Traitement des leucémies aiguës lymphoblastiques

de l’adulte (Ph1-)

Nicolas BoisselUnité d’Hématologie Adolescents et Jeunes Adultes

Hôpital Saint-Louis, Paris

DES Hématologie 12 avril 2019

Acute Lymphoblastic Leukemia –Progress in Children. Less in Adults

Treatment of Acute Lymphoblastic Leukemia –30 Years' Experience

at St. Jude Children's Research Hospital

D. Hoelzer

G.K. Rivera

1993

A question of biology ?

Moorman. 2007

Age

(yr)

Pts CR

(%)

EFS

(%)

France FRALLE 93 15-20 77 94 67

LALA 94 100 83 41

Netherland DCOG 15-18 47 98 69

HOVON 44 91 34

UK ALL97 15-17 61 98 65

UKALLXII 67 94 49

Sweden NOPHO92 15-20 36 99 74

Adult ALL Group 23 90 39

USA CCG 16-20 197 90 63

CALGB 124 90 34

Boissel, JCO, 2003

De Bont,Leukemia, 2004 Ramanujachar, Pediatr Blood Cancer, 2007

Hallböök, Cancer, 2006

Stock, Blood, 2008

A question of therapy ?

Biologists

C. AbbalV. AsnafiM. BakkusL. BarangerK. BeldjordMC. BénéML. BoullandH. Cavé JM. CayuelaA. ChasseventE. ClappierE. DelabesseN. GrardelM. LafageE. MacIntyreB. SchäferJ. Soulier

Clinicians

N. BoisselT. BraunA. BuzynJY. CahnY. ChalandonP. ChevallierA. DelannoyN. DhédinM. Escoffre-BarbeC. GardinC. Graux

Coordination

V. LhéritierN. IfrahH. Dombret

Biostatistics

J. LejeuneS. Chevret

… All GRAALL investigators

D. HeimU. HessF. HuguetA. HuynhM. HunaultT. LeguayS. LeprêtreJP. MarolleauS. MauryP. RousselotX. ThomasJP. VernantN. Vey

80 centers in Switzerland, Belgium, and France

The GRAALL-2003/05 protocol

GRAALL, Group for Research on Adult Acute Lymphoblastic Leukemia

Huguet F, et al. J Clin Oncol 2009;27:911–8

PDN (mg) 840 7,260 4,340VCR (mg) 6 22 19L-ASPA (IU.103) 9 144 180VP16 (mg) 0 450 1,200CPM (g) 12.5 6 or 7* 0Ara-C (g) 4,3 or 12** 24 0.96

LALA-94 GRAALL-2003 FRALLE 93

* single dose or repeted bolus

** without or with intensive consolidation

GRAALL-2003/05 vs LALA-94 :cumulative doses (/sqm)

Historical GRAALL risk factors

• Baseline – WBC ≥30 x 109/L for B-lineage ALL

– CNS disease

– Immature CD10-negative B-lineage ALL*

– t(4;11) and/or MLL-AF4, t(1;19) and/or TCF3-PBX1

– Low hypodiploidy, near triploidy

– Complex karyotype (≥5 abnormalities)*

• Early response– No haematological CR after the first induction course

– Slow PDN response at the end of pre-phase

– Slow BM blast clearance at Day 8 of chemotherapy

– Ig/TCR MRD ≥10-2 after induction†

*Introduced in GRAALL-2005 †In GRAALL-2003 only (1 single patient classified as high-risk due to MRD only)ASCT, allogeneic stem cell transplant; BM, bone marrow; CNS, central nervous system; CR, complete response; Ig, immunoglobulin; MRD, minimal residual disease; TCR, T-cell receptor; WBC, white blood cell count

Huguet F, et al. J Clin Oncol 2009;27:911–8;

Used for ASCT indication

GRAALL-2003 vs LALA-94Event-free survival in Ph- ALL

EFS, event-free survival; LALA, France-Belgium Group for Lymphoblastic Acute Leukemia in Adults

N Boissel, personal communication; Huguet F, et al. J Clin Oncol 2009;27:911–8 and supplemental data

