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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.
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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.
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About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact for details Slide credit: clinicaloptions.com 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.
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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.
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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.
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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.
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Bidirectional Antibody: Blinatumomab
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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.
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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.
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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.
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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.
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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:
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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Management of Treatment-Related Adverse Events
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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
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Antibody–Drug Conjugate: Inotuzumab Ozogamicin
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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:
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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.
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Inotuzumab in Relapsed/Refractory CD22+ ALL: Outcomes
OS 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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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:
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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:
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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:
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Chemoimmunotherapy Combinations
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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:
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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.
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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.
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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.
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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
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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
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