Updates in the Treatment of Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S

$Updates in the Treatment of Relapsed Or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S$

Updates in the Treatment of Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma Kirollos S. Hanna, PharmD, BCPS, BCOP Assistant Professor of Pharmacy Mayo Clinic College of Medicine Hematology/Oncology Clinical Pharmacist University of Minnesota Medical Center Minneapolis, Minnesota

At the completion of this activity, participants will be able to: • Describe the pathophysiology of follicular lymphoma (FL) and mantle cell lymphoma (MCL) and risk factors for disease progression that guide treatment decisions • Distinguish new and emerging agents for treating FL and MCL based on mechanisms of action and clinical efficacy and safety data • Explain appropriate prevention and management of therapy- induced adverse effects • Identify the multifaceted roles of the pharmacist in improving adherence and disease outcomes in patients receiving therapy for B-cell NHL Non-Hodgkin Lymphoma Overview

Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL) Non-Hodgkin Lymphoma (NHL) Overview

• Lymphoproliferative disorders originating in B-lymphocytes, T- lymphocytes, or natural killer cells • 74,200 new cases and 19,970 deaths in 2019 • Seventh most common; 4%-5% of new cases and 3%-4% of deaths • Diagnosis median age 67 years • Death median age 76 years • >60 specific NHL subtypes have been identified by the World Health Death rates have been falling on average Organization • Aggressive lymphomas: 60% of cases 2.2% each year over 2007-2016. • Indolent lymphomas: 40% of cases 5-year OS = 72%

SEER Cancer Stat Facts: non-Hodgkin Lymphoma. National Cancer Institute. Bethesda, MD. seer.cancer.gov/statfacts/html/nhl.html; National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. Clinical Presentation

“B” Symptoms Signs

Unintentional weight loss ≥10% of body weight Lymphadenopathy within the previous 6 months Splenomegaly Fevers of >100.5°F (>38°C) for ≥2 weeks without evidence of infection Hepatomegaly Drenching night sweats for ≥1 month without evidence of infection Skin and other organ involvement

Extreme fatigue Cytopenias and autoimmune diseases

Some patients are asymptomatic and are diagnosed on routine exams.

Hallek M, et al. Blood. 2018;131(25):2745-2760; NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. NHL Major Subtypes DLBCL CLL/SLL FL MZL MCL PTCL-NOS “Indolent” form of NHL, yet aggressive behavior that arises 4% 2% from cells originating in the mantle zone. 8% 32% Accounts for 3%-6% of all NHL. Median overall survival (OS), 17% 5-7 years.

Indolent form of NHL that arises 19% from B-lymphocytes. Approximately 20% of all NHL. 5-year OS rates all stages: ≈88%. CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; MCL, mantle cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified. Al-hamadani M, et al. Am J Hematol. 2015;90(9):790-795; Cheah CY, et al. J Clin Oncol. 2016;34(11):1256-1269; Herrmann A, et al. J Clin Oncol. 2009;27(4):511-518; Martin P, et al. Ann Oncol. 2008;19(7):1327-1330. FL and MCL Overview FL MCL • t(14;18) translocation (90%) • t(11;14) translocation • Deregulated expression of • Overexpression of cyclin D1 BCL2 • More aggressive disease • Indolent forms may not course compared with require treatment for years indolent lymphomas • Predictors of outcomes: • Predictors of outcomes: number of centroblasts • Age, performance status, • Activated B cell in the serum LDH, white blood germinal center cell (WBC) count, Ki-67 • WHO classification score • FL1 and FL2 → FL1-2 • WHO classification • FL3A → centrocytes present • MCL “in situ” Picture adapted from: Koues OI, et al. Trends Genet. 2015;31(12):720-731. • FL3B → sheets of • Stage I-II centroblasts • Stage II (bulky) and Stage III-IV NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Hoster E, et al. Blood. 2008;111(2):558-565. FL Treatment Decision Making

GELF Criteria FLIPI-1 Criteria

Involvement of ≥3 nodal sites, each with a diameter of ≥3 cm Age ≥60 y Ann Arbor Stage III-IV Any nodal or extranodal tumor mass with a diameter of ≥7 cm Hemoglobin level <12 g/dL B symptoms Serum LDH level >ULN Splenomegaly Number of nodal sites ≥5

Pleural effusions or peritoneal ascites Risk Group According to FLIPI Chart Low 0-1 Cytopenias (leukocytes <1.0 x 109/L and/or platelets <100 x 109/L) Moderate 2 9 Leukemia (>5.0 x 10 /L malignant cells) High ≥3 • Therapy with rituximab in patients not meeting the modified • FLIPI-1 developed in pre-rituximab era but still retains its GELF criteria does not improve OS and outside a clinical trial prognostic significance • Observation is still standard practice for patients with • FLIPI-2 (not mentioned) was developed for newly diagnosed advanced stage low-tumor-burden FL patients treated with rituximab ULN, upper limit of normal. NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Solal-Celigny P, et al. Blood. 2004;104(5):1258-1265. MCL Treatment Decision Making

Incurable with conventional chemotherapy Disease/Patient Factors • SOX11 expression—more aggressive phenotype • Age, Ki-67, ECOG PS, LDH, WBC define risk groups Observation plays a limited role and in select patients (ie, MCL in situ, smoldering MCL)* Treatment Pathway • Induction → consolidation → maintenance Chemotherapy Stage I-II: radiation ± chemoimmunotherapy • No accepted standard of care across practice • Aggressive induction reserved for patients able to tolerate therapy Stage II (bulky) and Stage III-IV: chemotherapy ± • Less aggressive induction for patients with autologous hematopoietic cell transplantation (HCT) comorbidities precluding aggressive treatment High-Dose Chemotherapy With Stem Cell Rescue • Best chance for long-term survival is to consolidate *Observation may be appropriate in select patients with Ki-67 remission with autologous HCT <30%, maximum tumor diameter <3 cm, normal serum LDH and β2- • Earlier application of HCT results in better outcomes microglobulin levels, lack of B symptoms, and nonblastoid/pleomorphic histology.

NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Cheah CY, et al. J Clin Oncol. 2016;34(11):1256-69; Mcculloch R, Rule S. Best Pract Res Clin Haematol. 2018;31(1):90-98. Simplified MIPI Calculations for MCL

• 4 prognostic factors for survival (age, PS, LDH, OS According to MIPI leukocyte counts) • Risk groups are well separated • Low: 0-3 points; Intermediate: 4-5 points; High: 6-11 points

Hoster E, et al. Blood. 2008;111(2):558-565; Republished with permission of American Society of Hematology from "A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma," Blood, Hoster E, et al; 111 © 2008; permission conveyed through Copyright Clearance Center, Inc. ” Management

Relapsed or Refractory FL Follicular Lymphoma NCCN Suggested Treatment Regimens

First-Line Therapy Elderly or Infirm Second-line and Subsequent Therapy Elderly or Infirm Preferred Regimens • Rituximab (preferred) Preferred Regimens • Rituximab (preferred) (375 • Bendamustine + obinutuzumab (375 mg/m2 weekly • Bendamustine + obinutuzumab or rituximab mg/m2 weekly for 4 doses) or rituximab for 4 doses) • CHOP + obinutuzumab or rituximab • Chlorambucil + rituximab • CHOP + obinutuzumab or • Chlorambucil + • CVP + obinutuzumab or rituximab • Cyclophosphamide + rituximab rituximab • Rituximab rituximab • CVP + obinutuzumab or • Cyclophosphamide + • Lenalidomide ± rituximab • Chlorambucil rituximab rituximab Other recommended regimens • Cyclophosphamide • Lenalidomide + dexamethasone • Chlorambucil • Ibritumomab tiuxetan • Ibritumomab tiuxetan Other Recommended Regimens • Cyclophosphamide • PI3K inhibitors (relapsed/refractory after 2 (category 2B) • Rituximab (375 mg/m2 weekly • Ibritumomab tiuxetan therapies) for 4 doses) (consider for low • Idelalisib tumor burden) • Copanlisib • Duvelisib Consolidation or Extended Dosing • DLBCL therapies • Rituximab maintenance 375 mg/m2 one dose every 8 weeks for Consolidation or Extended Dosing 12 doses for patients initially presenting with high tumor burden (category 1) • Rituximab maintenance 375 mg/m2 one dose every 12 weeks for 2 years (category 1) • Obinutuzumab maintenance (1000 mg every 8 weeks for 12 • Obinutuzumab maintenance for rituximab-refractory (1 g every 8 weeks for total of 12 doses) doses) • If initially treated with single-agent rituximab, consolidation with • High-dose therapy with autologous stem cell rescue rituximab 375 mg/m2 one dose every 8 weeks for 4 doses • Allogeneic hematopoietic cell transplant for highly selected patients • Ibritumomab tiuxetan (category 2B)

NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. Unmet Needs in Relapsed/Refractory FL Class FDA-Approved Pipeline • At least 20% of PI3K Inhibitors Idelalisib, copanlisib, duvelisib patients experience IMiDs Lenalidomide early relapse (within BCL2 Inhibitors Venetoclax 2 years of initiating Monoclonal Ocaratuzumab (CD20), epratuzumab and frontline treatment) Antibodies galiximab (CD22), otlertuzumab (CD37) • Drug resistance ADCs Polatuzumab vedotin* Inotuzumab ozogamicin BiTE antibody Blinatumomab • Cumulative toxicities BTK inhibitors Ibrutinib, acalabrutinib Immune checkpoint Nivolumab, pembrolizumab, inhibitors atezolizumab HDACs Vorinostat, panobinostat, mocetinostat Chimeric antigen Tisagenlecleucel, axicabtagene receptor (CAR) T-cells ciloleucel* *DLBCL

Casulo C, et al. J Clin Oncol. 2015;33(23):2516-2522; Younes A, et al. Nat Rev Clin Oncol. 2017;14(6):335-346. PI3K Inhibitors Approved for FL

Agent Indication in FL Administration Dosing Box Warnings Hepatotoxicity Diarrhea or colitis Patients with relapsed FL who have received 150 mg twice Idelalisib Oral tablets Pneumonitis ≥2 prior systemic therapies daily Infection Intestinal perforation Infection Adult patients with R/R FL after ≥2 prior Diarrhea or colitis Duvelisib systemic therapies Oral capsules 25 mg twice daily Cutaneous reactions Pneumonitis 60 mg on days 1, Adult patients with relapsed FL who have Copanlisib IV infusion 8, and 15 of a 28- None received ≥2 prior systemic therapies day cycle Accelerated approval, based on ORR.

Zydelig [prescribing information]. Foster City, CA: Gilead Sciences, Inc; 2018; Aliqopa [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2017; Copiktra [prescribing information]. Needham: MA: Verastem, Inc; 2018. Efficacy of PI3K Inhibitors

Idelalisib Duvelisib Copanlisib

Patients With Patients With Patients With Primary End Patients With FL Patients With FL Patients With FL iNHL iNHL iNHL Point (n = 72) (n = 83) (n = 104) (n = 125) (n = 129) (n = 142) ORR, n/N 40/72 71/125 35/83 61/129 61/104 84/142 • % (95% CI) 55.6 (43.4, 67.3) 57 (48, 66) 42 (31, 54) 47.3 (38.4, 56.3) 59 (49, 68) 59 (51, 67) • CR, n (%) 10 (13.9) 7 (6) 1 (1) 2 (1.6) 15 (14) 17 (12) • PR, n (%) 30 (41.7) 63 (50) 34 (41) 59 (45.7) 46 (44) 67 (47) Patients With Patients With Patients With Secondary End Patients With FL Patients With FL Patients With FL NHL iNHL iNHL Points (n = 72) (n = 83) (n = 83) (n = 125) (n = 129) (n = 129) Median PFS, 11.0 (95% CI: 8.0, 11.0 (range: 9.5 (8.1, 11.8) 11.2 (0.2, 24.0) months 14.0) 0.03, 16.6) Median OS, 20.3 (range: Not reached 28.9 (21.4, NE) Not reached months 0.7, 22.0)

Gopal AK, et al. N Engl J Med. 2014;370(11):1008-1018; Salles G, et al. Haematologica. 2017;102(4):e156-e159; Flinn IW, et al. J Clin Oncol. 2019;37(11):912-922; Copiktra [prescribing information]. Needham: MA: Verastem, Inc; 2018; Dreyling M, et al. J Clin Oncol. 2017;35:3898-3905. Select Toxicities of PI3K Inhibitors

Idelalisib Duvelisib Copanlisib

Adverse Reaction Any Grade (%) Grade ≥3 (%) Any Grade (%) Grade ≥3 (%) Any Grade (%) Grade ≥3 (%) Hematologic • Neutropenia 53 25 34 30 32 25 • Anemia 28 2 20 11 78 4 • Thrombocytopenia 26 6 17 10 22 8 Gastrointestinal • Diarrhea or colitis 47 14 50 23 36 5 • Nausea, vomiting 29, 15 1, 1 24, 16 <1, 1 26, 13 <1%, 0 • Abdominal pain 26 2 18 2 -- -- Skin • Rash 21 3 31 9 15 2 General disorders • Fatigue 30 1 29 5 36 4 • Pyrexia 28 2 26 2 -- -- Transaminase 50, 41 19, 12 40, 37 8, 6 -- -- elevation (ALT, AST) Musculoskeletal Musculoskeletal Hyperglycemia (54) Hyperglycemia (39) Other (drug-specific) Insomnia (12) Insomnia (0) pain (20) pain (1) Hypertension (35) Hypertension (27)