0.0

00.2

00.4

00.6

00.8

01.0

0

pro

ba

bili

ty o

f su

rviv

al

0 6 12 18 24 30 36 42 48months

trial = LALA-94

trial = GRAALL-2003

Event-free survival

From GRAALL-2003/05To GRAALL-2014

Post induction MRD andrisk of relapse

Best cutoff level, 10-4 Beldjord K et al., Blood. 2014;123(24):3739-3749

BCP-ALL

60% vs 20% at 5y*

HR, 3.62

T-ALL

60% vs 30% at 5y*

HR, 3.20

* Censored at SCT

Survival by post-induction MRD

(GRAALL-2003/05, data on file)

5y-OS: 74.0%, MRD<10-4

48.7%, MRD≥10-4

p <0.001

BCP-ALLMultivariate analysis

Beldjord K, et al. Blood 2014;123:3739–49

• Multivariate analysis

• High-risk group in GRAALL-2014-B trial :

IKZF1 deletion, or MLL+

or MRD1 ≥10-4

Events CIR (not censored) CIR (censored)

Hazard ratio P value Hazard ratio P value

WBC ≥30 x109/L 67/260 1.37 0.30 1.01 0.98

t(4;11) and/or MLL-AF4 or MLL+

29/253 1.73 0.17 3.15 0.028

DIKZF1 54/216 1.75 0.05 2.43 0.006

MRD1 ≥10-4 111/260 2.49 0.001 3.21 <0.001

T-ALL 4-gene classifierNOTCH1/FBXW7 and RAS/PTEN

Trinquand A, et al. J Clin Oncol 2013;31:4333–42

NOTCH1/FBXW7

Wild type Mutated

RAS/PTEN

Normal High Risk Low Risk

Alteration High Risk High Risk

55%

T-ALLFactors correlating with relapse

Beldjord K, et al. Blood 2014;123:3739–49Ben Abdelali R, et al. Blood 2011;118:5099–107Trinquand A, et al. J Clin Oncol 2013;31:4333–42

N=317 patients Number

CIR (not censored at ASCT) CIR (censored at ASCT)

Hazard ratio P value Hazard ratio P value

Age ≥45 years 55/317 0.85 0.56 0.65 0.18

WBC ≥100 x 109/L 69/317 1.87 0.005 1.95 0.009

CNS+ 33/313 1.78 0.046 2.45 0.013

Pre-T/cortical 39/288 0.63 0.07 0.67 0.17

Complex karyotype 27/266 1.39 0.33 1.24 0.62

TLX1 hyper-expression 63/294 0.62 0.10 0.65 0.15

TLX3 hyper-expression 28/294 1.24 0.52 0.79 0.60

ERG-BAALC overexpression 106/187 1.16 0.53 0.59 0.26

NOTCH1/FBXW7 mutation 164/236 0.43 <0.001 0.46 0.004

N/K-RAS mutation 23/218 2.45 0.004 2.13 0.032

PTEN alteration 25/196 1.78 0.08 2.50 0.01

Slow prednisone response 118/316 1.28 0.24 1.54 0.08

Slow BM blast clearance 129/311 1.36 0.14 1.65 0.04

MRD1 ≥10-4 47/163 2.50 0.001 2.93 0.002

• Multivariate analysis

• High-risk group in GRAALL-2014-T: high risk NOTCH1/FBXW7/RAS/PTEN classifier

or MRD1 ≥10-4

T-ALLMultivariate analysis

Beldjord K, et al. Blood 2014;123:3739–49

Events CIR (not censored) CIR (censored)

Hazard ratio P value Hazard ratio P value

WBC ≥100 x109/L 37/163 1.51 0.29 1.34 0.53

CNS+ 18/162 1.38 0.53 2.49 0.29

Phenotype: Pro-T/mature 22/151 1.22 0.63 1.01 0.98

NOTCH1/FBXW7/RAS/PTEN 60/125 4.39 0.002 5.59 0.003

MRD1 ≥10-4 47/163 3.13 0.002 2.50 0.036

Benefit from ASCTAccording to post-induction MRD

Dhédin N, et al. Blood 2015;125:2486–96

GRAALL-2014 Risk-stratification

0.00

0.20

0.40

0.60

0.80

1.00

Ove

rall

Su

rviv

al (p

roba

bili

ty)

