Management of Ph-positive and Ph-like ALL in 2020

Elias Jabbour, M.D.MD Anderson Cancer CenterUniversity of TexasHouston, Texas

Conflict of Interest Disclosure

• Research Grants• Pfizer, Takeda, Amgen, Abbvie, Novartis

• Consultancy and advisory roles• Pfizer, Takeda, Amgen, Abbvie, BMS

Survival of 39,697 Children With ALL Treated on Sequential CCG/COG Clinical Trials

Hunger. N Engl J Med. 2015;373(16):1541-1552

Survival of 972 Adults with Ph-negative ALL

4

• 972 pts Rx 1980-2016; median F/U 10.4 years

Sasaki. Blood 2016; 128:3975

16%

44%

28%

Reasons Why Pediatric ALL Does Better Than Adult ALL

Entity Prognosis % Pediatric % AdultHyperdiploid Favorable 25-30 5

t(12;21),ETV6-RUNX1

Favorable 20-25 2

Ph+ALL Unfavorable 5 25

Ph-like ALL Unfavorable 10 25

2016 WHO Classification

Arber. Blood 2016;127(20):2391-405

Ph-like ALL Occurs in 25-30% of Young Adults with B-cell ALL

Roberts et al. N Engl J Med. 2014

11.9%20.6%

27.4%

Recurring Kinase Alterations in Ph-like ALL

Roberts. N Engl J Med 2014;371:1005-1015

Ph-Like ALL-- Survival and EFS

Roberts, et al. JCO 35:394; 2017

Ph-like ALL Molecular Lesions

Ph-like ALL

JAK2 (JAK2R683) JAK1 Mutations

CRLF2 Overexpression Non-CRLF2 cases80% 20%

50%Fusions – ABL1, ABL2, JAK2, EPOR, PDGFRB

Mutations – IL7R, FLT3, RAS

Add MoAb/BCL-2 inhibitor

• Ph-like 25-30% of ALL; poor prognosis

Add TKI if ABL fusionsMoAb/BCL-2 inhibitor

BCR-ABL TKIs + Chemo Rx in Ph-like ALL• 24 pts with Ph-like ALL: NUP214-ABL1-- 6, ETV6-ABL1-- 3, others --

9. 19 frontline; 5 relapse.All Rx with chemo Rx + TKI

Tanasi. Blood 134: 1351; 2019

Ph-like ALL. Higher MRD + RateB-ALL Categories (N=155)

Ph-Like Ph+ B-other p-value

N 56 46 53

CR/CRp 50 (89) 43 (93) 50 (94) 0.57

MRD at CR

Positive 23 (70) 15 (44) 4 (13) <0.001Negative 10 (30) 19 (56) 27(87)

Jain. Blood 2017; 129:572-581

2 31 4 5 6 7

Hyper-CVAD

MTX-ara-C

Ofatumumab

IT MTX, ara-C

Intensive phase

Maintenance phase

POMP

1-5 6 7 8-17 18 19 12-24

MTX-Peg asp

20-301-5 8-1719

2 3 4 5 8

6 18

HCVAD + Ofatumumab: Design

Richard-Carpentier. Blood 134 : Abst 2577; 2019

HCVAD + OfatumumabPatient Characteristics (N=69)

Parameter (N=69) N (%)/ Median [range]

Age (yrs) 41 [18-71]

≥ 40 36 (52)

Sex Male 40 (58)

PS 0-1 62 (90)

WBC (x 109/L) 4.3 [0.6-201.7]

CNS + 2 (3)

CD20 + (%) 1-10 16 (24)

10-20 7 (10)

>20 43 (63)

Pos 2 (3)

TP53 mutation Pos 11/43 (26)

Ph-like CRLF2 10/37 (27)

RNA-seq 7/27 (26)

CG Diploid 24 (35)

Complex 27 (39)

Misc 9 (13)

IM/ND 9 (13)

Richard-Carpentier. Blood 134 : Abst 2577; 2019

HCVAD + Ofatumumab. Outcome (N=69)

• Median follow up of 44 months (4-91)• CR 98%, MRD negativity 93% (at CR 63%), early death 2%

