Learning Objectives. Case A: Presentation. Case A Question Not included in Activity Survey. Acute Leukemia: Diagnosis and Prognosis

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1 Learning Objectives Improve awareness of FDA-approved agents and/or therapies under development for the treatment of AML and ALL Incorporate FDA-approved agents and therapies under development into treatment paradigms for AML and ALL Increase awareness of the importance of long-term safety with BCR-ABL TKIs in CML management for individualized treatment based on patient history and any comorbidities Case A: Presentation 64-year-old lawyer presents with intermittent fevers, cough, fatigue WBC count: 12,860 cells/mm 3 64% peripheral blasts, 5% neutrophils Hematocrit: 22% Platelet count: 27,000 cells/mm 3 Physical exam: tired and ill-appearing: Afebrile HR = 110 BP = 104/79 RR = 18/min Ecchymoses at phlebotomy site; no frank bleeding Pulmonary: basilar crackles that clear BM aspiration: Hypercellular marrow (~90%) ~ 80% blasts Case A Question Not included in Activity Survey Which missing piece of data is vital to determining your patient s prognosis and developing the induction treatment plan? 1. ECOG performance status between 2-3 for last 12 months 2. History of prior adjuvant chemotherapy for colorectal CA from which the patient never really bounced back 3. Acute leukemia phenotype and WHO classification 4. Molecular mutation panel 5. Cytogenetic analysis 6. All of the above Acute Leukemia: Diagnosis and Prognosis Traditional Approach to Acute Leukemia Therapy History and physical Age and performance status Previous treatment history? Antecedent marrow disorder Extramedullary disease??? WBC at presentation Bone marrow aspirate and biopsy Wright s stain Flow cytometry Cytogenetics Molecular genetics Prognosis and treatment? Slide credit: clinicaloptions.com. Establish prognostic group Favorable Intermediate (I and II) Unfavorable (adverse) Induction Goals: - Stabilize patient - Restore hematopoiesis Consolidation Goals: - CURE the patient - Leukemia-free survival Salvage Therapy Goals: - Complete Remission FIT for Intensive Chemotherapy Chemotherapy-based Favorable = Chemotherapy Unfavorable = Allogeneic BMT Chemotherapy (Clinical Trial?) Acute Leukemia Phenotype AML ALL UNFIT for Intensive Chemotherapy Clinical Trial Low Intensity Chemo / Hospice 1

2 Newly Approved Agents for Acute Leukemia, 2017 AML = UPFRONT: Rydapt (midostaurin, FLT3-targeted) Vyxeos (, liposomal daunorubicin + cytarabine) AML = RELAPSE: Idhifa (enasidenib, IDH2-targeted) AML = BOTH: Mylotarg (gemtuzumab ozogamicin, CD33 targeted) ALL = RELAPSE: Blinatumomab (CD19 targeted, CD3) Besponsa (inotuzumab ozogamicin, CD22 targeted) CAR T-cells (pediatrics) Newly Approved Agents for Acute Leukemia, 2017 AML = UPFRONT: Rydapt (midostaurin, FLT3-targeted) Vyxeos (, liposomal daunorubicin + cytarabine) AML = RELAPSE: Idhifa (enasidenib, IDH2-targeted) AML = BOTH: Mylotarg (gemtuzumab ozogamicin, CD33 targeted) ALL = RELAPSE: Blinatumomab (CD19 targeted, CD3) Besponsa (inotuzumab ozogamicin, CD22 targeted) CAR T-cells (pediatrics) Case A: Presentation AML World Health Organization Classification 64-year-old lawyer presents with intermittent fevers, cough, fatigue WBC count: 2,860 