173 140 103 95 70 50 36 9 2HR124 112 100 94 78 57 29 11 5SR

Number at risk

0 1 2 3 4 5 6 7 8Time(years)

0.00

0.20

0.40

0.60

0.80

1.00

Ove

rall

Su

rviv

al (p

roba

bili

ty)

137 114 87 73 61 50 24 11 3HR78 76 68 64 54 38 26 12 4SR

Number at risk

0 1 2 3 4 5 6 7 8Time(years)

High-RiskIKZF1 deletion,

or KMT2A(MLL)+,or MRD1 ≥10-4

≈ 60%

HR, 5y: 45.9%

SR, 5y: 74.7%

Beldjord K et al., Blood. 2014;123(24):3739-3749

High-RiskNOTCH1/FBXW7/RAS/PTEN

unfavorable,or MRD1 ≥10-4

Ph- BCP-ALL T-ALL

≈ 65%Very High-RiskMRD1 ≥10-3

or MRD2 ≥10-4

ASCT

HR, 5y: 52.9%

SR, 5y: 84.9%

≈ 25-30%

Signaling pathways in Ph-like ALL

Iacobucci et Mullighan, J Clin Oncol. 2017 Mar 20;35(9):975-983Hunger S & Mullighan C, Blood. 2015 Jun 25; 125(26): 3977–3987

Ph-like ALL outcome in adults

1. Herold T, et al. Haematologica 2017;102:130–8;2. Jain N, et al. Blood 2017;129:572–81.

DFS

OS

MDACC: HyperCVAD/A-BFM2GMALL: 06/99 & 07/031

EFS

OS

Kinase rearrangements in Ph-like ALL

Roberts KG, et al. Cancer Cell 2012;22:153–66;Pui CH, et al. Clin Lymphoma Myeloma Leuk 2017;17:464–70.

Selected kinase-activating gene fusions Kinases with re-arrangements in Ph-like ALL

GRAALL-2014Ph-like ALL with targetable ABL-family gene

Slide courtesy of E. Clappier and P. Rousselot.

Pre-phase & induction

HDAC HD-MTX CPM

PDN PDN-VCR-DNR-CPM-ASPA

PDN-VCR-DNR-CPM-ASPA/ERW

MRD1

HDAC HD-MTX CPM

HDAC HD-MTX CPM

Consolidation n°1

Delayed intensification

Consolidation n°3

Consolidation n°2

2-year maintenance

MRD2

MRD3

Ph-likewith

targetable ABL gene

IM600

IM600

VHR (HSCT)MRD1≥10-3

or MRD2≥10-4

IM600

IM600

IM600

CPM, cyclophosphamide; IM600, imatinib 600 mg/day; MTX, methotrexate; VCR, vincristine; VHR, very high-risk.

COG ALL0434, Phase 3 nelarabine in T-ALL/LBLTreatment scheme

• Nelarabine is a soluble pro-drug of Ara-G• AraG is intracellularly converted to AraG triphosphate (AraGTP)• AraGTP accumulates in T-lymphoblasts and inhibits DNA synthesis

• Aim : To determine the relative safety and efficacy of the addition of Nelarabine to COG-modified ABFM therapy.

• Treatment scheme :• 4-Drug Induction• Consolidation: Augmented BFM (Similar to Ib) +/- NELA (x2)• Interim Maintenance: MTX Randomization : Capizzi MTX/ASNase vs HD MTX• Delayed Intensification: (similar to II A+B) +/- NELA (x1)• Maintenance Cycles: 7 (girls) or 11 (boys) : +/- NELA (x3)• CNS1 or CNS2: 1,200 cGy; CNS3: 1,800 cGy

• Nelarabine arms : 6 courses of nelarabine monotherapy (650 mg/m2/day, D1–5)Winter SS, et al. Pediatr Blood Cancer 2015;62:1176–83.