Design: phase 3b, multicenter, open-label Design: phase 3, multicenter, randomized AEs >20% study Neutropenia, fatigue, Patients: R/R FL or MZL (n = 358) Patients: R/R NHL diarrhea, constipation, (n = 155 with FL, MZL, or MCL) nausea, and cough Schematic: randomized (1:1) to receive lenalidomide and rituximab or rituximab and Schematic: 12 cycles of lenalidomide + rituximab 2 Lenalidomide 20 mg placebo (R ); if stable disease or better, randomized (1:1) to maintenance R2 or rituximab alone daily on days 1-21 every Outcomes: 28 days up to 12 cycles Median PFS (ITT) by IRC: 39.4 months vs 14.1 Outcomes: months (HR 0.46; 95% CI: 0.34, 0.62; P <0.001) ORR in FL: 59% (104/177; 95% CI: 51%, + ORR by IRC in FL: 80% (118/147; 95% CI: 73%, 66%) rituximab 86%) vs 55.4% (82/148; 95% CI: 47%, 64%) Median DOR: not reached with a median follow-up of 7.9 months (95% CI: 4.6, 9.2) MZL, marginal zone lymphoma.

Leonard JP, et al. J Clin Oncol. 2019;37(14):1188-1199; Andorsky D, et al. J Clin Oncol 2018;36(15 suppl):7516; FDA approves lenalidomide for follicular and marginal zone lymphoma [news release]. FDA: May 28, 2019; FDA website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lenalidomide-follicular- and-marginal-zone-lymphoma. Accessed August 3, 2019. Management of Aggressive FL

• No difference in survival outcomes between patients with FL3A and FL3B • FL3 with >50% diffuse component has inferior survival outcome similar to DLBCL • Some may treat FL3A as FL and others may treat it as DLBCL • FL3B is commonly treated as DLBCL • Stages I-IV DLBCL → R-CHOP 3-6 cycles ± radiation • R/R DLBCL • Salvage chemotherapy (ie, R-ICE, R-DHAP) followed by stem cell transplant, if eligible

Tisagenlecleucel and axicabtagene ciloleucel Indicated in R/R large B-cell lymphoma after ≥2 lines of systemic therapy including DLBCL-NOS, high grade B-cell lymphoma, and DLBCL arising from FL.

NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Hans CP, et al. Blood. 2003;101(6):2363-2367. CAR T-Cell Overview

• Genetically modified autologous T-cell immunotherapy (CD-19) • Tisagenlecleucel—ORR 52% (95% CI: 41, 62); CR 40%; PR 12% • Axicabtagene ciloleucel—ORR 82%; CR 54% • Administered as IV infusion and preceded by lymphodepleting chemotherapy • Safety: CRS and neurotoxicity • REMS: tocilizumab in stock

Barrett DM, et al. Annu Rev Med. 2014;65:333-347; Yescarta REMS website. www.yescartarems.com/. Accessed July 2, 2019; Schuster SJ, et al. N Engl J Med. 2019;380(1):45-56; Neelapu SS, et al. N Engl J Med. 2017;377(26):2531-2544; Republished with permission of Annual Reviews, from "Chimeric antigen receptor therapy for cancer," Ann Rev Med, Barrett DM, et al; 65 © 2014; permission conveyed through Copyright Clearance Center, Inc. Polatuzumab Vedotin-piiq

• MOA: CD79b-directed antibody conjugated to monomethyl auristatin E (MMAE) • Dosing: 1.8 mg/kg IV infusion over 90 minutes every 21 days for 6 cycles + BR • Efficacy • Study GO29365 (80 DLBCL and 80 FL) • Several arms with rituximab or obinutuzumab combinations • DLBCL efficacy, FL not yet reported • CR 40% (95% CI: 25-57%) with P+BR vs 18% (95% CI: 7%-33%) with BR • ORR 63% with P+BR vs 25% with BR • 64% response durations of ≥6 months and 48% response durations of ≥12 months in patients with either a CR or PR • Toxicity: peripheral neuropathy, infusion-related reactions, myelosuppression, TLS

Indicated in R/R DLBCL-NOS after ≥2 lines of systemic therapy.

Sehn LH, et al. J Clin Oncol. 2018;36(15 suppl):7507; Sehn LH, et al. Blood. 2018;132:Abstract 1683; Polivy [prescribing information]. South San Francisco, CA: Genentech, Inc; 2019. Antibody Drug Conjugates

Image reproduced from Tsuchikama K, An Z. Protein Cell. 2018;9(1):33-46 under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). FL Treatment Summary

• Many patients may be observed for years, never require treatment, and succumb to other causes • Treatment selection and initiation are often dictated by age, comorbidities, and disease-specific risk factors • Anti-CD20 therapies ± chemotherapy ± radiation remain as cornerstone therapies in the frontline setting • Anti-CD20 therapy may be used as consolidation or extended therapy to extend event-free survival • Anti-CD20 therapies ± chemotherapy are preferred treatment options as second-line options but many patient develop resistance • PI3K inhibitors have demonstrated efficacy following 2 prior lines of treatment • Lenalidomide + rituximab have demonstrated efficacy in R/R FL • Aggressive forms of FL may require treatment as DLBCL • R-CHOP is the standard of care • CAR T-cell therapies provide benefits in select patients following progression Management

Relapsed or Refractory MCL Mantle Cell Lymphoma NCCN Suggested Treatment Regimens Induction Therapy- Elderly or Infirm Second-line Therapy Aggressive Therapy Less Aggressive Short Response Duration to Prior Chemoimmunotherapy (< Expected Median PFS) • RDHA (rituximab, • Bendamustine + rituximab • Acalabrutinib dexamethasone, cytarabine) • VR-CAP (bortezomib, rituximab, • Ibrutinib ± rituximab + platinum cyclophosphamide, • Lenalidomide ± rituximab • Alternating R-CHOP/R-DHAP doxorubicin, and prednisone) • Venetoclax • NORDIC regimen (maxi- • R-CHOP Other Recommended Regimens CHOP alternating with • Lenalidomide + rituximab • Ibrutinib, lenalidomide, rituximab (category 2B) rituximab + HiDAC • Modified rituximab-HyperCVAD • Venetoclax + ibrutinib • HyperCVAD (>65 years) Extended Response Duration to Prior Chemoimmunotherapy (> Expected Median PFS) Other Recommended Other Recommended Regimens • Bendamustine ± rituximab (if not previously given) Regimens • RBAC (rituximab, • Bortezomib ± rituximab • Bendamustine + rituximab bendamustine, cytarabine) Other Recommended Regimens (category 2B) (category 2B) • Small molecule inhibitors as above • Bendamustine, bortezomib, and rituximab (category 2B) Consolidation after Aggressive Therapy • PEPC (prednisone, etoposide, procarbazine, cyclophosphamide) ± rituximab • High-dose therapy followed by autologous stem cell rescue (ASCR) (category 2B) • R-CHOP (if not previously given) (category 2B) Maintenance after High-dose Therapy (HDT)/ASCR • VR-CAP (if not previously given) (category 2B) • Maintenance rituximab every 8 weeks x 3 y (category 1) • Second-line DLBCL therapies • Less aggressive: until progression or intolerance (category 1 following Second-line Consolidation R-CHOP; 2-5 y following modified rituximab-HyperCVAD) • Allogeneic HCT (nonmyeloablative or myeloablative) NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019. Unmet Needs in R/R MCL