cells/mm 3 64% peripheral blasts, 5% neutrophils Hematocrit: 22% Platelet count: 27,000 cells/mm 3 Physical exam: tired and ill-appearing: Afebrile HR = 110 BP = 104/79 RR = 18/min Ecchymoses at phlebotomy site; no frank bleeding Pulmonary: basilar crackles that clear Past Medical History: Breast Cancer, tx with CMF x 6 cycles Cytogenetics: Complex Cytogenetics Molecular Genetics: ASXL1, DNMT3A BM aspiration: Hypercellular marrow (~90%) ~ 80% blasts SUBTYPE COMMENTS This category captures balanced chromosomal translocations that produce novel fusion genes. The most common subtypes in this category are shown below along with single gene mutations - AML can be diagnosed in these subtypes with <20% AML with recurrent genetic blasts: abnormalities Acute promyelocytic leukemia (APL) with PML-RARA AML with t(8;21)(q22;q22.1); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 One of the following criteria must be met: Previous history of myelodysplastic syndrome (MDS) AML with myelodysplasia-related changes Possession of a myelodysplasia-related cytogenetic abnormality, except for del(9q) Involvement of 1 abnormal myeloid cell type (only in cases in which a mutation of NPM1 or biallelic mutation of CEBPA is lacking) Cytotoxic agents associated with therapy-related hematologic neoplasms include Therapy-related myeloid neoplasms alkylating agents, radiation therapy, and topoisomerase II inhibitors AML, not otherwise specified (NOS) AML cases that do not fit into any of the other subtypes Tumor mass of myeloid blasts Myeloid sarcoma Cases of myeloid sarcoma without marrow disease should be investigated further Myeloid proliferations related to Down syndrome NCCN. Clinical practice guidelines in oncology: acute myeloid leukemia. v Phase III Study of in Newly-Diagnosed Adults With t-aml or AML-MRC (Study 301) 1-3 Induction n=153 Subsequent induction (if needed) Consolidation (1-2 cycles) Liposomal formulation of daunorubicin and cytarabine (1:5 molar ratio) 309 Patients on Days 1, 3, and 5 on Days 1 and 3 on Days 1 and n=156 Follow-up Approved for treatmentrelated AML (t-aml) and AML with MDS-related changes (AML-MRC) 7 days of cytarabine + 3 days of daunorubicin Key eligibility criteria for Phase 3 study: Previously untreated Aged Able to tolerate intensive therapy Performance status days of cytarabine + 2 days of daunorubicin Patient Distribution for Phase 3 study (n=309): Therapy-related AML = 20% AML-antecedent heme disorder = 54% De novo AML with MDS cytogenetics = 25% 5 days of cytarabine + 2 days of daunorubicin Primary endpoint: Overall survival 1. VYXEOS () [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. 2. Data on file. [VYX-2017-xxx]. Palo Alto, CA: Jazz Pharmaceuticals. 3. Lancet JE et al. Oral presentation at: American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, IL. 2

