1. Understanding ALL the Therapeutic Options for Acute Lymphoblastic Leukemia
This activity is supported by an educational grant from Shire.
Friday Satellite Symposium preceding the 58th ASH Annual Meeting.

2. New Developments in Monoclonal Antibody–Based Therapies for ALL
Anthony Stein, MD
Professor of Hematology Co-Director Gehr Family Center for Leukemia
Division of Hematopoietic Stem Cell Transplantation
Department of Hematology
City of Hope
Duarte, California
ALL, acute lymphoblastic leukemia.

3. About These Slides
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Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

4. Faculty
Program Director: Hagop M. Kantarjian, MD Chairman, Department of Leukemia Professor of Medicine The University of Texas M. D. Anderson Cancer Center Houston, Texas Anthony Stein, MD Professor of Hematology Division of Hematopoietic Stem Cell Transplantation Department of Hematology City of Hope Duarte, California
Dan Douer, MD Division of Hematology Keck School of Medicine Los Angeles, California Renier J. Brentjens, MD Associate Professor, Department of Medicine Weill Medical College of Cornell University Associate Professor Department of Pharmacology Weill Cornell Graduate School of Medical Sciences Associate Attending Memorial Sloan Kettering Cancer Center New York, New York
This slide lists the faculty who were involved in the production of these slides.

5. Faculty Disclosures
Renier J. Brentjens, MD, has disclosed that he has a royalty relationship with, receipt of intellectual property rights/patent holder relationship with, has ownership interest in, and has received consulting fees from Juno Therapeutics. Dan Douer, MD, has disclosed that he has received consulting fees from Amgen, Baxalta, Gilead Sciences, and Pfizer and fees for non-CME/CE services from Jazz Pharmaceuticals. Hagop M. Kantarjian, MD, has no real or apparent conflicts of interest to report. Anthony Stein, MD, has disclosed that he has received consulting fees and fees for non-CME/CE services from Amgen and funds for research support from Amgen and Pfizer.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

6. Agenda Blinatumomab in ALL Antibody–drug conjugates
Relapsed/refractory B-precursor Ph-negative ALL
MRD-positive ALL
Ph-positive ALL
Management of treatment-related adverse events
Antibody–drug conjugates
Inotuzumab ozogamicin in ALL
Chemoimmunotherapy combination in ALL
ALL, acute lymphoblastic leukemia; MRD, minimal residual disease; Ph, Philadelphia chromosome.

7. Bidirectional Antibody: Blinatumomab

8. OS With and Without Censoring of CR/CRh
Phase II Trial: Blinatumomab for Relapsed/Refractory, B-Precursor, Ph- ALL
Multicenter, single-arm, open-label phase II study
OS With and Without Censoring of CR/CRh
Parameter, %
N = 189
Pts < 55 yrs of age 72
≥ 2 salvage therapies 39
Prior alloHSCT 34
≥ 50% BM blasts 69
CR/CRh within 2 cycles
Went to alloHSCT
Excluding prior alloHSCT 43 40 50
100
Censored at the Time of CR or CRh
Median OS, Mos N
95% CI 80
No Yes Censored 60
OS (%) 40
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow; CRh, CR with incomplete hematologic recovery; Ph, Philadelphia chromosome. 20 2 4 6 8 10 12 14 16 18 20
Blinatumomab FDA approved for Ph-negative R/R ALL December 3, 2014
Mos
Slide credit: clinicaloptions.com
Topp MS, et al. Lancet Oncol. 2015;16:57-66.

9. Characteristics of Pts in Blinatumomab-Induced CR/CRh Receiving alloHSCT (N = 81/189)
Subanalysis of phase II study of blinatumomab for R/R B-precursor, Ph- ALL
Characteristic
N = 34
Pts > 55 yrs of age, n (%)
6 (18)
≥ 2 salvage therapies, n (%)
8 (24)
Prior alloHSCT, n (%)
7 (21)
MRD-ve prior to alloHSCT, n (%)
26 (77)
Median cycles of blinatumomab before alloHSCT, n (range)
2 (1-5)
Median time from last blinatumomab dose to first conditioning regimen, days (range)
23 (8-60)
Characteristic, n (%)
N = 34
Conditioning regimen
Myeloablative
Reduced intensity
Unknown/unavailable
15 (44) 12 (35) 7 (21)
Donor type
Haploidentical
Sibling
Unrelated
Missing
1 (3) 7 (21) 23 (68) 3 (9)
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow; CRh, CR with partial hematologic recovery; MRD, minimal residual disease; Ph, Philadelphia chromosome; R/R, relapsed/refractory.
Slide credit: clinicaloptions.com
Stein A, et al. ASBMT Abstract 22.