COG ALL0434, Ph 3 nelarabine in T-ALL/LLPatient outcome

0 2 4 6 8 10

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

bab

ilit

y

Nelarabine (n=323)

No Nelarabine (n=336) One-sided P = 0.0450

4yr DFS + Nel 88%4yr DFS – Nel 83%

Outcome of Randomized Patients

• Patients receiving nelarabine had fewer CNS relapses• No difference in peripheral neurotoxicities between arms

0 1 2 3 4 5 6 7

0.0

0.2

0.4

0.6

0.8

1.0

Years

Pro

bab

ilit

y

Nelarabine (n=60)

No Nelarabine (n=58) One-sided P = 0.2127

No benefit to nelarabine for T-LLy

DFS 4yr 85%

T-LBL arm not powered to evaluate efficacy

Dunsmore KP, et al. ASCO 2018; Abstract 10500.

GRAALL phase 2 study, HR-T-ALLATRIALL trial

Prephase & induction

HDAC HD-MTX CPM

PDN PDN-VCR-DNR-CPM-ASPA

PDN-VCR-DNR-CPM-ASPA/ERW

PDN-VCR-6MP-MTX

* MRD1

* MRD2

HDAC HD-MTX CPM HDAC HD-MTXCPM/NEL

HDAC HD-MTXCPM/NEL

PDN-VCR-DNR-CPM-ASPA/ERW

SRHR

Def. 4-gene classifieror MRD1≥10-4

VHR (ASCT)MRD1≥10-3

or MRD2≥10-4

HDAC HD-MTX CPM

PDN-VCR-6MP-MTX- NEL

Consolidation n°1

Delayed intensification

Consolidation n°3

Consolidation n°2

2-year maintenance

* MRD3

Benefits and limits ofpediatric-like therapyin adults

Age and increasing risk of failurein children (>1y) and AYAs with Ph- ALL

Hough R, Br J Haematol. 2016 Feb;172(3):439-51.

Toft N, Leukemia. 2018 Mar;32(3):606-615.

UKALL-2003 NOPHO-2008

• Even if TRM progressively increased with advanced age, patients aged 55 years or more displayed a significantly lower EFS, mostly due to higher TRM during induction and post-remission therapy, even if not transplanted.

Patients by age range N CR rate

Inductiondeath rate

5-yearCIF

5-year CITRM

5-yearEFS

w/o SCT censoring

with SCT censoring

18-24y 200 98.5% 0.5% 32.7% 7.6% 1.8% 60%

25-34y 172 95.3% 1.7% 29.4% 12.7% 6.4% 58%

35-44y 171 87.7% 7.6% 31.0% 15.0% 11.3% 54%

45-54y 151 89.4% 6.6% 26.7% 22.4% 16.7% 50%

55y+ 93 79.6% 18.3% 33.0% 39.7% 38.4% 26%

All 787 92% 5.5% 30.5% 17% 12% 52%

Huguet F. ASH 2016, #762

Age and increasing risk of TRMin adults (18-59y) with Ph- ALL

EFS event incidences, by age subgroups

18-24y 25-34y 35-45y 46-54y 55-59y

Cumulative incidence of failure(primary resistance, relapse)

Cumulative incidence of TRM(induction death, death in CR1)

Leukemia-related events Treatment-related events

Huguet F. ASH 2016, #762

Children Adults Elderly

Cu

mu

lati

ve in

cid

ence

of

TRM

/Fai

lure

Adult and pediatric strategies in ALLTRM and CI of Failure according to age & treatment intensity

Children Adults Elderly

Cu

mu

lati

ve in

cid

ence

of

TRM

/Fai

lure

Treatment Intensity : Low/Medium/HighTRMFailure

Treatment Intensity : Low/Medium/HighTRMFailure

AYA

Impact of age-based care organizationon the outcome of AYA 18-39y with ALL

Siegel SE, JAMA Oncol. 2018 Feb 15.