• Significant unmet need as Class FDA-Approved Pipeline no standard of care exists PI3K Inhibitors Idelalisib, copanlisib, duvelisib • Best outcome with salvage IMiDs Lenalidomide chemotherapy followed by BCL2 Inhibitors Venetoclax allogeneic HCT BiTE antibody Blinatumomab • Median age at diagnosis is BTK inhibitors Ibrutinib, acalabrutinib Zanubrutinib 68 years (ie, elderly, Proteasome Bortezomib comorbidities, less- Inhibitors aggressive) HDACs Vorinostat Chimeric antigen Zanubrutinib Prescription receptor (CAR) Lisocabtagene maraleucel Drug User Fee Act (PDUFA) T-cells date: February 27, 2020 Chemotherapy Cladribine Cheah CY, et al. J Clin Oncol. 2016;34(11):1256-1269; Jain P, et al. Am J Hematol. 2019;94(6):710-725; BeiGene Announces US FDA Acceptance and Grant of Priority Review for its New Drug Application of Zanubrutinib in Patients with Relapsed/Refractory Mantle Cell Lymphoma [news release]. BeiGene. http://ir.beigene.com/news- releases/news-release-details/beigene-announces-us-fda-acceptance-and-grant-priority-review. Accessed August 26, 2019. Efficacy and Safety of Ibrutinib

End Point Ibrutinib PCYC-1104 Phase 2 (n = 50) Phase 2 multicenter, combination with Phase 3, randomized (RAY) vs Trial (n = 50) + phase 2 lenalidomide and temsirolimus (n = 139) rituximab (n = 111) rituximab ORR (%) 67 -- 76 77 vs 47 (P <0.0001) CR (%) 23 58 56 -- 31% OS (months) -- -- 30 vs 24 (P = 0.06) (24 months) 47% PFS (months) 43 16 vs 6 (24 months) -- Diarrhea (51%), musculoskeletal pain (37%), nausea (31%), vomiting (23%), URI Toxicity (34%), grade ≥3 thrombocytopenia (17%), neutropenia (29%), pneumonia (8%)

Wang ML, et al. Blood 2015;126(6):739-745; Rule S, et al. Leukemia. 2018;32(8):1799-1803; Jain P, et al. Br J Haematol. 2018;182(3):404-411; Jerkeman M, et al. Lancet Haematol. 2018;5(3):e109-e116; Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019. Efficacy and Safety of Acalabrutinib

Primary End Point Acalabrutinib

ACE-LY-004 Trial Phase 2 (n = 124)

ORR (%) 81 CR (%) 40 DOR (months) -- OS (months) 12 (67%) PFS (months) 12 (87%) Infections (53%), headaches (39%), bleeding (31%), diarrhea (31%), myalgias (21%), nausea (18%), grade ≥3 anemia (12%) and neutropenia (10%)

Wang M, et al. Lancet. 2018;391(10121):659-667; Calquence [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. Chemotherapy-free Induction With BTKi

• Phase 2, single-center clinical trial • Ibrutinib + rituximab → R + hyperCVAD alternating with R + methotrexate-AraC • If CR after I+R → 4 cycles of intensive • If PR or progression → continue and give 2 additional cycles beyond CR • Rationale: 10.7-year survival with intensive chemo (8 cycles); 10-year cumulative incidence of therapy-related myeloid neoplasm 6.2%

Response Chemo‐free induction (Part 1), Chemo‐immune consolidation n = 50 (Part 2), n = 33 CR 40 (80%) 33 (100%) PR 10 (20%) 0 (0%) ORR 50 (100%) 33 (100%)

Wang M, et al. Blood. 2016;128:147; Wang M, et al. Hematol Oncol. 2017;35(suppl 2):142-143. Efficacy and Safety of Bortezomib

• Approved for patients with MCL after ≥1 prior therapy • Used in frontline less aggressive therapy in VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) Bortezomib Bortezomib + Rituximab Efficacy Efficacy • ORR 33% • ORR 40%; 29% in patients with MCL • CR 8% • 2-year PFS 24% for all patients and 60% in patients • Median time to progression 6.7 months with responding disease • Median OS 23.5 months • Long-term follow-up consistent • Toxicities: cytopenias, neuropathy (subcutaneous route preferred), viral infections • Antiviral prophylaxis recommended • Different concentration for SC vs IV (2.5 mg/mL vs 1 mg/mL)

Fisher RI, et al. J Clin Oncol. 2006;24(30):4867-4874; Goy A, et al. Ann Oncol. 2009;20(3):520-525; Baiocchi RA, et al. Cancer. 2011;117(11):2442-2451. Efficacy and Safety of Venetoclax

• Approved in acute myeloid leukemia and chronic lymphocytic leukemia

Venetoclax Venetoclax + ibrutinib Efficacy in all NHL (106 patients; 28 patients had MCL) Efficacy (MCL and poor prognostic factors) • ORR 44% (75% in MCL) • CR 42% • Median PFS 6 months (14 months in MCL) • 78% of patients with responding disease were • 12-month OS 70% (82% in MCL) estimated to have an ongoing response at 15 • CR in MCL 21% months • Toxicities: tumor lysis syndrome, neutropenia • Patients with high tumor burden, particularly those with MCL, are at risk for TLS • Start dose of 20 mg daily for 1 week, gradually escalate to target dose of 400 mg daily over 5 weeks • Reduce dose with CYP3A4 inhibitors Davids MS, et al. J Clin Oncol. 2017;35(8):826-833; Tam CS, et al. N Engl J Med. 2018;378(13):1211-1223; Venclexta [prescribing information]. North Chicago, IL: AbbVie Inc; 2019. MCL Treatment Summary

• MCL is an indolent lymphoma with unique features and characteristics associated with an aggressive course requiring long-term multimodal chemoimmunotherapy • Aggressive induction therapy is reserved for patients able to tolerate treatment • Less aggressive options are available for elderly, frail patients • HDT/ASCR + maintenance rituximab following aggressive induction have demonstrated high, durable remissions • Treatment of R/R disease remains a challenge, but consideration of novel agents provide new therapeutic options requiring close monitoring with management of unique toxicities associated with treatment Management of Adverse Effects and The Role of Pharmacists in Optimizing Care

Relapsed or Refractory B-Cell NHL Unmet Needs in Oral Oncology

Maintenance •AE management •Adherence and compliance Need for Coordination •Cyclic labs •Cyclic labs •Refills medically •Methods of communication Initiation •Refills •Drug-drug interactions •Provider appointments integrated •Inappropriate dosing •Updated insurance plans •Baseline labs and monitoring model. •Need for education •Insurance and procurement

Pharmacists provide clinical considerations and operational best practices to optimize oral chemotherapy dispensing and management.