0 12 24 36 48 60 72 84 960.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Fra

cti

on

su

rviv

al

Complete Remission Duration

Overall Survival

Total Fail 3 yr68

69

21

23

75%

68%

0 12 24 36 48 60 72 84 960.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Fra

ctio

n s

urv

ival

<40

>40p=0.40

Total Fail 3yr OS33

36

9

14

74%

63%

CRD and OS Overall OS by Age

Richard-Carpentier. Blood 134 : Abst 2577; 2019

Hyper-CVAD + OfatumumabMolecular Alterations and outcome

Richard-Carpentier. Blood 134 : Abst 2577; 2019

Hyper-CVAD + Blinatumomab in B-ALL (Ph-negative B-ALL < 60 years). Treatment schedule

1

Hyper-CVADMTX-Ara-C

Ofatumumab or Rituximab 8 x IT MTX, Ara-C

Intensive phase

Maintenance phase

POMPBlinatumomab

1-3

2 3 4

Blinatumomab phase*After 2 cycles of chemo for Ho-Tr, Ph-like, t(4;11)

1 2 3 4

4 wk 2 wk

5-7 9-11 12 13-1584

Richard-Carpentier. Blood 134: abst 3807; 2019

Hyper-CVAD + Blinatumomab in FL B-ALL. (N=31)

0 6 12 18 24 30 360.0

0.2

0.4

0.6

0.8

1.0

Months

Fra

cti

on

su

rviv

al

Overall Survival

Complete Remission Duration

Total Event 1yr31

29

2

5

92%

81%

0 12 24 36 48 60 72 84 96 1080.0

0.2

0.4

0.6

0.8

1.0

Months

Fra

cti

on

su

rviv

al

HCVAD+Blina+Ofa or Rtx

HCVAD+Ofa

Total Events 1yr OS69

31

26

2

92%

90%

• CR 100%, MRD negativity 97% (at CR 85%), early death 0%

CRD and OS Overall OS. HCVAD-Blina vs O-HCVAD

Richard-Carpentier. Blood 134: abst 3807; 2019

Hyper-CVAD + Inotuzmab + Blinatumomab in B-ALL (Ph-negative B-ALL < 60 years)

1

Hyper-CVADMTX-Ara-C

Rituximab or OfatumumabIT MTX, Ara-C

Intensive phase

Maintenance phase

POMPBlinatumomab

2 3 4 1 2 3 4

4 wk 2 wk

Inotuzumab 0.3 mg/m2 on D1 and D8

Blinatumomab phase*After 2 cycles of chemo for Ho-Tr, Ph-like, t(4;11)

1-3 5-7 9-11 12 13-1584

Ph-like ALL. Summary and Future Directions

• Ph-like 25-30% of ALL; poor prognosis• 50-80% have CRLF2 rearrangement, of

which 50% have JAK mutations• ABL and JAK fusions in CRLF2 non-

rearranged cases • FISH and RT-PCR identifies fusions• Plans: add TKI if ABL fusions, and

antibodies/venetoclax if CRLF2+, to frontline and salvage ALL

TKI for Ph+ ALLImatinib; 5-yr OS=43% Dasatinib; 5-yr OS=46% Ponatinib; 5-yr OS=71%

Daver, Haematologica 2015; Ravandi, Cancer 2015; Jabbour, Lancet Onc 2015; Jabbour, Lancet Hematology 2018

Low-intensity chemo Rx + Dasatinib in Ph + ALL ≥ 55 yrs

• 71 pts (2007-2010); median age 69 yrs (58-83)• Dasatinib 100-140 mg/D, VCR 1mg Q wk, Dex

20-40 mg/D x 2, Qwk• Consolidations: dasatinib 100 mg/D; MTX-Asp

C1,3,5; ara-C C2,4,6. Maintenance: dasatinib + POMP

• CR 96%; MMR 65%; CMR 24%• 5-yr survival 36%; EFS 25%• T315I at Dx 23% by NGS• 36 relapses; T315I in 75%

Rousselot. Blood 2016;128(6):774-82

Hyper-CVAD + Ponatinib in Ph+ ALL. Modified

2 3 1 4 5 6 7 8

24 months

Hyper-CVADMTX/cytarabine

Ponatinib 45 mg →30 mg →15 mgVincristine + prednisone

Maintenance phase

Intensive phase

IT CNS prophylaxis x 12 dosesRituximab x 8 doses if CD20+

Jabbour. Lancet Onc. 16:1547;2015. Jabbour. Lancet Hematology 2018. Short. Blood 134: Abt 283; 2019

