD assay
MRD-based remission assessment
Proportionleukemiccells

23. MINIMAL RESIDUAL DISEASE
Methodologies
• Detection sensitivity at least 1:10,000 cells
• Molecular
• Clonal rearrangements of T cell Receptor (TCR) genes
• Clonal rearrangement immunoglobulin (Ig) genes
• Flow cytometry
• Leukemia-associated phenotye (flow)
• FUTURE: high-throughput sequencing universally amplifies
antigen-receptor gene segments: more sensitive; use E1910
M Faham, D Campagna, et al. Blood 2012

24. ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Better Outcome MRDBetter Outcome MRDnegneg
vs MRDvs MRDpospos
PatientsPatients
R Bassan, Northern Italy Leukemia Group. Blood 113: 4153-4162, 2009
MRDneg
patients = < 10-4
via PCR @ wk 16 & totally undetectable @ wk 22;
all other patients classified MRDpos

25. MINIMAL RESIDUAL DISEASE: ALL
Kiel MRD ConferenceKiel MRD Conference
M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010
M Brüggemann, et al. Blood 2012
Technique Advantage Disadvantage
PCR Ig genes
& TCR genes
high sensitivity
highly
standardized
stability of DNA
time-consuming
requires extensive
knowledge/experience
expensive
Multiparameter
flow cytometry
quantitative
rapid
applicable most pt
low cellularity
requires extensive
knowledge/experience
less sensitive 3-4 color
(most now use 6 color)

26. MINIMAL RESIDUAL DISEASE: ALL
MRD Positive Patients
R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009
MRD pos @ 16 & 22 wk correlated with 10 wk

27. MINIMAL RESIDUAL DISEASE
Unresolved Issues
• Greater use in Europe; need to penetrate USA & other areas
• Time to perform assay; real-time availability
• Determine optimal methodologies
• Standardization of methodologies and definitions
• Ensure comparability
• Which time points to assay?
• Increased cost; who will pay?
• Effect of change in therapy?
• Transplant (positive) vs no transplant (negative)

28. SUMMARY
Factors to Consider For Transplant

29. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Likelihood To Recommend TransplantLikelihood To Recommend Transplant
Variable
Favor Transplant
Does Not
Favor Transplant
Clinical & laboratory risk high-risk standard-risk
Induction & consolidation “adult” regimen “pediatric” regimen
Sibling-matched donor available none available
Minimal residual disease (MRD):
result @ 12-16 weeks
positive negative

30. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Factors Affecting Transplant ConditioningFactors Affecting Transplant Conditioning
Variable Favor Myeloablative
Conditioning
Favor Reduced-Intensity
Conditioning
Age 35-55 years 56-70 years
Comorbidities absent present

31. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Factors Affecting Graft SourceFactors Affecting Graft Source
Variable Favor MUD Favor UCB
Institutional
experience
8/8 alleleic graft,
especially marrow
(rather than blood)
“Center of Excellence”,
extensive UCB experience

32. ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YR
Recommendations and *ParadoxRecommendations and *Paradox
Given greater use of more intensive induction &
consolidation therapy in younger patients:
**potentially more transplants in older patients
**Anthony H. Goldstone, MD
• Age <35 yr, enroll on “peds intensity” regimen:
• ? whether abrogates need for transplant
• ? age at which regimen not tolerated by adults
• Age 35-45 yr – gray area, assess risk factors
• strongly consider hematopoietic cell transplant
• Age > 45 yr – consider transplant, possibly RIC