Timmers L, et al. BMC Cancer. 2017;17(1):122; Mulkerin DL, et al. J Oncol Pract. 2016;12(10):e912-e923; Battis B, et al. J Oncol Pharm Pract. 2017;23(8):582-590. PI3K Inhibitors Boxed Warnings*

Cutaneous Hepatotoxicity Diarrhea/colitis Pneumonitis Infections reactions

Hold drug if Rule out infectious Rule out infectious PJP prophylaxis Grade 1-2: emollients, moderate/severe causes causes recommended antihistamines (>5-20 x ULN) (pruritus), or topical steroids Withhold for Withhold and manage Consider dose reduction Monitor CMV PCR if mild/moderate → with steroids, resume at once LFTs normalize CMV serostatus positive loperamide reduced dose Grade 3: withhold → emollients, Clinical CMV infection or antihistamines Discontinue for severe Withhold for severe → Discontinue for grade ≥3 viremia → withhold and (pruritus), or topical antidiarrheals + steroids (>20 x ULN) resume when resolved steroids → reduce dose

Discontinue for Discontinue for Discontinue for *Recommendations may life-threatening confirmed PJP infection life-threatening differ between agents. Weerdt I, et al. Haematologica. 2017;102(10):1629-1639; NCCN clinical practice guidelines in oncology. Chronic lymphocytic leukemia/small cell lymphoma v5.2019; Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019; Calquence [prescribing information]. Wilmington, DE: AstraZeneca; 2017; Copiktra [prescribing information]. Needham, MA: Verastem Oncology; 2018; Zydelig [prescribing information]. Foster City, CA: Gilead; 2018. Lenalidomide Management

• Toxicities • Cytopenias (black box warning), thrombosis (black box warning), rash, neuropathies • Withhold and dose reduce if indicated for cytopenias • Aspirin or therapeutic anticoagulation should be used to prevent against DVT/PE depending on risk factors • Teratogenicity Requirements • REMS requirements must be met prior to initiating therapy and any subsequent cycles • Females of reproductive potential → negative pregnancy tests, monthly surveys • Females of nonreproductive potential → surveys every 6 months • Men → monthly surveys • Providers → monthly survey for all patients indicating education has been provided and dose dispensing → will receive authorization number which must be included with Rx • Dispensing pharmacies → survey of education and dose dispensing → confirmation number

Revlimid REMS. Revlimid website. www.revlimidrems.com. Accessed July 3, 2019. BTK Inhibitor AEs: Hypertension

Prevention • Same as general patient population Management • Monitor blood pressure and adjust antihypertensive treatments as appropriate • Median time to onset, 5.9 months (range, 0.03-24 months) • Frequency of monitoring • Do not need to adjust dosing of therapy

Weerdt I, et al. Haematologica. 2017;102(10):1629-1639; Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019; Chai LK, et al. Leuk Lymphoma. 2017;58(12):2811-2814; Calquence [prescribing information]. Wilmington, DE: AstraZeneca; 2017; Jones JA, et al. Br J Haematol. 2017;178(2):286-291. BTK Inhibitor AEs: Atrial Fibrillation

Ibrutinib > Acalabrutinib Prevention • Monitor for signs and symptoms • Palpitations, lightheadedness, dizziness, fainting, shortness of breath, chest discomfort Management • If CHASDS2-VASc score ≥2, guidelines recommend anticoagulation • Consider non-warfarin anticoagulation • In combination with ibrutinib, prefer: rivaroxaban or apixaban • Monitor carefully; if uncontrolled, consider switching to alternative therapy Weerdt I, et al. Haematologica. 2017;102(10):1629-1639; Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019; Chai LK, et al. Leuk Lymphoma. 2017;58(12):2811-2814; Calquence [prescribing information]. Wilmington, DE: AstraZeneca; 2017; Jones JA, et al. Br J Haematol. 2017;178(2):286-291. BTK Inhibitor AEs: Bleeding

Ibrutinib > Acalabrutinib Prevention • Impact of platelet aggregation is reversible within 1 week of discontinuation • Clinical trials excluded patients receiving warfarin • Consider risks and benefits with antiplatelet and anticoagulation therapy • Monitor for signs of bleeding • Surgery: Evaluate risk and benefit • Acalabrutinib • Hold for 3 days pre and 3 days post surgery; consider the benefit-risk for 3-7 days pre and post surgery • Ibrutinib • Minor surgery: hold for 3 days pre and 3 days post surgery • Major surgery: hold for 7 days pre and 7 days post surgery

• If dose is missed, must be taken as 1st Occurrence: soon as possible on the same day Stop ibrutinib until resolves to grade 1 or better. • Next dose should be taken at regular time Resume ibrutinib at starting dose. on the next day 2nd Occurrence: • Do not take 2 doses in 1 day to make up Stop ibrutinib until resolves to grade 1 or better. for a missed dose Resume ibrutinib, reduce dose by 140 mg. • Drug–drug interactions with CYP3A 3rd Occurrence: inhibitors/inducers Stop ibrutinib until resolves to grade 1 or better. Resume ibrutinib, reduce dose by additional 140 mg. • Mid-cycle trade in program available 4th Occurrence: Stop ibrutinib permanently. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019. Dosing Guidance for Acalabrutinib Dose Modifications • 100 mg twice daily (every 12 hours) Any grade 3+ nonheme AEs, grade 3 • Can be taken with or without food thrombocytopenia + bleeding, grade 4 • If dose is missed by more than 3 thrombocytopenia, grade 4 neutropenia >7 days. hours, skip that dose and take the next one at the regularly scheduled time 1st or 2nd Occurrence: • Do not take extra dose to make up for a Stop acalabrutinib until resolves to grade 1 or better. missed dose Resume acalabrutinib at 100 mg twice daily. • Drug–drug interactions with CYP3A 3rd Occurrence: inhibitors/inducers AND gastric acid Stop acalabrutinib until resolves to grade 1 or better. reducing agents/proton pump Resume acalabrutinib at 100 mg once daily. inhibitors 4th Occurrence: Stop acalabrutinib permanently. Calquence [prescribing information]. Wilmington, DE: AstraZeneca; 2017. Treatment-related Lymphocytosis

Lymphocytosis does NOT indicate progressive disease.