3 Phase III Study 301 Patient Characteristics n = 153 (%) 7+3 n = 156 (%) Gender Male 94 (61.4) 96 (61.5) Race Caucasian 128 (83.7) 134 (89.1) Age Group 70 years 57 (37.3) 54 (34.6) Median ECOG PS (90.2) 134 (85.9) PS 2 15 (9.8) 22 (14.1) Cytogenetic Risk by NCCN Favorable 7 (4.6) 5 (3.2) Intermediate 64 (41.8) 58 (37.8) Poor 72 (47.1) 83 (53.2) Unknown 10 (6.5) 10 (6.4) Strata Therapy-related AML 30 (19.6) 33 (21.2) MDS AML with Prior HMA 50 (32.7) 55 (35.3) MDS AML without Prior HMA 21 (13.7) 19 (12.2) CMMoL AML 11 (7.2) 12 (7.7) De novo with MDS Karyotype 41 (26.8) 37 (23.7) CMMoL = chronic myelomonocytic leukemia AML-MRC Phase III Study 301: Response Rate Patients (%) P= P= Percentages reflect number with endpoint out of column total. Odds ratios are calculated with the 7+3 arm as the reference group. P-value is from a comparison of rates between treatment arms and is based on the Mantel-Haenszel test stratifying by age and AML type CR CR + CRi Odds Ratio 1.69 (1.03, 2.78) 1.77 (1.11, 2.81) (95% Conf. Int.) (n=153) 7+3 (n=156) HCT Rate CPX- 351 (n=153) 7+3 Odds Ratio (n=156) 34.0% 25.0% HCT RATE 1.54 (0.92, 2.56) P value Phase III Study 301: Overall Survival The first chemotherapy to demonstrate superior overall survival 7+3 in adults with newly-diagnosed t-aml or AML-MRC 1 Phase III Study 301: Safety Grades 3 to 5 (CTC 3.0) Grades 3 to 5 (CTC 3.0) (n=153) n (%) 7+3 (n=151) n (%) (n=153) n (%) 7+3 (n=151) n (%) Hemorrhage 15 (10) 9 (6) Fatigue 8 (5) 8 (5) Febrile Neutropenia 101 (66) 102 (68) Arrhythmia 10 (7) 7 (5) Rash 8 (5) 2 (1) Decreased appetite 2 (1) 5 (3) Edema 2 (2) 5 (3) Nausea 1 (1) 1 (1) Diarrhea/Colitis 4 (3) 10 (7) Mucositis 2 (1) 7 (5) Pneumonia (excluding 30 (20) 26 (17) fungal) Sleep disorders 2 (1) 1 (1) Bacteremia (excluding 35 (23) 31 (21) sepsis) Constipation 0 0 Vomiting 0 0 Musculoskeletal pain 5 (3) 4 (3) Abdominal pain 3 (2) 3 (2) Chills 0 0 Hypotension 7 (5) 1 (1) (n=153) Cough 0 1 (1) Headache 2 (1) 1 (1) Dyspnea 17 (11) 15 (10) Non-conduction cardiotoxicity 13 (9) 15 (10) VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. Phase III Study 301: 30-Day & 60-Day Mortality Rates : Conclusions Patients (%) day all-cause overall mortality Patients (%) day all-cause overall mortality compared favorably to 7+3 induction for patients with therapy-related AML, AML with MDS-related changes and/or cytogenetics: Improved OS and EFS without increased 30 and 60 day mortality Investigators suggest: Induction: (44 mg/100 mg per m 2 ) as 90 min infusion days 1, 3, 5 2nd Induction (if needed): (44 mg/100 mg per m 2 ) as 90 min infusion days 1, 3 Consolidation: (29/65 mg per m 2 ) as 90 min infusion days 1,3 Deaths 2º to Progressive AML VYXEOS [package insert]. Palo Alto, CA: Jazz Pharmaceuticals. Deaths 2º to Adverse Event 3

4 Case B: Presentation 64-year-old lawyer presents with intermittent fevers, cough, fatigue WBC count: 72,860 cells/mm 3 64% peripheral blasts, 5% neutrophils Hematocrit: 22% Platelet count: 27,000 cells/mm 3 Physical exam: tired and ill-appearing: - Afebrile - HR = BP = 104/79 - RR = 18/min Ecchymoses at phlebotomy site; no frank bleeding Pulmonary: basilar crackles that clear Past Medical History: no chemo, radiation, MDS Cytogenetics: Normal Cytogenetics Molecular Genetics: FLT3-ITD + BM aspiration: hypercellular marrow (~90%) ~ 80% blasts Cytogenetics Favorable Standard Unfavorable inv(16) or t(16;16) t(15;17) t(8;21) (Other cytogenetics don t alter exception complex karyotype) Normal, +8, +6, Y, del(12p) -5 / del(5q), -7 / del (7q), inv(3q), abnl of 11q23, 20q, 21q, 17p, del (9q), t(6;9), t(9;22), or complex karyotypes with 3 abnl clones Overall survival: 609 newly diagnosed AML pts Slovak et al. Blood. 2000;96:4075. Tallman et al. Blood. 