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Treatment of Philadelphia Chromosome positive
Acute Lymphoblastic Leukemia- Korean Persepectives
Young Rok Do, MD, Ph.DDepartment of Hematology-Oncology,
Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
I have no personal or financial interests to declare:
I have no financial support from an industry source at the current presentation.
대한혈액학회 Korean Society of Hematology
COI disclosureName of author : Young Rok Do
Table of Contents
• Incidence of Korean Lymphoid Malignancy• Current Tx Standard of International Guideline• Korean Treatment Outcome including HSCT• New agent for Ph’ALL• Summary
Nationwide Statistical Analysis of Lymphoid Malignancies in Korea
Lymphoid malignancies in Korea
Fig. Incident cases of lymphoid malignancies by age group in Korea, 2012. NK, natural killer. a)All lymphoid malignancies include one case of composite Hodgkin’s and non-Hodgkin’s lymphoma.
Precursor cell neoplasms• Lymphoblastic lymphoma• Lymphoblastic leukemia
Lee H, et al. Cancer Res Treat. 2018 Jan;50(1):222-238.
Trend in relative survival rate of lymphoid malignances between
1993 and 2012 in Korea
Current Tx Standard of International Guideline
I
Study N Age,y
CTintensity
CR, %(CMR)
HCT inCR1, %
DFS/OS,% (y)
MDACCBlood’04, Haematol’15
54 51 Intensive 93 (45) 30 43/43 (5)
JALSGJCO’06, Ann Hematol’18
99 45 Intensive 97 (72) 61 43/50 (5)
CMC, KoreaBlood’05, Leukemia’12
118 36 Intensive 92 (28) 78 62/64 (5): HCT
GMALLBlood’06
4745
4641
Intensive NR (19)95 (52)
7787
52/36 (2)61/43 (2)
GRAALLBlood’07, BBMT’13
45 45 Intensive 96 (29) 76 44/52 (4)
NILGJCO’10
59 45 Intensive 92 (29) 63 39/38 (5)
MRC/ECOGBlood’14
175 42 Intensive 92 (NR) 46 33/38 (4)
GRAALLBlood’15
268 47 Low v Intensive Intensive
95 (26) 60 37/46 (5)
GIMEMA (0904)Haematol’16
51 46 CT-free Intensive
96 (NR) 39 46/49 (5)
Prospective Trials using Imatinibin Front-line Treatment
Imatinib (n=175) v Pre-imatinib (n=266): MRC/ECOG (med. follow-up, 4 y)
CR: 92% (Imatinib) v 82% (Pre-imatinib), P=0.004HCT in CR1: 46% (Imatinib) v 31% (Pre-imatinib), P<0.01
Fielding AK, et al. Blood. 2014;123:843.
Imatinib v Pre-imatinib in HCT cohort
Mizuta S, et al. Blood. 2014;123:2325.
JSHCT: Imatinib (n=542)v Pre-imatinib (n=196)
Lee S, et al. Blood. 2005;105:3449.Lee S, et al. Leukemia. 2012;26:2367.
Median follow-up, 5 y
Imatinib group
Pre-imatinib group
P<0.001
CMC: Imatinib (n=95) v Pre-imatinib (n=33)
Median follow-up, 4 y
Imatinib + low v intensive induction CT Intensive CT ± HCT: GRAALL (n=268; med. follow-up, 4.8 y)
Chalandon Y, et al. Blood. 2015;125:3711.
Low (VD) v Intensive (H-CVAD) induction CT Intensive (H-CVAD)Primary end point: MMR (BM BCR-ABL1/ABL1 ≤0.1%) after cycle 2
All patients(n=268)
Low-intensity(n=135)
Intensive(n=133)
P
Age, y (range) 47 (18-59) 48.6 (18-59) 45 (21-59) 0.31CR, n (%) 254 (94.8) 133 (98.5) 121 (91.0) 0.006Early deaths, n (%) 10 (3.7) 1 (0.7) 9 (6.7) 0.01MMR, n (%)
After cycle 1 96/217 (44.2) 50/116 (43.1) 46/101 (45.5) 0.78After cycle 2 134/205 (65.4) 74/112 (66.1) 60/93 (64.5) 0.88
CMR, n (%)After cycle 1 21/217 (9.7) 11/116 (9.5) 10/101 (9.9) 0.99After cycle 2 53/205 (25.8) 32/112 (28.6) 21/93 (22.6) 0.34
Allo-HCT in CR1, n (%) 161 (60.1) 82 (60.7) 79 (59.4) 0.53
Chalandon Y, et al. Blood. 2015;125:3711.