Hyper-CVAD + Ponatinib in Ph+ ALL. Response Rates

Response n/N (%)CR* 68/68 (100)CCyR^ 58/58 (100)MMR# 83/85 (98)CMR# 73/85 (86)Flow negativity# 83/85 (95)Early death 0

* 18 pts in CR at start^ 28 pts diploid/IM at start# 1 pt no sample

Hyper-CVAD + Ponatinib in Ph+ ALL. EFS and OS

0 12 24 36 48 60 72 84 960.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Frac

tion s

urviv

al

Total Events 3-year rate 5-year rate

86 26 68%Event-Free Survival

Overall Survival 86 20 74%

71%

78%

Median follow-up: 44 months (4-94 months)

Short. Blood 134 : Abst 283; 2019

Hyper-CVAD + Ponatinib in Ph+ ALL. Impact of SCT (6-Month Landmark)

19 pts (22%) underwent SCT in first remission

0 12 24 36 48 60 72 84 960.0

0.2

0.4

0.6

0.8

1.0

Time (months)

Frac

tion

surv

ival

Total Events 3-year rate 5-year rate

19 6 66%SCT

No SCT 60 8 83%

66%

90%P=0.07

Propensity Score Analysis: HCVAD + Ponatinib vs HCVAD + Dasatinib in Ph-Positive ALL.

Sasaki. Cancer. 2016; 122(23):3650-3656

Event free survival / Overall survival (Entire cohort, N=107)

0.1 1 10

TKI type, ponatinibanti-CD20 mAb therapy

VPREB1 delPAX5 del

IKZF1(exon4-7) delIKZF1 del

CDKN2A2B delWBC, high

Sex, femaleAYA, age<40

Overall survival

Hazard ratio and 95% CI

0.3309 (0.1703-0.6427)1.345 (0.7382-2.45)2.145 (1.166-3.945)1.45 (0.7328-2.869)2.049 (1.107-3.792)1.694 (0.8978-3.197)1.181 (0.5842-2.389)1.246 (0.7027-2.211)0.7494 (0.4194-1.339)0.9522 (0.4723-1.92)

Hazard ratio (95% CI)

0.0010950.3330.014080.28590.022390.10370.64270.45130.32990.8911

p.valueUnivariate analysis

0.3959 (0.1894-0.8274)

0.8493 (0.3956-1.823)

Hazard ratio (95% CI)

0.01375

0.6753

p.valueMultivariate analysis

0.2918 (0.1385-0.6149)1.625 (0.8674-3.045)1.954 (1.019-3.749)1.664 (0.8268-3.35)2.517 (1.281-4.945)1.948 (0.9659-3.927)1.236 (0.5864-2.606)1.098 (0.5942-2.028)0.6641 (0.3539-1.246)0.7735 (0.3562-1.679)

Hazard ratio (95% CI)

0.00120.12960.043890.15360.0073920.062450.57750.76550.20250.5161

p.valueUnivariate analysis

0.3491 (0.1482-0.8223)

0.5868 (0.2487-1.384)

Hazard ratio (95% CI)

0.01606

0.6136 (0.3106-1.212) 0.15960.2234

p.valueMultivariate analysis

1.875 (0.923-3.81) 0.08213

1.597 (0.8075-3.157) 0.1785

0.1 1 10

TKI type, ponatinibanti-CD20 mAb therapy

VPREB1 delPAX5 del

IKZF1(exon4-7) delIKZF1 del

CDKN2A2B delWBC, high

Sex, femaleAYA, age<40

Event free survival

Hazard ratio and 95% CI

0.7017 (0.3761-1.309) 0.2657

1.67 (0.8854-3.149) 0.1132

IT x8 vs. ITx12 in Ph+ ALL6M Landmark: CNS Relapse-free Survival

Paul. Blood 134 : Abst 3810; 2019

Two Evolving Strategies to Treat Ph-positive ALL

Parameter Hyper-CVAD+Ponatinib

TKIs with minimal ChemoRx

% CR 90-100 90-100

% CMR 80 20

Allo-SCT required Only if no CMR In all

Outcome p190 vs p210

Same P190 better

%3-yr survival/DFS

70-80 40-50

Jabbour. Lancet Oncology 16: 1547; 2015. Chiaretti, Blood 126: abst 81, 2015

Blinatumomab and Inotuzumab in R-R Ph-positive ALL

Parameter Blinatumomab InotuzumabNo. Rx 45 38No. CR/marrow CR (%)