10. Outcomes of Pts in Blinatumomab Responders Receiving alloHSCT
100
N = 34 80
Median RFS, mos 95% CI RFS events, n
Relapse
Death Pts censored, n
NE 5.3-NE 60
RFS (%) 40 20
Censored
12-mo estimate: 54.0% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Mos Since AlloHSCT
Median follow-up: 13.9 mos (range: )
100 80
N = 34 60
Median OS, mos 95% CI OS events, n Pts censored, n
NE 7.1-NE 12 22
alloHSCT, allogeneic hematopoietic stem cell transplantation; NE, not estimable; RFS, relapse-free survival.
OS (%) 40 20
Censored
12-mo estimate: 62.1% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Median follow-up: 13.4 mos (range: )
Mos Since AlloHSCT
Slide credit: clinicaloptions.com
Stein A, et al. ASBMT Abstract 22.

11. Mortality Within 100 Days After AlloHSCT
Cause of Death
n = 4
Days After AlloHSCT
Infection
Sepsis after alloHSCT
Sepsis
Heart, lung, and renal failure; septic shock; E coli bacteremia; sepsis 1 75 59 8
Graft-vs-host disease
Of skin and gut 42
alloHSCT, allogeneic hematopoietic stem cell transplantation.
Slide credit: clinicaloptions.com
Stein A, et al. ASBMT Abstract 22.

12. Blinatumomab: OS by Age
100
Median OS, Mos (95% CI) 5.5 ( ) 7.6 ( )
Median Follow-up, Mos (95% CI) 23.9 ( ) 17.9 ( ) 80
Aged ≥ 65 yrs Aged < 65 yrs 60
Probability of OS (%) 40 20 4 8 12 16 20 24 28 32 36 40
Mos
Pts at Risk, n Aged < 65 yrs Aged ≥ 65 yrs
225 36
141 23
95 14
59 10
40 6
23 5
14 2
8 2
2 2
1 2
0 1
Slide credit: clinicaloptions.com
Kantarjian HM, et al. Cancer. 2016;122:

13. Induction/Consolidation
Phase III TOWER: Blinatumomab in Relapsed/Refractory, B-Precursor, Ph- ALL
Multicenter, randomized, open-label phase III study
Induction/Consolidation
(2 cycles/3 cycles)
Maintenance
(≤ 12 mos)
Stratified by age, prior salvage,
prior alloHSCT
Blinatumomab CIV
9 µg/day x 1 wk,
28 µg/day x 3 wks (cycle 1) 28 µg/day x 4 wks (cycle 2)
(4 wks on, 2 wks off)
(n = 271)
Blinatumomab CIV
28 µg/day x 4 wks
(4 wks on, 8 wks off)
Adult pts with relapsed or refractory B-precursor, Ph- ALL*
(N = 405)
Follow-up
Standard Chemotherapy
Investigator’s choice†
(n = 134)
*Refractory to initial or salvage intensive combination chemotherapy; untreated first relapse in remission < 12 mos; untreated second or greater relapse; relapse any time after alloHSCT.
†Options include:
FLAG ± anthracycline-based regimen
HiDAC-based regimen
High-dose methotrexate–based regimen
Clofarabine-based regimens
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; CIV, continuous intravenous; FLAG, fludarabine, high-dose cytarabine, granulocyte colony-stimulating factor; HiDAC, high-dose cytarabine; Ph, Philadelphia chromosome.
Primary endpoint: OS
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

14. TOWER: Pt Characteristics
Baseline characteristics well balanced between treatment arms
Characteristic
Blinatumomab ITT
(n = 271)
SoC ITT
(n = 134)
Median age, yrs (range)
37 (18-80)
37 (18-78)
Bone marrow blasts, n (%)
> 5 to < 10%
10 to < 50%
≥ 50%
9 (3)
60 (22)
201 (74)
7 (5)
23 (17)
104 (78)
Peripheral blasts, n (%)
1-5000/μL
> 5000/μL
117 (43)
72 (27)
32 (12)
51 (38)
47 (35)
15 (11)
WBC at diagnosis, n (%)
< 30,000/μL
≥ 30,000/μL
143 (53)
71 (26)
62 (46)
40 (30)
ITT, intent to treat; SoC, standard of care; WBC, white blood cells.
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

15. TOWER: Prior Treatment
Prior treatment similar between blinatumomab and SoC arms
Characteristic, n (%)
Blinatumomab ITT
(n = 271)
SoC ITT
(n = 134)
Prior salvage regimens
None 1 2
≥ 3
114 (42)
91 (34)
45 (17)
21 (8)
65 (49)
43 (32)
16 (12)
10 (7)
Prior alloHSCT
94 (35)
46 (34)
Primary refractory
46 (17)
27 (20)
Refractory to salvage
87 (32)
34 (25)
alloHSCT, allogeneic hematopoietic stem cell transplantation; ITT, intent to treat; SoC, standard of care.
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