EFS OS
Low-intensity induction CT: 42% at 5 y
Intensive induction CT: 32% at 5 y
Low-intensity induction CT: 48% at 5 y
Intensive induction CT: 43% at 5 y
P=0.13 P=0.37
RFS OS
P=0.036 P=0.020No allo-HCT in CR1 No allo-HCT in CR1
Allo-HCT in CR1 Allo-HCT in CR1
Reference N Age,y
TKI CTintensity
CR, %(CMR)
HCT inCR1,%
DFS/OS,% (y)
MDACCBlood’10, Cancer’15
72 55 Das Intensive 96 (65) 17 44/46 (5)
US intergroupBlood Adv’16
94 44 Das Intensive 88 (NR) 44 62/69 (3)
Korea, multicenterAnn Oncol’16
51 46 Das Intensive 98 (45) 77 52/51 (5)
GIMEMA (1205)Blood’11
53 54 Das CT Free 100 (15) 34 51/69 (2)
GIMEMA (1509)ASH’15
60 42 Das CT-free Intensive(no CMR)
97 (19) 37 49/58 (3)
EWALLBlood’16
71 69 Das Low 96 (24) 10 28/36 (5)
Korea, multicenterBlood’15
90 47 Nil Intensive 91 (77;PB)
63 72/72 (2)
MDACCLancet Oncol’15, ASCO’17
64 48 Pon Intensive 100 (77) 16 79/76 (3)
GIMEMA (1811)ASH’17
42 68 Pon CT-free 91 (61) NR NR/88 (1)
Prospective Trials using More Potent TKIsin Front-line Treatment
Median age: 55 (21-80) yDas: 100 mg/d (cycles 1~8/maintenance; post-HCT prophylaxis)CR: 96%, MMR + CMR: 37% (CMR: 20%) after cycle 1 MMR + CMR: 93% (CMR: 65%) during consolidation HCT in CR1: 17%
Ravandi F, et al. Cancer. 2015;121:4158.
Dasatinib + intensive CT : MDACC (n=72; med. follow-up, 5.6 y)
DFS at 5 y: 46% OS at 5 y: 46%
RFS at 3 y: 62% OS at 3 y: 69%
Ravandi F, et al. Blood Adv. 2016;1:250.
Median age: 44 (20-60) yDas: 10070 mg/d (cycles 1~8/maintenance; post-HCT prophylaxis) CR: 88% after cycle 1 (MRD response: not reported) HCT in CR1: 44%
Dasatinib + intensive CT : US intergroup (n=94; med. follow-up, 3 y)
Median age: 46 (19-64) yDas: 100 mg/d (cycles 1~4/maintenance; no post-HCT prophylaxis)CR: 98%, MMR + CMR: 49% (CMR: 18%) after cycle 1 MMR + CMR: 78% (CMR: 45%) after cycle 2HCT in CR1: 77%
Dasatinib + intensive CT : Korea, multicenter (n=51; med. follow-up, 4.5 y)
Yoon JH, et al. Ann Oncol. 2016;27:1081.
Median age: 69 (59-83) yInduction (Das 140 + VD) Consolidation (Das 100 + MTX-Asp [C1,3,5]↔AraC [C2,4,6]) Maintenance (Das 100 + POMP)CR: 96%, MMR + CMR: 60% (CMR: 20%) after induction MMR + CMR: 65% (CMR: 24%) during consolidation
Rousselot P, et al. Blood. 2016;128:774.
OS: 36% at 5 y RFS: 28% at 5 y
Dasatinib + low-intensity CT (≥55 y): EWALL (n=71; med. follow-up, 5.5 y)
II
Chiaretti S, et al. ASH. 2015. Abstract 81.
Median age: 42 (19-59) yDas: 140 mg/d (until D+84 with Pd) Das for 6 mo (CMR) v CT ± HCT (no CMR; HCT in CR1: 37%)CR: 97%, CMR: 19% at D+85DFS at 3 y: 49%, OS at 3 y: 58%
DFS by CMR after induction
CMR: 78.8%
No CMR: 44.2%
P=0.05
1.0
0.8
0.6
0.4
0.2
00 10 20 30 40
Months from CR
Prop
ortio
n al
ive
and
dise
ase-
free
CT-free induction with dasatinibMRD-based Tx: GIMEMA 1509 (n=60; med. follow-up, 2.3 y)
Median age: 48 (21-80) yPon: 45 mg/d (cycle 1) 30 mg/d (cycle 2~) 15 mg/d (CMR)CR: 100%, MMR + CMR: 97% (CMR: 77%, Time-to-CMR: 10 wk)HCT in CR1: 16%, 3-y CRD: 79%, 3-y OS: 76%No grade ≥3 vascular events occurred after protocol amendment
Jabbour E, et al. Lancet Oncol. 2015;16:1547.Short NJ, et al. ASCO. 2017. Abstract 7013.