BTK Inhibitors Immunomodulatory PI3K Inhibitors Ibrutinib Drug Idelalisib Acalabrutinib Lenalidomide Duvelisib

• Tumor flare reaction is correlated with clinical response with lenalidomide • BTK and PI3K inhibitors lead to transient lymphocytosis due to redistribution or release of cells from lymph nodes to peripheral blood • Often resolves within 8 months from treatment initiation (prolonged durations have been reported)

Chanan-Khan A, et al. Cancer. 2011;117(10):2127-2135; Woyach JA, et al. Blood. 2014;123(12):1810-1817; Brown JR, et al. Blood. 2014;123(22):3390-3397; NCCN clinical practice guidelines in oncology. Chronic lymphocytic leukemia/small cell lymphoma v5.2019. Venetoclax TLS Laboratory TLS • Uric acid: hyperuricemia Prevention • Potassium: hyperkalemia • Consider patient comorbidities (eg, renal • Phosphorous: hyperphosphatemia dysfunction) • Calcium: hypocalcemia • Appropriate dose ramp-up (venetoclax)

Clinical TLS = MEDICAL EMERGENCY • Hydrate, hydrate, hydrate • Complications include: • Initiate allopurinol 2 or 3 days prior to start of • Nausea/vomiting venetoclax • Lethargy • 4-week ramp-up recommended in MCL starting at • Edema 50 mg • Renal failure • Congestive heart failure • Potentially—sudden death

Cheson BD, et al. Oncologist. 2017;22(11):1283-1291; Venclexta [prescribing information]. North Chicago, IL: AbbVie; 2018; NCCN clinical practice guidelines in oncology. Chronic lymphocytic leukemia/small cell lymphoma v5.2019. Venetoclax Initiation

Tumor Burden Prophylaxis Site of Care Blood Chemistry Monitoring 1st dose of 20 mg and 50 mg: LOW Oral hydration (1.5-2 L) Pre-dose, 6-8 hours, 24 hours Outpatient All lymph nodes <5 cm AND Allopurinol Pre-dose at subsequent ramp-up ALC <25 x 109 doses Outpatient 1st dose of 20 mg and 50 mg: MEDIUM Oral hydration (1.5-2 L) and consider Pre-dose, 6-8 hours, 24 hours additional IV hydration In-patient (if CrCl <80 Any lymph node 5 cm to <10 cm OR mL/min at 1st dose of Pre-dose at subsequent ramp-up ALC ≥25 x 109 Allopurinol 20 mg and 50 mg) doses Oral hydration (1.5-2 L) and IV In-patient at 1st dose of hydration as tolerated (150-200 mL/h) 1st dose of 20 mg and 50 mg: HIGH 20 mg and 50 mg Pre-dose, 4, 8, 12 and 24 hours Allopurinol or febuxostat Any lymph nodes ≥10 cm OR Outpatient subsequent Subsequent ramp-up doses: ALC ≥25 x 109 AND any lymph node ≥5 cm ramp-up doses Consider rasburicase if baseline elevated Pre-dose, 6-8 hours, 24 hours uric acid Cheson BD, et al. Oncologist. 2017;22(11):1283-1291; Venclexta [prescribing information]. North Chicago, IL: AbbVie; 2018. Drug–Drug Interactions*

Agent 3A4 Strong 3A4 Inhibitor Moderate 3A4 Inhibitor Strong 3A4 Inducer Miscellaneous Avoid Avoid Avoid Acalabrutinib Substrate Short-term anti-infective: 100 mg once daily or increase to PPI (entirely); H2RA and antacids interrupt acalabrutinib 200 mg daily (separate by 2 hours) Avoid except voriconazole or 280 mg once daily Ibrutinib Substrate Avoid n/a posaconazole (NCCN: avoid) 70 mg or 140 mg once daily Substrate n/a Duvelisib 15 mg bid - Avoid inhibitor Substrate n/a Idelalisib Monitor - Avoid inhibitor Copanlisib Substrate 45 mg - Avoid n/a P-gp inhibitor: Reduce dose by ≥50% Venetoclax Substrate Avoid or reduce by 75% Reduce dose by ≥50% Avoid P-gp substrate: Separate by ≥6 hours *Additional recommendations are available. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics; 2019; Calquence [prescribing information]. Wilmington, DE: AstraZeneca; 2017; Copiktra [prescribing information]. Needham, MA: Verastem Oncology; 2018; Zydelig [prescribing information]. Foster City, CA: Gilead; 2018; Venclexta [prescribing information]. North Chicago, IL: AbbVie; 2018; Aliqopa [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2017. Cost Saving/Convenience Initiatives • Biosimilar: rituximab-abbs (Truxima) and rituximab-pvvr (Ruxience) • NCCN panel supports rituximab-abbs only for patients with low-grade indolent lymphomas (FL and MZL)

• SC administration: rituximab and hyaluronidase (Rutixan Hycela) • SABRINA and MabEase trials: phase 3; confirmed the noninferiority for SC rituximab (1400 mg) compared with IV rituximab (375 mg/m2) when used in combination with chemotherapy for patients with previously untreated FL or DLBCL • FL and DLBCL dosing: 1400 mg rituximab and 23,400 units hyaluronidase human • Guidelines support substitution after patients have received the first full dose of rituximab by IV infusion

NCCN clinical practice guidelines in oncology. B-Cell Lymphomas v4.2019; Rituxan Hycela [prescribing information]. South San Francisco, CA: Genentech; 2017; Truxima [prescribing information]. North Wales, PA: Teva Pharmaceuticals; 2018; Ruxience [prescribing information]. New York, NY: Pfizer; 2019; Davies A, et al. Lancet Haematol. 2017;4(6):e272-e282; Lugtenburg P, et al. Haematologica. 2017;102(11):1913-1922. Conclusion

FL MCL • Indolent disease and may not require treatment for • Classified as indolent disease yet exhibits years components and characteristics of aggressive • t(14;18) hallmark translocation lymphomas • Age, comorbidities, and disease-specific risk factor • t(11;14) hallmark translocation influence treatment selection • Age, comorbidities, and disease-specific risk factors • Anti-CD20 therapies ± chemotherapy ± radiation influence treatment selection remain • HDT/ASCR play a major role in treatment and • Novel therapies provide additional options in R/R outcomes setting • Novel therapies provide additional options in R/R • Aggressive disease treated as DLBCL setting Pharmacists play an integral role in disease stage management. • Symptom management, adherence and compliance, education, and monitoring • Appropriate medication use and handling • Optimizing REMS and ensuring compliance • Recommending cost-saving initiatives when appropriate Additional Resources