Five-Year Relative Survival Rate by Single Year of Age at Diagnosis, 2000 to 2007 (SEER)

Relapsed Ph-negative ALLin adults

Post-relapse survival

LALA 94

• Median OS: 6.3 mois

• 2y OS : 11%

• 5y OS : 9%

GRAALL 2003 & 2005

• Median OS : 6.7 mois

• 2y OS : 19.3%

• 5y OS : 13.3%

Tavernier E. et al. Leukemia. 2007 Sep;21(9):1907-14.Desjonquères A. et al. Blood Cancer J. 2016 Dec 9;6(12):e504

Prognostic factors at relapseGRAALL study

Desjonquères A. et al. Blood Cancer J. 2016 Dec 9;6(12):e504

CR2

No CR2

SCT

No SCT

Standard chemotherapy in late relapse

GMALL n CR, n (%)

Total 224 95 (42%)

< 18 months 160 58 (36%)

SCT in relapse 18 10 (56%)

≥ 18 months 64 37 (58%)

Standard induction 30 27 (90%)

FLAG-IDA 15 4 (27%)

GRAALL n CR, n(%)

Total 229 121 (53%)

< 18 months 179 87 (49%)*

≥ 18 months 50 34 (68%)

*p=.02

GRAALL, data out of fileAdapted from Gökbuget N et al., Blood. 2012 Sep 6;120(10):2032-41.

New immunostrategies

Immunostrategies in BCP-ALL

Batlevi et al., Nat Rev Clin Oncol. 2015

Inotuzumab Ozogamicin

Inotuzumab phase III (INO-VATE)BCP-ALL, R/R

Kantarjian, N Engl J Med. 2016 Aug 25;375(8):740-53

MRD < 0.01% in patients with CRInotozumab: 78.4% vs. SOC: 28.1%, P<0.001

Inotuzumab phase III (INO-VATE)BCP-ALL, R/R

Duration of remission

Progression-free Survival

Kantarjian, N Engl J Med. 2016 Aug 25;375(8):740-53

Overall Survival

2-year survival rate: InO 23% (95% CI 16–30) vs SOC 10% (95% CI 5–16)

Inotuzumab phase III (INO-VATE) Liver toxicity

Kantarjian, Lancet Haematol. 2017 Aug;4(8):e387-e398

Inotuzumab and HSCT• SOS in 17/77 (22%)• 5 deaths

Inotuzumab frontlineEWALL-INO Phase 2 study

Followed by six INO-free consolidation cycles and maintenance.

• N= 130 patients aged 56y+ with Ph-negative BCP-ALL

• Sequential INO for first 2 courses :• 0.8/0.5/0.5 mg/m2 for cycle 1; 0.5/0.5 mg/m2 for cycle 2

BlinatumomabMechanism of action

1. Baeuerle PA, Reinhardt C. Cancer Res 2009;69:4941–4; 2. Bargou R, et al. Science 2008;321:974–7; 3. Klinger M, et al. Blood 2012;119:6226–33; 4. Hoffmann P, et al. Int J Cancer 2005;115:98–104.

Blinatumomab phase III (TOWER)BCP-ALL, R/R, complete remission

Katarjian H, N Engl J Med. 2017 Mar 2;376(9):836-847.

MRD < 0.01% in patients with CR/CRh/CRiBlinatumomab: 76% vs. SOC: 48%, P<0.001

Blinatumomab phase III (TOWER)BCP-ALL, R/R, OS according to salvage status

Dombret H, et al. EHA 2017; Abstract S478

KM median, months (95% CI) P-value*

S1: Blinatumomab 11.1 (8.2–NR)0.016

S1: SOC 5.5 (3.7–9.0)S2+: Blinatumomab 5.1 (3.2–7.1)

0.055S2+: SOC 3.0 (2.1–4.0)

00

20

40

100

Time (years)

Overa

ll surv

ival (%

)

1.0

60

0.5 1.5

80

2.0

104 2680 1463 1139 5

167 1996 13

S1: blinatumomabS1: SOCS2+: blinatumomab

Patients at risk:592665

391840

71 632 2S2+: SOC 15 9

5341

1031

0

00

0

Censored

Blinatumomab, LAL-Ph1-, MRD+BLAST Study, OS by CMR

48

Landmark analysis from day 45;

Complete MRD response was defined as no target amplification, with a minimum sensitivity of 10–4.

