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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
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