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
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Definitions In This Presentation
Philadelphia chromosome t(9;22)(q34;q11) negative
“Adults” = age > 35 years
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
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
MRC UKALL XII / ECOG 2993: N=1,929
INDUCTION
HLA donor
< 50 (or 55) yr
No donor
Randomize
Assign
High-dose
methotrexate x 3
Sibling
Allograft
Autograft
Consolidation/
Maintenance
JM Rowe, MRC & ECOG. Blood 106: 3760-3767, 2005
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Clinical and Laboratory Risk Factors
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
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.
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Clinical and Laboratory Risk Factors (con’t)
Factors After Therapy
Prognosis Association
Time to initial response
Adverse: no CR within 4 weeks
Minimal residual disease
Adverse: detection at various times
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.
ACUTE LYMPHOBLASTIC LEUKEMIA
“BCR-ABL-Like”
JR Downing, CG Mullighan. Am Soc Hematol Educ Prog 118-22, 508, 2006.
ML den Boer, Erasmus. Lancet Oncol 10: 125–134, 2009.
PROSPECTIVE POST-REMISSION TRIALS
Chemotherapy vs Autograft vs Allograft
Design and Outcome
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Autologous Transplant vs Chemotherapy
Autotransplants not efficacious (unlike Ph pos ALL)
AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.
ADULT ALL POST-REMISSION
> 100 Patients/Trial: Age 15-64 Years
Group/Year
No.
Pts
PETHEMA
2005
MRCECOG
2008
156 OS:
HOVON
2009
JALSG
2011
Disease-Free Survival or Overall Survival
Donor
No Donor
40% @ 5 yr
1031 High-risk
OS: 41% @ 5 yr
Standard-risk
OS: 62% @ 5 yr
257 DFS: 60% @ 5 yr
649 High-risk
OS: 54% @ 10 yr
Standard-risk
OS: 38% @ 10 yr
49% @ 5 yr
35% @ 5 yr
52% @ 5 yr
42% @ 5 yr
40% @ 10 yr
25% @ 10 yr
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
ALTERNATIVE DONORS
Graft Source Considerations
Time-censoring bias may improves URD outcome:
correction required
J Mehta. Blood 112: 447-448, 2008
ACUTE LYMPHOBLASTIC LEUKEMIA
Leukemia-Free Survival
Matched-Related vs Matched-Unrelated Donor
N=483
N=189
O Ringden, CIBMTR. Blood 113: 3110-3118, 2009.
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
33% @ 2 yr
-
44% @ 2 yr
1360 MUD 40% @ 2 yr
-
50% @ 2 yr
Atsuta:
Japan
Ferra:
GETH,
PETHEMA
114 UCB
24% @ 2 yr 31% @ 2 yr
49% @ 2 yr
222 MUD
25% @ 2 yr 24% @ 2 yr
57% @ 2 yr
87 UCB
31% @ 1 yr 29% @ 5 yr
33% @ 5 yr
62 MUD
48% @ 1 yr 29% @ 5 yr
22% @ 5 yr
GRAFT SOURCES IN ALL CR1 PhUCB vs Matched Related & Unrelated Donor
Overall Survival
95 UCB, ‘CB’
388 related, ‘RD’
434 unrelated, ‘URD’
Cumulative incidence relapse
S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract #6533).
REDUCED INTENSITY CONDITIONING
Relying On “Allogeneic Effect”
Evidence For GVL Effect In Adult ALL?
Yes
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)
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Reduced Intensity Conditioning
Author/Center No. Pts (CR1)
Stein:
City of Hope
Bachanova:
U Minnesota
Cho:
Korea
Nishiwaki:
Japan
Mohty:
EBMTR
Marks:
CIBMTR
Relapse
DFS/LFS/OS
24 (11)
21% @ 2 yr
62% @ 2 yr
22 (12)
36% @ 3 yr
50% @ 3 yr
37 (30)
20% @ 3 yr
64% @ 3 yr
26 (21)
26% @ 2 yr
63% @ 2 yr
127 (105)
47% @ 2 yr
32% @ 2 yr
93 (55)
35% @ 3 yr
45% @ 3 yr
ACUTE LYMPHOBLASTIC LEUKEMIA PhRIC vs Full-Intensity in CR1/CR2: Survival
100
Survival (%)
75
Full-intensity conditioning
(n=1,428)
50
25
Reduced-intensity conditioning
(n=93)
0
0
2
4
6
8
Years
DI Marks, CIBMTR. Blood 116: 366-374, 2010.
10
E1910 INTERGROUP
New diagnosis Ph-, Age 35-70 Yr
Remission Induction/Consolidation; start donor search
CR
Intensification
MRD Assessment
Randomize (stratify by):
Intent: chemotherapy vs HCT after Blinatumumab; MRD status
Blinatumomab
Bispecific anti-CD3,
anti-CD19 antibody
No Blinatumomab
Chemotherapy ± Blinatumomab versus HCT (optional)
MINIMAL RESIDUAL DISEASE
Theoretic Time Course Leukemia
Proportion leukemic cells
Minimal Residual Disease (MRD) Assessment
100
10-1
Complete remission
Hematologic relapse
Detection limit
Morphology
10-2
MRD persistence
10-3
MRD relapse
10-4
Lower limit
MRD assay
10-5
Sensitivity limit
MRD assay
Complete MRD response
MRD-based remission assessment
M Brüggemann, et al. Blood 2012
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
ADULT ACUTE LYMPHOBLASTIC LEUKEMIA
Better Outcome MRDneg vs MRDpos Patients
MRDneg patients = < 10-4 via PCR @ wk 16 & totally undetectable @ wk 22;
all other patients classified MRDpos
R Bassan, Northern Italy Leukemia Group. Blood 113: 4153-4162, 2009
MINIMAL RESIDUAL DISEASE: ALL
Kiel MRD Conference
Technique
PCR Ig genes
& TCR genes
Advantage
Disadvantage
high sensitivity
time-consuming
highly
standardized
requires extensive
knowledge/experience
stability of DNA
expensive
Multiparameter quantitative
flow cytometry
rapid
low cellularity
requires extensive
knowledge/experience
applicable most pt less sensitive 3-4 color
(most now use 6 color)
M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010
M Brüggemann, et al. Blood 2012
MINIMAL RESIDUAL DISEASE: ALL
MRD Positive Patients
MRD pos @ 16 & 22 wk correlated with 10 wk
R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009
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)
SUMMARY
Factors to Consider For Transplant
ALL CR1 PATIENTS AGE 35-70 YR
Likelihood 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
ALL CR1 PATIENTS AGE 35-70 YR
Factors Affecting Transplant Conditioning
Variable
Favor Myeloablative
Conditioning
Favor Reduced-Intensity
Conditioning
Age
35-55 years
56-70 years
Comorbidities
absent
present
ALL CR1 PATIENTS AGE 35-70 YR
Factors 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
ALL CR1 PATIENTS AGE 35-70 YR
Recommendations and *Paradox
• 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
Given greater use of more intensive induction &
consolidation therapy in younger patients:
*potentially more transplants in older patients
*Anthony H. Goldstone, MD