16. TOWER: Hematologic Response During Induction
100
Blinatumomab (n = 271) SoC (n = 134) 80
HR for EFS: 0.55 (95% CI: ; P < .001)
P < .001 60
Proportion of Pts (With Upper 95% CI)
P < .001 40
44%
34%
ANC, absolute neutrophil count; BM, bone marrow; CRh, CR with partial hematologic recovery; CRi, CR with incomplete blood count recovery; EFS, event-free survival; NED, no evidence of disease; PBCs, peripheral blood counts; SoC, standard of care. 20
25%
16%
Overall Response (CR/CRh/CRi) CR
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

17. TOWER: OS (Intent to Treat)
Median OS, Mos (95% CI)
Blinatumomab: 7.7 ( )
SoC: 4.0 ( )
Stratified log-rank P = .012
HR: 0.71 (95% CI: ) | | | |
1.0 | | | | | | | |
0.9 | | | | | | | | | |
0.8
0.7 | | | | | | | | | | | | | | | | | | | |
0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.5 | | | | | | | | | | | |
Survival Probability | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.3 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.2 | | | |
0.1
SoC, standard of care.
0.0
Pts at Risk, n
Blinatumomab
271
176
124 79 45 27 9 4
SoC
134 71 41 27 17 7 4 1 3 6 9 12 15 18 21 24 27
Mos
At 76% of events, the stratified log-rank test surpassed the O’Brien-Fleming boundary (P < .0194) to stop the study for benefit
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

18. TOWER: OS (Censoring for AlloHSCT)| | | |
1.0
Median OS, Mos (95% CI)
Blinatumomab: 6.9 ( )
SoC: 3.9 ( )
Stratified log-rank P = .004
HR: 0.66 ( ) | | | | | | | |
0.9 | | | | | | | | | | | | | |
0.8 | | | | | | | | | | | | | | | |
0.7 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.6 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Survival Probability
0.5 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.4 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
0.3 | | | | | | | | | | | | | | | | | | | | | |
0.2 | | | | | | | | | | | | | | | | | | | | | |
0.1
Pts at Risk, n
271
163 80 44 21 13 2
134 56 12 5 1
Blinatumomab
alloHSCT, allogeneic hematopoietic stem cell transplantation; ITT, intent to treat; SoC, standard of care
SoC 3 6 9 12 15 18 21 24 27
Mos
Blinatumomab (n = 271)
SoC (n = 134)
AlloHSCT postbaseline, n (%)
65 (24)
95% CI: 19-30
32 (24)
95% CI: 17-32)
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

19. TOWER: OS by Subgroup Subgroup Blinatumomab, n/N (%) SoC, n/N (%)
HR (95% CI)
Age
0.70 ( )
< 35 yrs
68/123 (55.3)
34/60 (56.7)
0.77 ( )
≥ 35 yrs
96/148 (64.9)
53/74 (71.6)
Prior salvage therapy
0.60 ( ) S0
53/114 (46.5)
39/65 (60.0)
0.59 ( ) S1
61/91 (67.0)
32/43 (74.4)
1.13 ( )
S2+
50/66 (75.8)
16/26 (61.5)
Prior alloHSCT
0.81 ( )
Yes
58/94 (61.7)
26/46 (56.5)
0.70 ( ) No
106/177 (59.9)
61/88 (69.3)
Baseline BM blasts
0.66 ( )
31/69 (44.9)
16/30 (53.3)
< 50%
alloHSCT, allogeneic hematopoietic stem cell transplantation; BM, bone marrow; NE, not estimable; SoC, standard of care.
0.78 ( )
132/201 (65.7)
71/104 (68.3)
≥ 50% NE
1/1 (100.0)
0/0 (0.0)
Unknown
0.71 ( )
Overall
164/271 (60.5)
87/134 (64.9)
*NE = not estimable.
0.1 1 10
Favors Blinatumomab
Favors SoC
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

20. TOWER: AEs AE Regardless of Causality, n (%) Blinatumomab (n = 267)
SoC
(n = 109)
Any AE
Grade 3 AE
Grade 4 AE
Grade 5/fatal AE
Grade 5 infection
263 (99)
98 (37)
82 (31)
51 (19)
30 (11)
108 (99)
33 (30)
48 (44)
19 (17)
13 (12)
Grade ≥ 3 AE of interest
Neutropenia
Infection
Neurologic event
Cytokine release syndrome
101 (38)
91 (34)
25 (9)
13 (5)
63 (58)
57 (52)
9 (8)
alloHSCT, allogeneic hematopoietic stem cell transplantation; AE, adverse event; SoC, standard of care.
*AEs occurring up to 30 days after last dose of protocol-specified therapy or before alloHSCT.
Slide credit: clinicaloptions.com
Topp MS, et al. EHA Abstract S149.