2005;106:1154. Cytogenetically Normal AML Recurring Mutations in AML NPM1 CEBPA Favorable FLT3-ITD (internal tandem duplication) FLT3-TKD (point mutation in TK domain) KIT MLL-PTD (partial tandem duplication) RAS WT1 TP53 DNMT3A TET2 IDH1, IDH2 ASXL1 Dohner et al. Blood. 2010;115:453. FLT3-ITD Mutations and Treatments Structurally related to other TKR KIT, FMS, PDGFR FLT3-activating mutations (ITD, D835) constitutively activate the receptor Common in AML ~ 1/3 Associated w / worse prognosis Midostaurin = multi-kinase inhibitor of FLT3, KIT, VEGFR, PDGFR and protein kinase C Approved for FLT3-mutation positive AML Results in blockade of cellular proliferation and survival signal cascades RATIFY: Midostaurin in FLT3-Positive AML Stratified by ITD/TKD; randomized yrs of age with FLT3- mutated (non-apl) AML (n = 717) Induction (1-2 cycles) Daunorubicin 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Midostaurin 50 mg PO BID D8-21 (n= 360) Daunorubicin 60 mg/m 2 IVP D1-3 + Cytarabine 200 mg/m 2 /d IVCI D1-7 + Placebo D8-21 (n = 357) CR CR Consolidation (up to 4 cycles) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Midostaurin 50 mg PO BID D8-21 (n = 231) Cytarabine 3 g/m 2 over 3h q12h D1,3,5 + Placebo D8-21 (n = 210) Maintenance (12 cycles) Midostaurin 50 mg PO BID D1-28 (n = 120) Placebo D1-28 (n = 85) Double-blind, placebo-controlled, randomized phase III study of midostaurin, an FLT3 inhibitor 1 endpoint = OS (not censored for SCT) 2 = EFS Sayjin C et al. J Hematol Oncol. 2017;93. Stone RM et al. ASH Abstract 6. 4

5 RATIFY: Efficacy Midostaurin + Chemo Placebo + Chemo Characteristic (n = 360) (n = 357) Median OS, mos (range) 74.7 (31.7-NE) 25.6 ( ) 4-yr OS, % (95% CI) Uncensored* Censored for SCT 51.4 ( ) 63.8 ( ) SCT, n (%) Any time CR1 only CR, n (%) By Day 60 In induction/consolidation Median EFS, mos (range) By day 60 In induction/consolidation Stone RM et al. ASH Abstract (59) 100 (28) 212 (59) 239 (66) 8.0 ( ) 11.3 ( ) 44.2 ( ) 55.7 ( ) 196 (55) 79 (22) 191 (53) 211 (59) 3.0 ( ) 6.1 ( ) P Value DFS, mos (range) 25.9 (19.4-NE) 14.4 ( ).002 *HR: HR: Longer OS shown in midostaurin arm in all FLT3 cohorts. 4-yr EFS rate = 28% with midostaur 20% in placebo, regardless of FLT3 status RATIFY: Safety Grade 3/4 Nonhematologic AEs ( 10% Pts), % Midostaurin + Chemo (n = 360) Placebo + Chemo (n = 357) p Value Febrile neutropenia Infection Diarrhea Hypokalemia Pain Rash/desquamation ALT/SGPT Fatigue (asthenia, lethargy, malaise) Deaths: 5% (18/360) in midostaurin arm 5.3% (19/357) in placebo; Infection (4 midostaurin 7 placebo) pneumonitis (3 midostaurin 0 placebo) CNS bleed (1 midostaurin 2 placebo) Stone RM et al. ASH Abstract 6. RATIFY: OS (Primary Endpoint) OS (%) % reduced risk of death in midostaurin arm HR: 0.77 P = Pts at Risk, n Mos MIDO PBO Stone RM et al. ASH Abstract Median, Mos (95% CI) Midostaurin 74.7 (31.7-NE) Placebo 25.6 ( ) 4-Yr Survival, % (95% CI) Midostaurin 51.4 (46-57) Placebo 44.2 (39-50) Midostaurin Placebo RATIFY: Conclusions Midostaurin + standard chemo in patients with newly diagnosed FLT3-mutated AML Improved OS and EFS placebo: Regardless of ITD/TKD stratification AND despite high SCT rate (57%) Reduced risk of death by 23% placebo Safety/tolerability similar in midostaurin