When, How, and What Cell Source for Transplantation in ALL CR1

Hillard M. Lazarus, MD, FACPProfessor of Medicine

Director of Novel Cell TherapiesUniversity Hospitals Case Medical Center

Case Western Reserve University

ADULT ACUTE LYMPHOBLASTIC LEUKEMIADefinitions In This Presentation

Philadelphia chromosome t(9;22)(q34;q11) negativePhiladelphia chromosome t(9;22)(q34;q11) negative

““Adults” = age Adults” = age >> 35 years 35 years

ADULT ACUTE LYMPHOBLASTIC LEUKEMIABackground

• 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

AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.

ADULT ACUTE LYMPHOBLASTIC LEUKEMIAMRC 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

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 expressionT-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-likeFavorable: high hyperdiploid; del 9q

Molecular abnormalities Adverse: JAK2; IKFZ1; PAX5; TLX3; BAALCFavorable: 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.

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.

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 LEUKEMIAAutologous Transplant vs Chemotherapy

AH Goldstone, MRC, ECOG. Blood 111: 1827-1833, 2008.

Autotransplants not efficacious (unlike Ph pos ALL)

ADULT ALL POST-REMISSIONADULT ALL POST-REMISSION> 100 Patients/Trial: Age 15-64 Years> 100 Patients/Trial: Age 15-64 Years

Group/Year

No. Pts

Disease-Free Survival or Overall Survival Donor No Donor

PETHEMA2005

156 OS: 40% @ 5 yr 49% @ 5 yr

MRC-ECOG2008

1031 High-riskOS: 41% @ 5 yrStandard-riskOS: 62% @ 5 yr

35% @ 5 yr

52% @ 5 yr

HOVON 2009

257 DFS: 60% @ 5 yr 42% @ 5 yr

JALSG2011

649 High-riskOS: 54% @ 10 yrStandard-riskOS: 38% @ 10 yr

40% @ 10 yr

25% @ 10 yr

TRANSPLANT INTENT-TO-TREAT TRIALSPitfalls 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 requiredJ Mehta. Blood 112: 447-448, 2008

ACUTE LYMPHOBLASTIC LEUKEMIAMatched-Related vs Matched-Unrelated Donor

O Ringden, CIBMTR. Blood 113: 3110-3118, 2009.

N=483

N=189

Leu

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ree

Su

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ALTERNATIVE GRAFT SOURCES IN ALLUCB 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

GRAFT SOURCES IN ALL CR1 Ph-UCB vs Matched Related & Unrelated Donor

S Nishiwaki, Japan Society for HCT. Proc ASCO 2012 (abstract #6533).

95 UCB, ‘CB’388 related, ‘RD’434 unrelated, ‘URD’

Overall Survival

Cumulative incidence relapse

REDUCED INTENSITY CONDITIONING

Relying On “Allogeneic Effect”

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)

ADULT ACUTE LYMPHOBLASTIC LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIAReduced 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

0

25

50

75

100

0 2 4 6 8 10

ACUTE LYMPHOBLASTIC LEUKEMIA Ph-RIC vs Full-Intensity in CR1/CR2: Survival

Su

rviv

al (

%)

Years

Full-intensity conditioning(n=1,428)

Reduced-intensity conditioning(n=93)

DI Marks, CIBMTR. Blood 116: 366-374, 2010.

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

MINIMAL RESIDUAL DISEASE

Theoretic Time Course LeukemiaMinimal 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 limitMorphology

Lower limit MRD assay

Sensitivity limitMRD assay

MRD-based remission assessment

Pro

po

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n le

uk

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ce

lls

MINIMAL RESIDUAL DISEASEMethodologies

• 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 LEUKEMIAADULT ACUTE LYMPHOBLASTIC LEUKEMIABetter Outcome MRDBetter Outcome MRDnegneg vs MRD vs MRDpos pos 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

MINIMAL RESIDUAL DISEASE: ALLKiel MRD ConferenceKiel MRD Conference

M Brüggemann, Kiel MRD Conference. Leukemia 24: 521-535, 2010M 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)

MINIMAL RESIDUAL DISEASE: ALLMRD Positive Patients

R Bassan, Northern Italian Leukemia Group. Blood 113: 4153-4162, 2009

MRD pos @ 16 & 22 wk correlated with 10 wk

MINIMAL RESIDUAL DISEASEUnresolved 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 YRALL CR1 PATIENTS AGE 35-70 YRLikelihood To Recommend TransplantLikelihood To Recommend Transplant

VariableFavor 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 YRALL CR1 PATIENTS AGE 35-70 YRFactors Affecting Transplant ConditioningFactors 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 YRALL CR1 PATIENTS AGE 35-70 YRFactors 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

ALL CR1 PATIENTS AGE 35-70 YRALL CR1 PATIENTS AGE 35-70 YRRecommendations 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