21. ALCANTARA: Pt Characteristics
All Pts (N = 45)
Median age (range), yrs
55 (23-78)
n/N* %
Cytogenetics and molecular analyses
Ph + other cytogenetic abnormalities
ABL kinase domain mutations
T35I mutation
22/38
17/37
10/37 58 46 27
Prior relapses
0 (primary refractory) 1 2
≥ 3
3/45
25/45
13/45
4/45 7 56 29 9
Characteristic
All Pts (N = 45)
n/N* %
Prior alloHSCT
20/45 44
Prior tyrosine kinase inhibitors
Imatinib
Dasatinib
Nilotinib
Ponatinib
45/45
25/45
39/45
16/45
23/45
100 56 87 36 51
Bone marrow blasts†
< 50%
≥ 50%
11/45
34/45 24 76
HSCT, hematopoietic stem cell transplantation; Ph, Philadelphia chromosome.
*Number of pts with evaluable data
†central review
Slide credit: clinicaloptions.com
Martinelli G, et al. ASH Abstract 679.

22. ALCANTARA: Blinatumomab for Relapsed/Refractory Ph+ ALL
Parameter (N = 45)
n/N
Response, %
Primary endpoint
CR/CRh (first 2 cycles)
T315l mutation
≥ 2 prior 2+-generation TKI
Prior ponatinib treatment
16/45
4/10
11/27
8/23 36 40 41 35
Secondary endpoints
Best response (first 2 cycles) CR
CRh
CRi (not including CRh)
14/45
2/45 31 4
Complete MRD response in pts with CR/CRh
MRD response in pts with ABL-kinase mutations
14/16
6/6 88
100
Pts in CR/CRh who proceeded to allogeneic HCT
4/16 25
ALL, acute lymphoblastic leukemia; CRh, CR with partial hematologic recovery; CRi, CR with incomplete blood count recovery; HCT, hematopoietic cell transplantation; MRD, minimal residual disease; NE, not estimable; Ph, Philadelphia chromosome; RFS, relapse-free survival; TKI, tyrosine kinase inhibitor.
Response to therapy was independent of T315Imutation
Slide credit: clinicaloptions.com
Martinelli G, et al. ASH Abstract 679.

23. ALCANTARA: Overall Survival
Median OS, mos
7.1
95% CI, mos
5.6-NE
1.0
0.8
Median follow-up: 8.8 mos
0.6
Survival Probability
0.4
0.2
NE, not estimable 2 4 6 8 10 12 14 16 18 20 22
Mos
Pts at Risk, n 4 5 4 3 4 2 4 1 1 8 3 1
Martinelli G, et al. ASH Abstract 679.

24. Case: Julia
40-yr-old pt with relapsed/refractory ALL has completed 1 cycle of blinatumomab and achieves a CR
No donor identified at start of cycle 2
On Day 2 of cycle 2 of 28-μg blinatumomab, pt is found to be aphasic
ALL, acute lymphoblastic leukemia.

25. Management of Treatment-Related Adverse Events

26. Blinatumomab: Boxed Warning Toxicities
Cytokine Release Syndrome
Systemic inflammatory response; ranges from mild to severe, life threatening
Can lead to vascular leak, fever, hypotension, respiratory and renal insufficiency, cytopenias, coagulopathy
Prophylaxis:
Dexamethasone prior to initiating therapy, when dose is increased, or during > 4-hr interruption
C1 step-up dose: 9μg/d D1-7; 28μg/d D8-28
Management:
Dexamethasone
Hold therapy and follow dose modifications
Tocilizumab (very rarely used)
CNS Toxicity
Can include delirium, confusion, global encephalopathy, aphasia, seizures or seizure-like effects
Prophylaxis:
Dexamethasone
Antiepileptics only in pts who experience seizure during therapy
Management:
Hold therapy and follow dose modifications
Antiepileptics as indicated
CNS, central nervous system; CRS, cytokine release syndrome.
Blinatumomab [package insert]. December Maude SL, et al. N Engl J Med. 2014;371: Benjamin JE, et al. Ther Adv Hematol. 2015;7: Lee KJ, et al. Ther Clin Risk Manag. 2016;12:
Slide credit: clinicaloptions.com