placebo Ratify Investigators suggest: Induction: 7+3+Midostaurin (50 mg BID, days 8-21) Consolidation: HiDAC + Midostaurin (50 mg BID, days 8-21) Maintenance following chemo or BMT with Midostaurin x 12 mos Stone RM et al. ASH Abstract 6. Approach to AML Therapy in FIT for Intensive Chemotherapy UNFIT for Intensive Chemotherapy Newly Approved Agents for Acute Leukemia, 2017 Induction Goals: - Stabilize patient - Restore hematopoiesis Consolidation Goals: - CURE the patient - Leukemia-free survival Salvage Therapy Goals: - Complete Remission History = Secondary AML History = Secondary AML Cytogenetics = complex, favorable (CBF) Cytogenetics = complex, favorable (CBF) Molecular = FLT3-ITD, TP53, NPM1, IHD2 Molecular = FLT3-ITD, TP53, NPM1, IHD2 Favorable Intermediate Unfavorable FLT3-ITD = Midostaurin Hypomethylating Agents Secondary = Hospice HiDAC HiDAC + Midostaurin Allogeneic BMT Allogeneic BMT Chemotherapy gemtuzumab ozogamicin enasidenib AML = UPFRONT: Rydapt (midostaurin, FLT3-targeted) Vyxeos (, liposomal daunorubicin + cytarabine) AML = RELAPSE: Idhifa (enasidenib, IDH2-targeted) AML = BOTH: Mylotarg (gemtuzumab ozogamicin, CD33 targeted) ALL = RELAPSE: Blinatumomab (CD19 targeted, CD3) Besponsa (inotuzumab ozogamicin, CD22 targeted) CAR T-cells (pediatrics) 5

6 Case C: Presentation Approach to ALL Therapy in year-old lawyer presents with intermittent fevers, cough, fatigue WBC count: 18,860 cells/mm 3 64% peripheral blasts, 5% neutrophils Hematocrit: 22% Platelet count: 27,000 cells/mm 3 Physical exam: tired and ill-appearing: - Afebrile - HR = BP = 104/79 - RR = 18/min Ecchymoses at phlebotomy site; no frank bleeding Pulmonary: basilar crackles that clear History: pre-b ALL treated with BFM induction and intensification followed by maintenance for 2 years with relapse 1 year later Cytogenetics: Philadelphia Chromosome Negative BM aspiration: hypercellular marrow (~90%) ~ 80% blasts Ph+Like Disease Induction Goals: - Stabilize patient - Restore hematopoiesis Consolidation Goals: - CURE the patient - Leukemia-free survival Salvage Therapy Goals: - Complete Remission FIT for Intensive Chemotherapy History / Genetics T ALL Ph- Pre-B ALL Ph+ Pre-B ALL Chemotherapy-based Favorable = Chemotherapy Unfavorable = Allogeneic BMT Chemotherapy + TKI Chemotherapy Blinatumomab or Inotuzumab or CAR T Cells UNFIT for Intensive Chemotherapy Ph+Like Disease History / Genetics T ALL Ph- Pre-B ALL Ph+ Pre-B ALL Low Intensity Chemo TKI +/- Low Intensity Chemo Blinatumomab Blinatumomab Single-chain bispecific T cell engager (BiTE) One anti-cd3 variable region linked to one anti-cd19 variable region Induction of CD19+ cell death via cytotoxic T cells Bassan R. Blood. 2012; Wu J. J Hematol Oncol. 2015;104. Kantarjian H et al. N Engl J Med. 2017;376: Blinatumomab Blinatumomab Kantarjian H et al. N Engl J Med. 2017;376: Kantarjian H et al. N Engl J Med. 2017;376:

7 Blinatumomab Blinatumomab: Conclusions Blinatumomab chemotherapy for Relapsed/Refractory Ph- Pre-B ALL Improved response rate (CR/CRi/CRp) and overall survival. chemotherapy Less hematologic toxicity than chemotherapy Increased incidence of infusion reactions and cytokine release syndrome Dosing Each cycle of blinatumomab is given as a 28-day continuous infusion Cycle 1 Week 1 Dosing: 9 mcg/day preceded by 20 mg IV dexamethasone on day 1 Cycle 1 Week 2-4 and Cycle 2+ Dosing: 28 mcg/day preceded by 20 mg IV dexamethasone prior to dose escalation Kantarjian H et al. N Engl J Med. 2017;376: Inotuzumab Ozogamicin Inotuzumab Ozogamicin Chemotherapy drug, calicheamicin, attached to a anti- CD22 monoclonal antibody Topoisomerase 2 inhibitor + DNA polymerase inhibitor Breakthrough therapy for ALL Ricart AD. Clin Cancer Res. 2011; Kantarjian HM et al. N Engl J Med. 2016;375: Inotuzumab Ozogamicin Inotuzumab Ozogamicin Kantarjian HM et al. N Engl J Med. 2016;375: Kantarjian HM et al. N Engl J Med. 2016;375:

8 Inotuzumab Ozogamicin Inotuzumab: Conclusions Inotuzumab chemotherapy for relapsed/refractory Pre-B ALL Improved response rate (CR/CRi/CRp) and PFS chemotherapy Improved clearance of MRD chemotherapy Similar rate of Grade 3 adverse events chemotherapy Increased incidence of veno-occlusive liver disease Dosing Cycle 1 (21 days): Day 1: 0.8 mg/m 2 IV infusion Days 8 and 15: 0.5 mg/m 2 IV infusion Cycle 2 and beyond (28 days): Days 1, 8, and 15: 0.5 mg/m 2 IV infusion (if in remission) Kantarjian HM et al. N Engl J Med. 2016;375: Approach to ALL Therapy in Ph+Like Disease Induction Goals: - Stabilize patient - Restore hematopoiesis Consolidation Goals: - CURE the patient - Leukemia-free survival Salvage Therapy Goals: - Complete Remission FIT for Intensive Chemotherapy History / Genetics T ALL Ph- Pre-B ALL Ph+ Pre-B ALL Chemotherapy-based Favorable = Chemotherapy Unfavorable = Allogeneic BMT Chemotherapy + TKI Chemotherapy Blinatumomab or Inotuzumab or CAR T Cells UNFIT for Intensive Chemotherapy Ph+Like Disease History / Genetics T ALL Ph- Pre-B ALL Ph+ Pre-B ALL Low Intensity Chemo TKI +/- Low Intensity Chemo Survival in Early CP-CML Proportion Alive Busulfan, Hydroxyurea Yrs From Referral The University of Texas M.D. Anderson Cancer Center database. 93% 84% Year Total Dead Imatinib (censored : non-cml deaths) Imatinib Start of the TKI era Interferon Approach to CML Therapy in Approach to CML Therapy in CML chronic (or accelerated) phase CML blast phase CML chronic (or accelerated) phase CML blast phase Risk Score* LOW or INTERMEDIATE Risk Score* HIGH Risk Score* LOW or INTERMEDIATE Risk Score* HIGH First Line TKI Therapy: - Faster, deeper response of 2 nd generation TKIs - OS similar btwn 1 st and 2 nd Generation TKIs - Possible benefit to upfront 2 nd generation TKI in pts with high risk presentation First Line Therapy Milestones: - Comp Heme Remission: 2-3 weeks - Cy Comp Response: 6-12 mos - Major Mole Response: mos - Comp Molecular Remission:??? Meet Milestones = continue Imatinib 400 mg daily Dasatinib 100 mg daily Nilotinib 300 mg BID Bosutinib 400 mg daily Imatinib or Dasatinib or Nilotinib +/- Chemo Allogeneic Stem Cell Transplant in CP2 First Line TKI Therapy: - Faster, deeper response of 2 nd generation TKIs - OS similar btwn 1 st and 2 nd Generation TKIs - Possible benefit to upfront 2 nd generation TKI in pts with high risk presentation First Line Therapy Milestones: - Comp Heme Remission: 2-3 weeks - Cy Comp Response: 6-12 mos - Major Mole Response: mos - Comp Molecular Remission:??? Meet Milestones = continue Imatinib 400 mg daily Dasatinib 100 mg daily Nilotinib 300 mg BID Bosutinib 400 mg daily Imatinib or Dasatinib or Nilotinib +/- Chemo Allogeneic Stem Cell Transplant in CP2 * Sokal or Hasford Score Miss Milestones = consider switching to a different TKI - mutation testing may guide - if compliance an issue side effect profiles may guide * Sokal or Hasford Score Miss Milestones = consider switching to a different TKI - mutation testing may guide - if compliance an issue side effect profiles may guide How do we improve upon the success of current TKI therapies? 8

