allogeneic hsct for all: cr1 or cr2? · ash 2013 with 34 pts: orr 41% (cr 35%) chimeric antigen...

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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


Older Patient

ALL

HCVAD +/- RPediatric regimens



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


Older Patient

ALL




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


Older Patient

ALL




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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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

allogeneic hsct for all: cr1 or cr2? · ash 2013 with 34 pts: orr 41% (cr 35%) chimeric antigen...

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