Frac
tion
CR
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60
Months
P=0.36
HCT (n=10): 88%
No HCT (n=35): 75%
Frac
tion
Surv
ival
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60
Months
P=0.81
HCT (n=10): 79%
No HCT (n=35): 86%
Landmark analysis at 4 months by HCT
Updated results of ponatinib + intensive CT : MDACC (n=64; med. follow-up, 33 mo)
Median age: 68 (27-85) y Pon: 45 mg/d for up to 48 weeksSteroids given day-14 to day+29 of course 1
CT-free ponatinib + steroids: GIMEMA 1811 (n=42; med. follow-up, 11.4 mo)
Response Ponatinib + SteroidsComplete hematologic response, n/N (%)
at 6 wkat 24 wk
40/42 (95.2)38/42 (90.5)
CMR at 24 wk, n/N (%)* 20/33 (60.6)OS at 6 mo, % (95% CI) 97.6 (93.1-100)OS at 1 y, % (95% CI) 87.5 (76.5-99.9)
Martinelli G, et al. ASH. 2017. Abstract 99.
Meta-Analysis Results
Outcomes Imatinib & 2G TKIs(25 studies)
Ponatinib(1 study)
All(26 studies)
CMR, % (95% CI) 32 (25-40) 79 (66-89) 34 (26-43)OS at 2 y, % (95% CI) 58 (53-63) 83 (70-92) 59 (53-65)OS at 3 y, % (95% CI) 50 (42-58) 79 (66-89) 52 (43-60)
Meta-regression OR 95% CI PPonatinib v Others
CMR 6.09 1.16-31.90 0.034OS at 3 y 4.49 1.00-20.13 0.050
Ponatinib v ImatinibOS at 3 y 5.21 1.19-22.78 0.031
Ponatinib v 2G TKIsOS at 3 y 2.99 0.62-14.51 0.159
Jabbour E, et al. Clin Lymphoma Myeloma Leuk. 2018;18:257.
Rituximab plus Multiagent Chemotherapy for Newly Diagnosed CD20-positive ALL:
Final Results of Prospective Multicenter Phase II Study (RADICAL; KALLA0804) by Korean Adult ALL Working Party
Data were frozen up in May 2017
44%, Ph(+)
GRAALL. BBMT. 2013;19:1150.
MRDneg
MRDlow
MRDhighP=0.014
MDACC. Haematol. 2015;100:653.
GIMEMA. Haematol. 2016;101:1544.
EWALL. Blood. 2016;128:774
Prognostic Factors: MRD
Yoon JH, et al. Ann Oncol. 2016;27:1081.
RQ-PCR using BM (central): BCR-ABL1/ABL1 (4.5-log sensitivity)MMR: ≤0.1%IS (p210BCR-ABL1) or ≥3 log ⇓ (p190BCR-ABL1)Imatinib + HCT (n=95; med. follow-up, 5 y)Dasatinib ± HCT (n=51; med. follow-up, 4.5 y)
Impact of early-persistent deep MRD response: CMC (Imatinib) and Korea-multicenter (Dasatinib)
Late molecular responders: 64.2±8.4% (event=12/35)
Poor molecular responders: 25.0±8.5% (event=21/27)
Early-stable molecular responders: 87.8±5.7% (event=4/33)
Lee S, et al. Leukemia. 2012;26:2367.
Short NJ, et al. Blood. 2016;128:504.