Median follow-up for survival was 53.1 months (approximately 4.5 years)

Gökbuget N, et al. ASH 2018, abstract 554

Blinatumomab, LAL-Ph1-, MRD+BLAST Study, Outcome by HSCT in CCR

49Gökbuget N, et al. ASH 2018, abstract 554

Early response after blinatumomabImpact of tumor burden

0

10

20

30

40

50

60

70

80

90

>50% blasts<50% blasts≥10-3

& <10-2

≥10-2

& <10-1

≥10-1

& <1

R/R (TOWER)MRD (BLAST)

45%53%

CR rate67%

84%78%

CR/CRh/CRi

CMR

Extrapolated CMR* Res

po

nse

rate

Katarjian H, N Engl J Med. 2017 Mar 2;376(9):836-847Gokbuget et al., ASH2015, #680

Tumor burden

* Considering a 76% CMR rate in CR/CRh/Cri patients

GRAALL-QUEST phase 2 studyfor Ph- HR BCP-ALL

Prephase & induction

HDAC HD-MTX CPM

PDN PDN-VCR-DNR-CPM-ASPA

PDN-VCR-DNR-CPM-ASPA/ERW

PDN-VCR-6MP-MTX

* MRD1

* MRD2

HDAC HD-MTX CPM

HDAC HD-MTXBLIN

HDAC HD-MTX

PDN-VCR-DNR-CPM-ASPA/ERW

SR HRIKZF1del, or KMT2A+

or MRD1≥10-4

VHR (ASCT)MRD1≥10-3

or MRD2≥10-4

HDAC HD-MTX CPM

PDN-VCR-6MP-MTX- BLIN

Consolidation n°1

Delayed intensification

Consolidation n°3

Consolidation n°2

2-year maintenance

BLIN

BLIN

* MRD3

GRAALL-2014Toward pediatric-inspired age-adapted trial

• Next step of pediatric-inspired approach• Increased HD-methotrexate doses in patients <45y• No CNS irradiation in CNS-1 patients• MRD-based indication for allogeneic SCT• Asparaginase switch in immunized patients• Rituximab in CD20+ patients

• Decreased toxicity in older patients• Desescalated doses in patients >45y• RIC in patients >45y

• New drugs in high-risk patients• Blinatumomab in HR BCP-ALL (QUEST study)• Nelarabine in HR T-ALL (ATRIALL Study)• Targeted therapy in Ph-like ALL

Chimeric antigen receptor generations

Heczey A, Louis CU. Discov Med 2013;16:287–94.

• T-cell activation is improved by costimulation domains:

- CD28, 4-1BB

- CD27, OX-40, CD244, ICOS

• Consequences:

- ↑ cytokine release

- ↑ cytotoxicity

- ↑ proliferation

- ↑ in vivo expansion & persistence

Autologous CD19 CAR-T in R/R B-ALL Phase 1/2 studies

1. Maude SL, et al. N Engl J Med 2014;371:1507–17;2. Lee DW, et al. Lancet 2015;385:517–28;

3. Gardner RA, et al. Blood 2017;129:3322–31;4. Maude SL, et al. N Engl J Med 2018;378:439–48;

5. Park JH, et al. N Engl J Med 2018;378:449–59;6. Hay KA, et al. Blood 2019; doi: 10.1182/blood-2018-11-883710 [Epub].

Study Population CD19-CAR V N Cond. T-cells ORR

Maude, 20131

Ped+adult 4-1BB LV 30 CyF unselected 90%

Lee, 20152

Ped+YA CD28 gRV 21 Cy unselected 68%

Gardner, 20173 Ped+YA 4-1BB LV 45 CyF 1:1 CD4/8 93%

Maude, 20184

Ped+YA 4-1BB LV 75 CyF unselected 81%

Park, 20185

Adult CD28 gRV 53 Cy/CyF unselected 83%

Hay, 20196

Adult 4-1BB LV 53 Cy/CyF 1:1 CD4/8 85%

Cy, cyclophosphamide; CyF, cyclophosphamide + fludarabine; Ped, paediatric; YA, young adults;LV, lentivirus; gRV, gamma-retrovirus; Auto, autologous.