27. Antibody–Drug Conjugate: Inotuzumab Ozogamicin

28. Inotuzumab in Relapsed/Refractory ALL
MDACC phase II study: efficacy, tolerability of single-agent inotuzumab demonstrated in 90 pts with relapsed/refractory ALL
mg/m2 Day 1 (n = 49) or 0.8 mg/m2 Day 1, 0.5 mg/m2 Day 8, Day 15 (n = 41) Q3-4W
ORR: 58% (CR: 19%; CRp: 30%; CRi: 9%)
Improved safety with weekly schedule
17% of pts experienced SOS post-HSCT
ALL, acute lymphoblastic leukemia; CRi, CR with incomplete platelet and neutrophil recovery; CRp, CR with incomplete platelet recovery; HSCT, hematopoietic stem cell transplantation; MDACC, M. D. Anderson Cancer Center; SOS, sinusoidal obstruction syndrome.
Slide credit: clinicaloptions.com
Kantarjian H, et al. Cancer. 2013;119:

29. Inotuzumab Ozogamicin
Phase I/II B Trial: Inotuzumab Ozogamicin in Relapsed/Refractory CD22+ ALL
ALL, acute lymphoblastic leukemia; CRi, CR with incomplete blood count recovery; HSCT, hematopoietic stem cell transplantation; Ph, Philadelphia chromosome; TKI, tyrosine kinase inhibitor.
Multicenter, open-label phase I/II study
Primary endpoints: CR, CRi
Phase II dose and schedule determined in phase I dose-escalation and expansion cohorts
Adult pts with relapsed or refractory CD22+ ALL (Ph- or Ph+) in second or later salvage; peripheral lymphoblasts < 25,000 µL; no prior HSCT or anti-CD22 therapy within 4 mos; if Ph+, failed ≥ 1 TKI
(N = 35)
Inotuzumab Ozogamicin
Starting dose 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 mg/m2 on Days 8, 15 of a day cycle) for up to 6 cycles*
*Inotuzumab dose reduced to 1.6 mg/m2/cycle once pt achieves CR/CRi.
Slide credit: clinicaloptions.com
DeAngelo DJ, et al. ASH Abstract Advani AS, et al. ASH Abstract 2255.

30. Inotuzumab in Relapsed/Refractory CD22+ ALL: OutcomesOS
Median follow-up: 6.9 mos
100
Median OS: 6.4 mos (95% CI: ) 80
Response
N = 35
CR/CRi, n (%) CR
CRi
24 (69)
10 (29)
14 (40)
Median time to CR/CRi, days (range)
26 (15-91)
MRD negativity,* n (%)
In CR
In CRi
18 (75)
7 (70)
11 (79)
Median time to MRD negativity, days (range)
26 (21-80) 60
OS (%) 40 20 3 6 9 12 15
Mos
PFS
100
Median PFS: 3.7 mos (95% CI: ) 80
ALL, acute lymphoblastic leukemia; BM, bone marrow; CRi, CR with incomplete blood count recovery; MRD, minimal residual disease. 60
PFS (%) 40 20
*Negative MRD defined as < 1 abnormal cell out of 104 mononuclear cells in BM by flow cytometry based on central laboratory analysis. 3 6 9
Mos
Slide credit: clinicaloptions.com
Advani AS, et al. ASH Abstract 2255.

31. Phase III INO-VATE: Inotuzumab vs SoC in Relapsed/Refractory CD22+ ALL
ALL, acute lymphoblastic leukemia; Ara-C, cytarabine; CRi, CR with incomplete blood count recovery; DoR, duration of response; FLAG, fludarabine, cytarabine, and granulocyte colony-stimulating factor; HiDAC, high dose cytarabine; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; Ph, Philadelphia chromosome; SoC, standard of care.
Multicenter, randomized, open-label phase III study
Primary endpoints: CR/CRi and OS
Secondary endpoints: MRD negativity, DoR, PFS, HSCT rate, safety
Stratified by duration of first remission (≥ 12 vs < 12 mos), salvage (2 vs 1),
age (≥ 55 vs < 55 yrs)
Inotuzumab Ozogamicin*
Starting dose 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1; 0.5 mg/m2 on Days 8, 15 of a day cycle)
for up to 6 cycles
Pts with relapsed or refractory CD22+, Ph- or Ph+ ALL in salvage 1 or 2 (N = 326)
Standard of Care
FLAG or Ara-C + mitoxantrone or HiDAC
for up to 4 cycles
*Inotuzumab dose reduced to 1.5 mg/m2/cycle once pt achieves CR/CRi.
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

32. INO-VATE: Pt Characteristics
Baseline characteristics well balanced between treatment arms
Characteristic
InO
(n = 164)
SoC
(n = 162)
Median age, yrs (range)
47 (18-78)
48 (18-79)
Salvage status, n (%) 1 2
111 (68)
51 (31)
104 (64)
57 (35)
Duration of CR1, n (%)
< 12 mos
≥ 12 mos
98 (60)
66 (40)
108 (67)
54 (33)
Prior HSCT, n (%)
28 (17)
29 (18)
Median WBC,
103 cells/mm3 (range)
4.1 (0-47.4)
4.0 ( )
Characteristic
InO
(n = 164)
SoC
(n = 162)
Bone marrow blasts, n (%)
< 50%
≥ 50%
Missing
53 (32)
109 (67)
2 (1)
48 (30)
113 (70)
1 (1)
Karyotype, n (%)
Normal
Ph+
t(4;11)
Complex
Other/unknown/missing
46 (28)
22 (13)
6 (4)
27 (16)
63 (38)
42 (26)
28 (17)
7 (4)
22 (14)
63 (39)
HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; Ph, Philadelphia chromosome; SoC, standard of care; WBC, white blood cells.
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

