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Allogeneic HSCT for ALL:CR1 or CR2?
H. Jean Khoury, MD, FACPR. Randall Rollins Chair in Oncology
Professor of Hematology and Medical OncologyDirector Division of Hematology
External Industry Relationships *
Company Name(s) Role
Equity, stock, or options in biomedical industry companies or publishers**
NONE
Board of Directors or officer NONE
Royalties from Emory or from external entity
NONE
Industry funds to Emory for my research
NONE
Other Novartis, BMS, Chemgenix, Wyeth/Pfizer, Ariad, Igenica,
PI clinical trials
H. Jean Khoury Personal/Professional Financial Relationships with Industry
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High-Riskpatients
Low-RiskYoung Adults
Older Patient
ALL
HCVAD + RPediatric regimens
Individualized Medicine
Intermediate-RiskWith CR2
achievable
Overall survival: Childhood ALL on St. Jude’s Trials 1962-2007
Pui et al. NEJM 2006
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Pui, et al. NEJM 2004
Children
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Survival on hyper-CVAD regimen by age
Kantarjian et al. JCO 2000
Pieters R & Carroll WL. Ped Clin NA 2008;55:1‐20
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Nachman JB, et al. JCO 2009;27:5189
CCSG Study 1961: ALL in Young Adult Gp (age 16-21)
High-Riskpatients
Low-RiskYoung Adults
Older Patient
ALL
HCVAD +/- RPediatric regimens
Individualized Medicine
Intermediate-RiskWith CR2
achievable
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MRC ‐ UK
Study Group # patients aged > 50-60
CR PFS OS
SWOG L-10M 40 35% 8.3 months Median 1 monthCALGB 8811 18 (> 60) 39% 12 months Median 1 monthGMALL 94 (> 65) 48% NR < 10%ECOG 108 (> 50) NR NR 15% at 5 yearsMDACC 59 (> 60) 80% NR 17 % at 5 years
Outcome of older patients
with ALL
High-Riskpatients
Low-RiskYoung Adults
Older Patient
ALL
HCVAD +/- RPediatric regimens
Individualized Medicine
Intermediate-RiskWith CR2
achievable
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Results of the ALL-R87 trial of 61 adults (median age 28) with relapsed ALL
•Only 9 patients were transplanted (5 autologous, 4 allogeneic).•Autografted patients: four relapsed after 1, 3, 4 and 25 months. One is currently in continuous CR (CCR) at 46 months from BMT. •Allografted patients, 1 relapsed 5 months from BMT and 3 are alive in CR at 22, 43, 63 months from BMT.
34/61 (56%) achieved CR
Fiorina et al. Italian cooperative group BJH 1997
Portell & Avandi. Leuk/Lymp 2014;55:737
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An open label, multicenter, phase II study to evaluate efficacy and safety of the BiTE antibody blinatumomab in adult patients with relapsed/refractory B-precursor acute
lymphoblastic leukemia(ALL)
• 220 pts enrolled at last report from ASH :
-36 evaluable
-26 (72%) CR/Cri w/i 2 cycles—24 molecular resp
- Med OS=9.0 mos; 13/26 went to allo SCT
- Major toxicities: CNS (seizures; encephalopathy), infection, thrombocytopenia, cytokine release syndrome
• Phase I pediatric trial in rel/ref B-ALL reported at ASH 2013 with 34 pts: ORR 41% (CR 35%)
Chimeric Antigen Receptors: CARs
Autologous T-cells modified to express a surface receptor that mediates binding of the target tumor antigen, e.g., CD19, which in turn activates a signal to the T-cell to induce target cell lysis.a. Single chain variable fragment antibody
specific to tumor antigenb. Fused to transmembrane domain and a
T-cell signaling moiety, e.g., CD3 zeta or FcRγ
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CARS in ALL
• Chimeric T cells (CTL019)
• 16 patients, age 5-22 with rel/ref ALL
• CR = 81% (10 of 16 persist up to 16mos)
• Continued expansion of CARs in vivo
• Persistence of CARs in blood and BM for >6 mos.
• CARs found in CSF
• Toxicity: Cytokine release syndrome
High-Riskpatients
Low-RiskYoung Adults
Older Patient
ALL
HCVAD +/- RPediatric regimens
Individualized Medicine
Intermediate-RiskWith CR2
achievable
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Durrant et al. MRC. Hem/Onc Clin of N. Am.. 2000
Outcomes Adult ALL
Elevated BC >30k (B-cell)
>100k (T-cell)
Cytogenetics
&
Molecular
Genetics
t(9;22), t(4;11), t(1;19)
Complex
Hypodiploidy
NOTCH 1 activating mutation
BAALC inc expression
IKZF1 deletion/mutation
Age >35 (a continuum)
Time to CR >4 (?6) weeks
Molecular failure (MRD)
Risk Factors in ALL
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MRD and prognosis in ALL
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Improving Outcomes
• Targeted therapy against MRD:– Monoclonal antibodies
– TKI
Rituximab-HCVAD
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Blinatumomab for MRD
A: RFS entire group (n= 20) = 61% (12 remain in CR)
B: RFS 9 patients receiving HSCT = 65% (6 remain in CR)
C: RFS 11 patients no subsequent Rx = 60% (6 remain in CR)
f/u 33 mos
Topp MS, et al. Blood; 2012;120(26):5185‐5187)
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HyperCVAD-Imatinib in Ph+ ALL
Thomas et al, Blood 2004, 103:4396-4467
HyperCVAD-dasatinib in Ph+ ALL
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Treatment options for Relapsed Ph+ ALL
Blood. 2007;109:3207-3213
Myeloid BP-CMLN=52
Lymphoid BP-CMLN=10
MaHR 29% 40%
Any CyRa 37% 50%
MCyR 19% 40%
CCyR 15% 30%
Ponatinib
Dasatinib
Myeloid BP-CMLN=52
MaHR 28%
CHR 15%
MCyR 37%
CCyR 28%
Bosutinib
Goldstone AH, et al. Blood 2008;111:1827‐33
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Goldstone AH, et al. Blood 2008;111:1827‐33
Goldstone AH, et al. Blood 2008;111:1827‐33
0.02
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Post-Transplant Rituximab
BLOOD, 22 AUGUST 2013 x VOLUME 122, NUMBER 8
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Conclusions
• Landscape for adult ALL is changing
• Monoclonal antibodies and TKIs – upfront, post-transplant, at relapse
• Allogeneic HSCT is curative and the use can be individualized –
• Allogeneic HSCT can be postponed to CR2 in adult ALL