16 (36) 25 (66)

% MRD negative in CR

88 63

Median OS (mos) 7.1 8.1

% later allo SCT 44 32

Martinelli. JCO 35: 1795; 2017. Stock. Proceedings ASCO 2018

Dasatinib-blinatumomab in Ph-positive ALL

• 63 pts, median age 54 yrs (24-82)• Dasatinib 140mg/D x 3 mos ; add blinatumomab x 2-5 • 53 post dasa-blina x 2--molecular response 32/53 (60%), 22 CMR (41%) . MRD

↑ in 15— 6 T315I;12-mos OS 96%; DFS 92%

Chiaretti. Blood 134; abst 615; 2019

OS DFS89.7% (95% CI: 82.3-97.9)95.2% (95% CI: 90.1-100)

D-ALBA: ABL1 mutational screeningPerformed by Sanger sequencing, in case of MRD increase (n = 15)

Num

ber o

f cas

esAll mutations but 1

occurred in p190 cases

Blinatumomab treatment was effective in reducing MRD levels also in mutated cases

7(47%)8

(53%)

Mutated

WT6

1T315I

E255K

01234567

Day 85/pre-I cycle ofblinatumomab

Pre-II cycle of blinatumomab

Blinatumomab-ponatinib in Ph-Positive ALL

IT MTX, Ara-C

Induction phase

Maintenance phase

Ponatinib 30 mgBlinatumomab

Consolidation phase: C2-C5

1

4 wk 2 wk 4 wk 2 wk

Ponatinib 15 mg

15 mg for 5 years

30 mg 15 mg in CMR

2

Assi. Clin Lymphoma Myeloma Leuk. 2017;17(12):897-901

Blinatumomab + PonatinibSwimmer Plot (N=15)

2 3 1 4

30

30/15

16 months

Mini-Hyper-CVDMini-MTX-cytarabine Vincristine + prednisone

Maintenance phase

Intensive phase

CNS prophylaxis (N=12)

30/15

30/15

3 4

4 wk 2 wk

4 8 125 years

Blinatumomab

Ponatinib 30 mg →15 mg

1 2

Hyper-CVD + Ponatinib + Blinatumomab in Ph-positive ALL

CMR in Ph-Positive ALL. OS for CMR vs. others

HR 0.42 (95% CI 0.21-0.82)

At CR At 3 months

• MVA for OSCMR at 3 months (HR 0.42 [95% CI 0.21-0.82], P=0.01)

Short. Blood. 2016;128(4):504-7

Outcome of 3-month CMR by TKI. PFS OS

• MVA for OutcomePonatinib only predictive factor for PFS (HR=0.39; P=0.03) and OS (HR=0.38; P=0.04)

Sasaki. Blood 134 : Abst 1296; 2019

Indications for HSCT. Ph+ ALL

MRD– MRD+

Chemotherapy + TKI Or

Blinatumomab + TKI

MRD assessment (within 3 months)

Blinatumomab+ TKI

HSCT + maintenance TKI

Blinatumomab+ TKI x 2-4 cycles

≤ 3 logs > 3 logs

Short. Blood. 2016;128(4):504-7; Sasaki. Blood 134 : Abst 1296; 2019; Samra. Blood 134 : Abst 1296; 2019

40

Questions in Ph-positive ALL• Do we need allo SCT? --not always; never?– Identify patients who can be cured without allo-SCT; e.g.

3-mos CMR, others

• Ponatinib best TKI?-- 3 mos-CMR 86%; 5-year OS rate 74%– Phase III low-dose CT + Imatinib vs low-dose CT +

ponatinib

• How much chemoRx-- low-Intensity versus intensive chemo Rx?–Mini-HCVD-Ponatinib-Blinatumomab

• Can we cure Ph-positive ALL without chemoRx or allo SCT?--ponatinib+blinatumomab

• Duration of TKI maintenance–At least 5 years

41

Thank You