at CR at 3 mo
at CR at 3 mo
Impact of CMR on TKI + CT outcomes without HCT: MDACC (n=85; 23 Ima, 39 Das, 23 Pon)
Treatment of Rel Ph’ALL
III
Outcomes With Inotuzumab Ozogamicin in Patients With Philadelphia Chromosome–Positive Relapsed/RefractoryAcute Lymphoblastic Leukemia
1University of Chicago, Chicago, IL, USA; 2Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola (FC), Italy; 3Universitätsklinikum Münster, Münster, Germany; 4Dana-Farber Cancer Institute, Boston, MA, USA; 5Goethe University, Frankfurt, Germany; 6Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 7University of California, Irvine Medical Center, Orange, CA, USA; 8Stanford Cancer Institute, Stanford, CA, USA; 9University of Southern California, Los Angeles, CA, USA; 10University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 11Pfizer Inc, Groton, CT, USA; 12Pfizer Inc, Shanghai, China; 13Pfizer Inc, Cambridge, MA, USA; 14University Hospitals Bristol, Bristol, UK; 15University of Texas MD Anderson Cancer Center, Houston, TX, USA
Wendy Stock1, Giovanni Martinelli2, Matthias Stelljes3, Daniel J DeAngelo4, Nicola Gökbuget5, Anjali Advani6, Susan O’Brien7, Michaela Liedtke8, Akil Merchant9, Ryan Cassaday10, Tao Wang11, Hui Zhang12, Erik Vandendries13, David I Marks14, Hagop Kantarjian15
Poster #7073; American Society of Clinical Oncology (ASCO) Annual Meeting, June 1–5, 2018; Chicago, Illinois
Efficacy Endpoints in Ph+ Patients
39
CI=confidence interval; CR/CRi=complete remission/complete remission with incomplete hematologic recovery; HSCT= hematopoietic stem cell transplant; InO=inotuzumab ozogamicin; MRD=minimal residual disease; Ph=Philadelphia chromosome; SC=standard chemotherapy
Study 1022 Study 1010
Efficacy EndpointsInO
n=22SC
n=27InO
n=16
CR/CRi, % (95% CI) 72.7 (49.8–89.3) 55.6 (35.3–74.5) 56.3 (29.9–80.3)
MRD negativity, % (95% CI) 63.6 (40.7–82.2) 18.5 (6.3–38.1) 62.5 (35.4–84.8)
HSCT• In study 1022, patients in the InO group were ~2 times more likely to proceed to
HSCT vs patients in the SC group– 9 (41%) InO vs 5 (19%) SC patients
• In study 1010, 3 (19%) InO patients proceeded to HSCT
Conclusions
• Among Ph+ patients in the INO-VATE trial (study 1022), those in the InO arm (vs SC) had:
– Higher rate of CR/CRi– Higher rate of MRD negativity– Higher rate of subsequent HSCT– Similar PFS and OS
• InO is an important treatment option for patients with R/R Ph+ ALL for whom prior TKIs have failed
40
ALL=acute lymphoblastic leukemia; CR/CRi=complete remission/complete remission with incomplete hematologic recovery; HSCT=hematopoietic stem cell transplant; InO=inotuzumab ozogamicin; MRD=minimal residual disease; OS=overall survival; PFS=progression-free survival; Ph=Philadelphia chromosome; R/R=relapsed/refractory; TKI=tyrosine kinase inhibitor; SC=standard chemotherapy
New Agent
• Blinatumomab; salvage Tx for ALL-insurance reimbursement(Ph(-) ALL),-only approval Ph’ ALL
• Inotuzumab; in HIRA process
IV
Efficacy and safety of blinatumomab treatment in adult Korean patients with RelRef ALLon behalf of the KSH ALL Working Party
Between Jun. 2016 and Aug. 2017 in Korea
CR+CRi 44.9%EFS 7.5moOS 8.1mo
Ann Hematol .2019.98:151–8
Proposed therapeutic algorithm for standard treatment of Ph’ ALL
Ther Adv Hematol. 2018, 9(12) 357–68
Allogeneic HSCT
Summary
• TKI(1st/2nd/3rd Gen) has improved the outcomes of Ph-positive ALL dramatically
• Earlier-more prolonged use of TKI better outcomes• CR can be induced without intensive induction CT• MRD useful for risk stratification & guiding treatment
approach, trying to set up in Korea• Mab is available, CART not now
Open Issues
• Optimal CT regimen & intensity in the TKI era?->More potent TKI induce faster & deeper MRD response
• Survival advantage of more potent TKI? (no direct comparisons)->Further validation
• Deep MRD and genomic data-based decision for sparing HCT?-> role of alloHSCT in Ph+ ALL, esp. in deep MR
• Development of new therapeutic approaches• Combination of highly active targeted agents (e.g., potent TKI
+ MoAb or immunotherapy)
Relapse incidence
Brissot E, et al. Haematologica. 2015 Mar;100(3):392-9.
At 5 years, In univariate analysis, the cumulative incidence of Relapse Incidence(RI) in the group of patients with TKIs before allo-SCT was 33% (95%CI: 28-38) versus 50% (95%CI: 38-60) in the group with no TKIs before transplant (P=0.006)
Allo SCT for adult patients with Ph+ALL
P=0.006
Inotuzumab vs. Standard Therapy for RelRef ALL
• Primary End Point; CR, CRh, OS
• Result;
Inotuzumab Std. Tx
CR 80.1% 29.4%
MRD 78.4% 28.1%
NEJM 2016; 375:740-753