• Armitage JO, Gascoyne RD, Lunning MA, et al. Non-Hodgkin lymphoma. Lancet. 2017;390(10091):298-310. • Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806-813. • Khan N, Moskowitz AJ. Where do the new drugs fit in for relapsed/refractory Hodgkin lymphoma? Curr Hematol Malig Rep. 2017;12(3):227-233. • Lee SQ, Raamkumar AS, Li J, et al. Reasons for primary medication nonadherence: a systematic review and metric analysis. J Manag Care Spec Pharm. 2018;24(8):778-794. • Kavookjian J, Wittayanukorn S. Interventions for adherence with oral chemotherapy in hematological malignancies: a systematic review. Res Social Admin Pharm. 2015;11(3):303-314. • Oral Chemotherapy Education Sheets. Available at: oralchemoedsheets.com Evolving Pharmacotherapy Options in Melanoma Laura Alwan, PharmD, BCOP Oncology Clinical Pharmacist University of Washington/Seattle Cancer Care Alliance Seattle, Washington This activity is supported by an educational grant from Merck Sharp & Dohme Corp. Educational Objectives At the completion of this activity, participants will be able to:

• Recognize mutations in melanoma that have pharmaceutical targets and recommended tumor mutation testing options • Examine recommended adjuvant therapies for patients with melanoma including nuances in efficacy and safety • Identify therapy options for advanced or metastatic melanoma based on disease- and patient-specific characteristics • Explain the role of clinical and specialty pharmacists in improving care of patients receiving therapy for melanoma Pathophysiology of Melanoma

• Different melanoma subtypes • Different presentation, genetic profiles, prognosis, and response to therapy • Cutaneous melanoma (vs uveal, mucosal) • Chronic sun-induced damage, non chronic sun-induced damage, acral

Seuradge J, Wong E. Melanoma. McMaster Pathophysiology Review website. www.pathophys.org/melanoma/melanoma-progression/. Accessed September 16, 2019; NCCN Clinical Practice Guidelines Melanoma, v2.2019. Epidemiology and Statistics

• Estimated 96,480 new cases in 2019 • Increasing in men more rapidly than any other malignancy • 7230 deaths due to melanoma (DOWN) • Men: 4740 • Women: 2490 • Median age at diagnosis: 63 years

Siegel R, et al. CA Cancer J Clin. 2019;69(1):7-34; NCCN Clinical Practice Guidelines Melanoma, v2.2019; About melanoma skin cancer. American Cancer Society website. www.cancer.org/content/dam/CRC/PDF/Public/8823.00.pdf. Updated May 20, 2016. Accessed July 3, 2019. Risk Factors for Melanoma

• Caucasians • Blond or red hair • Blue, green, or gray eye color • Higher degree of freckling • Personal history of melanoma • Family history of melanoma • Exposure to sun lamps and tanning beds • Presence of melanocytic nevi and atypical nevi

Gandini S, et al. Eur J Cancer. 2005;41(1):45-60; NCCN Clinical Practice Guidelines Melanoma, v2.2019. Diagnosis of Cutaneous Melanoma

• Biopsy suspicious lesion • Complete history (including risk factors) • Total body skin examination • Additional testing • CT scan • Chest x-ray • Lactate dehydrogenase (LDH) • Indications for genetic testing • BRAF testing – Stage III at high risk for recurrence (to guide adjuvant therapy) and Stage IV • Broader genomic profiling for eligibility in a clinical trial

NCCN Clinical Practice Guidelines Melanoma, v2.2019. Prognostic Significance of Mutations: BRAF

BRAF • Most common mutation – BRAF V600E (also V600K) • Found in 30%-60% of melanomas • Higher in non-chronic sun damage subtype, younger patients • BRAF V600E activates MAPK-ERK signal transduction pathway, enhancing proliferation • Combination BRAF inhibitors/MEK inhibitors considered drug regimens of choice • Dabrafenib/trametinib • Vemurafenib/cobimetinib • Encorafenib/binimetinib

Ernstoff MS. N Engl J Med. 2011;364(26):2547-2548; Chapman PB, et al. N Engl J Med. 2011;364(26):2507-2516; About melanoma skin cancer. American Cancer Society website. www.cancer.org/content/dam/CRC/PDF/Public/8823.00.pdf. Updated May 20, 2016. Accessed July 3, 2019. NCCN Clinical Practice Guidelines Melanoma, v2.2019. Prognostic Significance of Mutations: cKIT cKIT • Most common in mucosal melanomas: 10-15% • Usually originating from head/neck, oral, genital regions • Also in chronic sun-damage and acral (palms, soles) subtypes • Very rare in non chronic sun-damage type • Drug of choice currently • Imatinib

NCCN Clinical Practice Guidelines Melanoma, v2.2019 Goldinger SM, et al. EJC Suppl. 2013;11(2):92-6.Hodi FS, et al. J Clin Oncol. 2008;26(12):2046-2051. Prognostic Significance of Mutations: NRAS

NRAS • Additional common mutation, but no current drug targets • Mutation predominantly at codon 61 • Mutation is found in 15-20% of melanomas • Highly aggressive and are associated with shorter patient survival • Multiple regimens under evaluation • MEK inhibition and CDK4/6 inhibition

NCCN Clinical Practice Guidelines Melanoma, v2.2019; Goldinger SM, et al. Eur J Cancer Suppl. 2013;11(2):92-6. History of Melanoma Treatment

Immune component to Anti-CTLA 4 spontaneous regressions in indication melanoma Brain IL-2 approved as cancer metastases immunotherapy BRAF/MEK data

1970 1980 1990 2000 2011 2014 2015 2017

Use of dacarbazine and temozolomide in Intralesional IFN-α approved as melanoma cancer immunotherapy PD-1 inhibitors

Kirkwood JM, et al. J Clin Oncol. 2008;26(20):3445-3455; NCCN Clinical Practice Guidelines Melanoma, v2.2019. Adjuvant Treatment of Melanoma

Stage II Stage III Stage IB, IIA (node negative) (node positive)

Surgery, consider adjuvant therapy: Surgery, Surgery, Nivolumab Observation Observation Pembrolizumab Dabrafenib/Trametinib