Impact of conditioning regimen

Hay KA, et al. Blood 2019; doi: 10.1182/blood-2018-11-883710 [Epub].

Fludarabine associated with higher AUC (D28–D90) and better EFS

FHCRC>18 years

CD19/4-1BB/CD3z

CAR-T cells cross the blood-brain barrier

Jacoby E, et al. Am J Hematol 2018;93:1485–92.Lee DW, et al. Lancet 2015;385:517–28.

CRS and neurotoxicity in CD19 CAR-T ALL studies

1. Maude SL, et al. N Engl J Med 2014;371:1507–17;2. Lee DW, et al. Lancet 2015;385:517–28;

3. Gardner RA, et al. Blood 2017;129:3322–31;4. Maude SL, et al. N Engl J Med 2018;378:439–48;

5. Park JH, et al. N Engl J Med 2018;378:449–59;6. Hay KA, et al. Blood 2019; doi: 10.1182/blood-2018-11-883710 [Epub].

Study CD19-CAR N Population CR CRS Neurotoxicity/CRES

Maude, 20131

4-1BB 30 Ped+Adult 90%100%

27% severe43% encephalopathy, seizure,

aphasia

Lee, 20152

CD28 21 Ped+YA 68%76%

28% severe29% encephalopathy,

hallucination

Gardner, 20173 4-1BB 45 Ped+YA 93%93%

23% severe49%

21% severe

Maude, 20184

4-1BB 75 Ped+YA 81%77%

46% severe40%

13% severe

Park, 20185

CD28 53 Adult 83%85%

26% severe43%

42% severe

Hay, 20196

4-1BB 53 Adult 85%75%

19% severe23% severe

Escape mechanisms to CD19-targeted therapy

Kohnke T, et al. J Hematol Oncol 2015;8:111;Sotillo E, et al. Cancer Discov 2015;5:1238–40;

Rayes A, et al. Pediatr Blood Cancer 2016;63:1113–5;Ruella M, et al. Nat Med 2018;24:1499–503.

• Mutation/deletion of CD19 gene

oGene deletion

o Exon 2 mutations → alternative splicing

• Lineage switch

oALL → AML (MLL+ disease)

• Loss of CD81 and disruption of CD19 trafficking

• Transduction of ALL blasts and antigen masking

CD19-positive vs CD19-negative relapse

1. Park JH, et al. N Engl J Med 2018;378:449–59;2. Gardner RA, et al. Blood 2017;129:3322–31;

3. Maude SL, et al. N Engl J Med 2018;378:439–48.

MSKCC1

CD19/CD28/CD3z

SEATTLE2

CD19/4-1BB/CD3

ELIANA3

CD19/4-1BB/CD3

Median CAR-T persistance

14 days (7–138) 90 days 168 days (20–617)

Relapse rate 25/41 (61%) 18/40 (45%) 22/61 (36%)

% of CD19- relapse 4/25 (16%) 7/18 (40%) 15/16* (94%)

The rate of CD19-negative relapseincreases with CAR-T persistence

Hay KA, et al. Blood 2019; doi: 10.1182/blood-2018-11-883710 [Epub].

* Patients with known CD19 status at relapse among 22 relapses

Conclusion

• Avant l’ère des immunothérapies, 2 progrès thérapeutiques en 20 ans :• L’intensification “pediatric-like” des chimiothérapies

• La combinaison de la chimiothérapie aux ITK (Ph+)

• Deux outils majeurs dans la stratification : • Génétique de la tumeur

• MRD

• Intensification des chimiothérapies limitée par l’âge

• L’avenir :• Identification de nouveaux oncogènes cibles (ITK)

• Combinaison des approches conventionnelles avec les immunostratégies(comment et pour quelle toxicité ?)