33. INO-VATE: CR/CRi of Remission-Analysis Population (ITT218)
Remission analysis population: first 218 pts randomized in the ITT population
Among this population, more than 4 x the number of pts achieved CR/CRi and proceeded directly to HSCT with inotuzumab vs SoC (n = 41/109 [38%] vs n = 10/109 [9%]; P < .0001)
Response, % (95% CI)
InO
(n = 109)
SoC
1-Sided
P Value
CR/CRi
80.7 ( )
29.4 ( )
< .0001
MRD negative
78.4 ( )
28.1 ( )
CRi, CR with incomplete blood count recovery; HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; ITT, intent to treat; MRD, minimal residual disease; SoC, standard of care.
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

34. INO-VATE: PFS 1.0 Median PFS, Mos (95% CI) InO (n = 164) SoC (n = 162)
5.0 ( ) 1.8 ( )
HR: 0.45 (97.5% CI: ; 1-sided P < .001)
0.9
0.8
0.7
0.6
Probability of PFS
0.5
0.4
0.3
0.2
InO, inotuzumab ozogamicin; SoC, standard of care.
0.1 5 10 15 20 25
Pts At Risk, n
Mos
InO SoC
72 24
28 6
16 2
6 0
1 0
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

35. INO-VATE: OS
Median OS, Mos (95% CI)
InO (n = 164)
SoC (n = 162)
7.7 ( ) 6.7 ( )
HR: 0.77 (97.5% CI: ; 1-sided P = .0203)
1.0
OS data appeared to depart from proportional hazards assumption
2-yr OS probability higher with InO vs SoC
23% (95% CI: ) vs 10% (95% CI: 5-16)
0.9
0.8
0.7
0.6
Probability of OS
0.5
0.4
0.3
0.2
InO, inotuzumab ozogamicin; SoC, standard of care.
0.1 5 10 15 20 25 30 35 40
Mos
Pts at Risk, n
InO SoC
112 85
62 51
41 30
24 6
13 5
8 4
2 1
0 0
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

36. INO-VATE: Subgroup Analysis of OS
Events, n
Median OS, Mos
Favors InO
InO
SoC
HR (97.5% CI)
All pts
164 (122)
162 (130)
7.7
6.7
0.77 ( )
Duration of CR1
<12 mos
109 (89)
107 (89)
6.6
5.3
0.83 ( )
≥12 mos
55 (33)
55 (41)
11.1
9.4
0.59 ( )
Salvage status 1
108 (75)
107 (87)
8.6
7.1
0.65 ( ) 2
56 (47)
55 (43)
6.2
5.2
0.97 ( )
Age at randomization
< 55 yrs
104 (70)
103 (79)
8.0
0.68 ( )
≥ 55 yrs
60 (52)
59 (51)
5.6
0.90 ( )
Cytogenetics
Ph+
22 (18)
28 (22)
8.7
0.99 ( )
Ph-
142 (104)
134 (108)
7.4
5.9
0.71 ( )
Complex
27 (22)
7.2
3.9
0.61 ( )
Normal with ≥ 20 metaphases
35 (24)
34 (28)
8.9
0.64 ( )
Prestudy transplant
Yes
28 (23)
29 (20)
8.5
13.1
1.31 ( ) No
136 (99)
133 (110)
5.5
0.67 ( )
BM blasts
< 50%
53 (37)
48 (42)
9.1
0.69 ( )
≥ 50%
109 (84)
113 (87)
0.77 ( )
BM, bone marrow; InO, inotuzumab ozogamicin; Ph, Philadelphia chromosome; SoC, standard of care.
HR:
3.0
1.0
1.5
2.0
0.5
0.25
0.1
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

37. INO-VATE Substudy: Inotuzumab in Older Pts With Relapsed/Refractory ALL
Response*
< 55 Yrs
(n = 66)
≥ 55 Yrs
(n = 43)
CR/CRi,† % (95% CI) CR
CRi
80 (69-89)
35 (24-48)
46 (33-58)
81 (67-92)
37 (23-53)
44 (29-60)
MRD negativity in responders, % (95% CI)
74 (60-85)
86 (70-95)
Median DoR, mos
5.4 ( )‡
5.2 ( )§
*Data from ITT population (n = 218). †Best response in 1-6 cycles. ‡n = 51. §n = 34.
ALL, acute lymphoblastic leukemia; CRi, CR with incomplete blood count recovery; DoR, duration of response; ITT, intent to treat; MRD, minimal residual disease.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASCO Abstract 7029.