9 Treatment Options Based on Adverse Event Spectrum of TKIs in CML ELN Recommendations Around TKI Adverse Events Ponatinib Pancreatic enzymes, hypertension, skin toxicity, thrombotic events Nilotinib Pancreatic enzyme, indirect hyperbilirubinemia, hyperglycemia QT prolongation, cardiovascular events Imatinib Edema/fluid retention, myalgia, hypophosphatemia, GI effects (diarrhea, nausea) Common Effects Myelosuppression Transaminase Electrolyte Δ Dasatinib Pleural/pericardial effusions, bleeding risk, pulmonary arterial hypertension Bosutinib Diarrhea, nausea, emesis, rash Main purpose of CML treatment is the anti-leukemic effect Suboptimal management of AEs must not compromise this Most patients will have AEs mild to moderate; will resolve or can be controlled by simple means Reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways Need frequent monitoring to help recognize resolution early Attention must be given to comorbidities and drug interactions and to new events that are inevitable during prolonged therapy Some TKi-related AEs have emerged which were not predicted nor detected in earlier studies Possible suboptimal attention to or absence from the clinical data Trials of Imatinib Discontinuation Optimal Responders Trials of Nilotinib/Dasatinib Discontinuation Treatment before Study n discontinuation IFN then IM for STIM years STIM2 200 IM for 3 years ALLG CML8 40 IM for 3 years According to 80 IM for 3 years STIM (A-STIM) EUROSKI 200 IM, NIL, DAS Response required for discontinuation MR 4.5 for 2 years MR 4.5 for 2 years MR 4.5 for 2 years MR 4.5 for 2 years MR 4.5 for 1 years Definition of relapse Loss of MMR or 1-log increase in BCR-ABL Loss of MMR or 1-log increase in BCR-ABL Loss of MMR or confirmed loss of MR Loss of MMR Loss of MMR TFR % (median follow-up time) 38% (60 months) 46% at 2 years (preliminary) 45% (42 months) 64% (23 months) 61% at 6 months (preliminary) Treatment before Response required Definition of TFR % (median Study n discontinuation for discontinuation relapse follow-up time) CMR for median STOP 2G-TKI 61.1% 50 NIL or DAS 29 months Loss of MMR pilot (preliminary) (range 21 39) ENESTfreedom 175 NIL front-line MR % at 24 weeks for 1 years Loss of MMR 48.9% at 96 weeks Second-line NIL Confirmed loss of ENESTop 117 ( 3 years total; MR 4.5 for 1 years MR 4 or any loss of 53.2% at 96 weeks 2 years NIL) MMR MR IM ( 2 years) 4.5 for 1 year Confirmed loss of ENESTpath 1058 MR and NIL 4.5 for 2 years MR 4 or any loss of 46% at 24 months (randomized) MMR DASFREE Dasatinib Functional Cure ~74 >2 years DAS MR 4.5 for 1 year Loss of MMR 63% at 1 year CA Study DAS=dasatinib; IFN=interferon; IM=imatinib; MMR=major molecular response; MR=molecular response; MR 4.5 =deep molecular response with a 4.5-log reduction; NIL=nilotinib; TFR=treatment-free remission. Mahon FX. Ann Hematol. 