38. INO-VATE: SOS Among Inotuzumab-Treated Pts
Parameter
InO
SoC
Overall SOS incidence, % (n/N)
13 (22/164)
1 (1/162)
SOS incidence during study treatment, % (n/N)
3 (5*/164) --
Post-study HSCT, % (n/N)
47 (77/164)
20 (33/162)
Post-HSCT SOS, % (n/N)
22 (17†/77)
Median time to post-HSCT SOS, days (range)
15 (3-57)
*2/5 pts with prestudy HSCT. †5/17 pts with prestudy HSCT.
Multivariate analysis of factors associated with post-HSCT SOS
HSCT, hematopoietic stem cell transplantation; InO, inotuzumab ozogamicin; OR, odds ratio; SoC, standard of care; SOS, sinusoidal obstruction syndrome.
Factors Associated With Post-HSCT SOS
OR (95% CI)
P Value
Alkylator conditioning: dual vs single
7.6 ( )
.008
Age: ≥ 55 yrs vs < 55 yrs
4.8 ( )
.043
Slide credit: clinicaloptions.com
Kantarjian HM, et al. N Engl J Med. 2016;375: Kantarjian HM, et al. EHA Abstract LB2233.

39. AlloHSCT After Inotuzumab Salvage Therapy in Pts With Advanced ALL: Pt Characteristics
Parameter
N = 26
Median age, yrs (range)
33 (5-70)
Cytogenetic risk, n (%)
High
Intermediate
Unknown
9 (35)
11 (42)
6 (23)
Disease status at HSCT, n (%)
Active
Remission
MRD present
MRD absent
3 (12)
23 (88) 11 15
Median time to HSCT, mos (range)
19 (6-50)
Parameter
N = 26
HSCT preparative regimen, n (%)
Busulfan, clofarabine
Busulfan, clofarabine, thiotepa
Fludarabine, melphalan
Fludarabine, melphalan, thiotepa
Cyclophosphamide or etoposide/TBI
11 (42)
4 (15)
3 (13)
Allotype, n (%)
Matched related donor
Matched-unrelated or 1 Ag mismatched
Mismatched cord
9 (35)
16 (62)
1 (3)
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; TBI, total body irradiation.
Slide credit: clinicaloptions.com
Kebriaei P, et al. Clin Lymphoma Myeloma Leuk. 2013;13:

40. Event-Free Survival Probability
AlloHSCT After Inotuzumab Salvage Therapy in Pts With Advanced ALL: EFS and OS
EFS
OS by MRD Status
1.0
1.0
MRD by Flow Cytometry
Total 15 11
Died 8 11
Total = 26; Events = 20
Negative Positive
0.8
0.8
0.6
0.6
P = .04
Event-Free Survival Probability
Survival Probability
0.4
0.4
0.2
0.2
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation; EFS, event-free survival; MRD, minimal residual disease. 3 6 9 12 15 18 3 6 9 12 15 18
Mos
Mos
Slide credit: clinicaloptions.com
Kebriaei P, et al. Clin Lymphoma Myeloma Leuk. 2013;13:

41. AlloHSCT After Inotuzumab Salvage Therapy in Pts With Advanced ALL: Liver Toxicities
Liver Toxicity, n (%)
All Grade
Grade 3/4
Transaminitis
24 (92)
7 (27)
Bilirubin elevation
17 (65)
10 (38)
Sinusoidal obstruction syndrome NR
5 (19)
ALL, acute lymphoblastic leukemia; alloHSCT, allogeneic hematopoietic stem cell transplantation.
Slide credit: clinicaloptions.com
Kebriaei P, et al. Clin Lymphoma Myeloma Leuk. 2013;13:

42. Chemoimmunotherapy Combinations

43. Trends in Survival of Elderly Pts With B-ALL: Analysis of SEER Data
Survival in Pts Yrs of Age
Survival in Pts ≥ 70 Yrs of Age
1.0
1.0
Yr of Diagnosis
censored
censored
Yr of Diagnosis
censored
censored
0.8
0.8
0.6
0.6
Cumulative Survival Probability
Cumulative Survival Probability
0.4
0.4
P = .002
P = .326
0.2
0.2
ALL, acute lymphoblastic leukemia; SEER, Surveillance, Epidemiology, and End Results. 24 48 72 96
120
144
168 24 48 72 96
120
144
168
Mos Since Diagnosis
Mos Since Diagnosis
Slide credit: clinicaloptions.com
Guru Murthy GS, et al. Leuk Lymphoma. 2015;56:

44. Phase II Trial: Frontline Mini-HCVD + Inotuzumab in Older ALL Pts
ALL, acute lymphoblastic leukemia; ALT, alanine transaminase; AST, aspartate transaminase; ECOG PS, Eastern Cooperative Oncology Group performance status; mini-HCVD, hyper reduced-dose cyclophosphamide, dexamethasone, methotrexate, cytarabine; Ph, Philadelphia chromosome; POMP, 6-mercaptopurine, vincristine, methotrexate, prednisone.
Single-center, open-label phase II safety/efficacy trial
Study endpoints: PFS, response rate, OS, safety
Intensive Phase
Pts with newly diagnosed Ph- B-precursor ALL ≥ 60 yrs of age; ECOG PS 0-3; bilirubin ≤ 1.5 mg/dL; ALT and AST < 3 x ULN; creatinine ≤ 2 mg/dL
(N = 38)
4 cycles
4 cycles
Cyclophosphamide 150 mg/m2 x 6
Dexamethasone 20 mg
Methotrexate 250 mg/m2
Cytarabine 0.5 g/m2 x 4
Inotuzumab on Day 3*
Intrathecal chemotherapy Days 2, 8
If CD20+, Rituximab on Days 2, 8
Cyclophosphamide 150 mg/m2 x 6
Dexamethasone 20 mg
Methotrexate 250 mg/m2
Cytarabine 0.5 g/m2 x 4
*Inotuzumab dose, mg/m2:
First 6 pts
7-34
35 and Beyond C1
1.3
1.8
C2-4
0.8
1.0
Maintenance Phase
POMP (3 yrs)
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

45. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Response
Response, n (%)
N = 35 CR
28 (80)
CRp
6 (17)
ORR
34 (97)
No response
1 (3)
Early death
3 pts were enrolled with CR
ALL, acute lymphoblastic leukemia; mini-HCVD, hyper reduced-dose cyclophosphamide, dexamethasone, methotrexate, cytarabine; CRp, CR with incomplete platelet recovery.
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

46. Frontline Mini-HCVD + Inotuzumab in Older ALL Pts: Outcomes
CR Duration and OS
OS vs Historical HCVAD Results
1.0
1.0
0.8
0.8
0.6
0.6
Fraction Survival
Fraction Survival
0.4
0.4
P = .09
0.2
Total, n 37 38
Fail, n 4 14
2-Yr OS, % 81 64
0.2
Total, n 38 46
Fail, n 14 33
2-Yr OS, % 64 38
Median 35 mos 16 mos
ALL, acute lymphoblastic leukemia; InO, inotuzumab ozogamicin; mini-HCVD, hyper reduced-dose cyclophosphamide, dexamethasone, methotrexate, cytarabine; HCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; Rtx, rituximab.
CR duration OS
HCVD + InO ± Rtx
HCVAD ± Rtx 12 24 36 48 12 24 36 48 60
Mos
Mos
Slide credit: clinicaloptions.com
Jabbour E, et al. ASH Abstract 83.

47. Ongoing Chemoimmunotherapy Combination Trials in ALL
Study Description
Pt Population
Planned N
Study Arms
Primary Endpoint
Phase III ECOG 1910[1]
Newly diagnosed adult Ph- B-lineage ALL
360
Induction chemotherapy ± blinatumomab OS
Phase II MD Anderson[2] 60
Hyper-CVAD in sequential combination with blinatumomab
RFS
Phase II SWOG 1318[3]
Pts ≥ 65 yrs of age with:
Cohort 1: newly diagnosed Ph- B-precursor ALL 44
Cohort 1: blinatumomab + maintenance chemotherapy (POMP)
Toxicity, OS
Cohort 2: newly diagnosed Ph+ or R/R DSMKF
Cohort 2: Dasatinib, prednisone followed by blinatumomab + dasatinib
Phase I S1312[4]
Relapsed/refractory adult CD22+ acute leukemia 38
Inotuzumab + combination chemotherapy (CVP)
Safety
ALL, acute lymphoblastic leukemia; CVP, cyclophosphamide, vincristine, prednisone; DSMKF, dasatinib-sensitive mutations or kinase fusions; ECOG , Eastern Cooperative Oncology Group; Ph, Philadelphia chromosome; POMP, 6-mercaptopurine, vincristine, methotrexate, prednisone; R/R, relapsed/refractory.
1. ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT
Slide credit: clinicaloptions.com

48. Go Online for More CCO Coverage of Acute Lymphoblastic Leukemia!
Additional downloadable slidesets from the live symposium Expert analyses with downloadable summary slidesets highlighting key data presented at ASH 2016 ClinicalThought commentaries on new developments in treating patients with ALL
clinicaloptions.com/oncology