2015;94(suppl 2):S187-S193. DAS=dasatinib; IM=imatinib; MMR=major molecular response; MR=molecular response; MR 4.5 =deep molecular response with a 4.5-log reduction; NIL=nilotinib; TFR=treatment-free remission. Mahon FX. Ann Hematol. 2015;94(suppl 2):S187-S193. Commonly Used Dosing for Chronic Phase CML TKI Dose De-escalation in CML Patients with Stable MMR (DESTINY Trial) Imatinib: Dasatinib: Nilotinib: Bosutinib: Ponatinib: 300mg daily, 400mg daily, 600 mg daily, 800 mg daily 50 mg, 70 mg, 100 mg, 140 mg daily 200 mg BID, 300 mg BID, 400 mg BID 300 mg, 400 mg daily, 500 mg daily 15 mg daily, 30 mg daily, 45 mg daily Patients 18 years or older with CML (n = 174 patients enrolled) 20 centers in United Kingdome Treated with IM: > 3 years with MR4 or stable MMR x 12 months Dosing changed to 50% of standard dose x 12 months Imatinib 400mg daily = 200mg daily Dasatinib 100mg daily = 50mg daily Nilotinib 400mg BID = 200mg BID Recurrence Rate: MR4 = 2% MMR = 19% Time to Recur: MR4 = 8.7 months MMR = 4.4 months Clark RE et al. Lancet Haematol. 2017;4:e

10 Approach to CML Therapy in Conclusions First Line TKI Therapy: - Faster, deeper response of 2 nd generation TKIs - OS similar btwn 1 st and 2 nd Generation TKIs - Possible benefit to upfront 2 nd generation TKI in pts with high risk presentation First Line Therapy Milestones: - Comp Heme Remission: 2-3 weeks - Cy Comp Response: 6-12 mos - Major Mole Response: mos - Comp Molecular Remission:??? Risk Score* LOW or INTERMEDIATE Stopping Trials to reduce long term toxicity: - CMR x 1-2 years Dose Reduction Trials to reduce long term toxicity: - MMR or MR4 stable x at least 12 mos CML chronic (or accelerated) phase Imatinib 400 mg daily Dasatinib 100 mg daily Nilotinib 300 mg BID Bosutinib 400 mg daily Risk Score* HIGH Meet Milestones = continue Miss Milestones = consider switching to a different TKI - mutation testing may guide - if compliance an issue side effect profiles may guide If considering stopping OR dose reduction: - PCR monitoring every month x 6 mos - PCR monitoring QOM x 18 mos CML blast phase Imatinib or Dasatinib or Nilotinib +/- Chemo Allogeneic Stem Cell Transplant in CP2 FDA has recently approved new agents for leukemia AML agents for upfront and relapsed therapy ALL agents for relapsed disease CML a fourth drug approved for upfront treatment To optimally use these agents, it is vital to understand each patient s history, the morphology of the acute leukemia, and the genetics (cytogenetic and molecular genetics) of the leukemia It is important to continually assess your long-term CML patients being treated with TKIs for their response and tolerance consideration of dose reduction or discontinuation may apply to some of them CME Credit Post-activity Survey Now that the program has completed, please take a moment to answer the Post-activity Survey questions on your form Your answers are important and will help us identify remaining educational gaps and shape future CME activities CME Evaluation If you re seeking credit, ensure you fill in your name and demographic information and complete the CME Evaluation on your form (after the Post-activity Survey) Return all forms to on-site CME staff Thank you for joining us today! 10