NCCN Clinical Practice Guidelines Melanoma, v2.2019. Mechanism of Action: PD-1 Inhibitors

https://www.cancer.gov/images/cdr/live/CDR774646-750.jpg © 2015 Terese Winslow LLC, U.S. Govt. has certain rights. Adjuvant Immunotherapy: Nivolumab vs Ipilimumab: CheckMate 238 Primary end point: RFS Secondary end points: OS, AE profile, RFS according to PD-L1 expression, and HRQOL • RFS (12-month) Arm 1 (n = 453) • 71% (nivo) vs 61% (ipi) (HR, 0.65; 97.56% CI, 0.51-0.83; P<0.001) Nivolumab 3 mg/kg • Treatment-related AEs every 2 weeks • Grade 3 or 4: 14.4% (niv) vs 45.9% (ipi) • Any AE leading to discontinuation • 9.7% (nivo) and 42.6% (ipi) • 2 deaths (0.4%) Arm 2 (n = 453) • Reported in ipilimumab more than 100 days after treatment Ipilimumab 10 mg/kg every 3 weeks x 4 doses, Conclusion then every 12 weeks • Adjuvant use of nivolumab • Longer RFS, less toxicity than ipilimumab AE, adverse effect; HRQOL, health-related quality of life; Weber J, et al. N Engl J Med. 2017;9:1824-1835. OS, overall survival; RFS, recurrence-free survival. Adjuvant Immunotherapy: Pembrolizumab vs Placebo: KEYNOTE-054 Primary end point: RFS Secondary end points: Distant MFS, OS, safety measures, and measures of HRQOL

R Inclusion Criteria A Arm 1 (n = 514) • 18 years or older N Pembrolizumab 200 mg • Stage IIIA, IIIB, or IIIC D every 3 weeks until disease • Complete regional lymphadenectomy 1:1 O recurrence or toxicity M Exclusion Criteria I • ECOG >1 Z Arm 2 (n = 505) • Uncontrolled infections A Placebo every 3 weeks • T Autoimmune disease until disease recurrence • Systemic therapy for melanoma I or toxicity • Systemic corticosteroids O N Eggermont A, et al. N Engl J Med. 2018;378(19):1789-1801. MFS, metastasis-free survival. Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma: KEYNOTE-054

P <0.001 • Treatment-related AEs: 77.8% (pem) vs 66.1% 75.4 (placebo) 1-year RFS • Rates of fatigue, asthenia, and diarrhea were 61 similar between the 2 groups • 1 pembrolizumab death • IRAEs: 37.3% (pem) vs 9% (placebo) (mostly P <0.001 endocrine) 77.1 1-year RFS PD-L1 62.6 Conclusion • Pembrolizumab 200 mg every 3 weeks results in Pembrolizumab Placebo significantly longer RFS regardless of PD-L1 status 0 10 20 30 40 50 60 70 80 90 • No new toxicities that haven’t been documented already Eggermont A, et al. N Engl J Med. 2018;378(19):1789-1801. IRAE, immune-related adverse effect. Mechanism of Action of BRAF and MEK Inhibitors: Mitogen-Activated Protein Kinase (MAPK) Signaling

NRAS NRAS Vemurafenib Dabrafenib V600E BRAFV600E BRAF Encorafenib MEK MEK Trametinib Cobimetinib Binimetinib ERK ERK

Proliferation and Survival Apoptosis

Adapted from Ribas A, Flaherty KT. Nat Rev Clin Oncol. 2011;8(7):426-433. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma: COMBI-AD

Primary end point: RFS Secondary end points: OS, distant MFS, freedom from relapse, and safety

Arm 1 (n = 435) 58 3-year RFS Dabrafenib 150 mg bid 39 + trametinib 2 mg daily for 12 months

86 3-year OS Arm 2 (n = 432) 77 HR, 0.57 Placebo for 12 months CI, 0.42-0.79 D + T Placebo P = 0.0006 0 10 20 30 40 50 60 70 80 90 100 Long GV, et al. N Engl J Med. 2017;377(19):1813-1823. Adjuvant Dabrafenib plus Trametinib: COMBI-AD • Median RFS Observed in ≥10% of Patients in Any • NR (combo) vs 16.6 mo (placebo) Treatment Group • Deaths Event Dabrafenib + Trametinib Placebo • 14% (combo) vs 22% (placebo) (N = 435) (N = 432) • Skin AEs Pyrexia 273 (63%) 47 (11%) • Squamous cell/keratoacanthoma: 8 (2%) vs 7 (2%) Fatigue 204 (47%) 122 (28%) • Basal cell carcinoma: 19 (4%) vs 14 (3%) Nausea 172 (40%) 88 (20%) • Noncutaneous cancers: 10 (2%) vs 4 (1%) Headache 170 (39%) 102 (24%) Conclusion Chills 161 (37%) 19 (4%) • Dabrafenib/trametinib significantly reduces risk of Diarrhea 144 (33%) 65 (15%) recurrence in V600E or V600K Vomiting 122 (28%) 43 (10%) • Toxicity profile is the same as studied in other trials with combo therapy

Long GV, et al. N Engl J Med. 2017;377(19):1813-1823. Adjuvant Treatment Summary: Take-Home Points • Single-agent immunotherapy with PD-1 inhibitors (category 1) • Nivolumab 240 mg every 2 weeks or 480 mg every 4 weeks until progression or toxicity for up to 1 year • Pembrolizumab 200 mg every 3 weeks until disease progression or toxicity for up to 1 year • Targeted therapy: Dabrafenib + trametinib (category 1) • For patients with BRAF V600E or V600K mutation • 150 mg twice daily + 2 mg daily until disease progression or unacceptable toxicity for up to 1 year • No head-to-head study to determine which agent or strategy is most effective • If +BRAF mutation, can use either strategy: patient preference, toxicity profile, cost • PD-L1 status doesn’t appear to matter

NCCN Clinical Practice Guidelines Melanoma, v2.2019. Metastatic Melanoma Treatment

Stage II Stage III Stage IB, IIA Stage IV (node negative) (node positive)

Pembrolizumab Nivolumab Nivolumab Pembrolizumab Nivolumab + Observation Observation ipilimumab Dabrafenib/ BRAF/MEK trametinib combinations Clinical trial

NCCN Clinical Practice Guidelines Melanoma, v2.2019. KEYNOTE–006: Pembrolizumab versus Ipilimumab Primary end point: PFS, OS Secondary end points: ORR, duration of response, and safety Arm 1 (N = 279) Pembrolizumab 10 mg/kg Pembrolizumab Pembrolizumab Ipilimumab every 2 weeks 10 mg/kg 10 mg/kg 3 mg/kg every 2 weeks every 3 weeks every 3 weeks N = 279 N = 277 N = 278 Median PFS 5.5 mo 4.1 mo 2.8 mo Arm 2 (N = 279) Pembrolizumab 10 mg/kg every 3 weeks Median OS 74.1% 68.4% 58.2% (at 12 months) (p <.0005) (p = 0.0036) ORR 33.7% 32.9% 11.9% (p<0.001) (p<0.001) Arm 3 (N = 277) Ipilimumab 3 mg/kg every • Median time to response all groups: ~86 days 3 weeks x 4 doses • Grade 3-5 toxicity: 19.9% ipilimumab vs. 10-13.3% pembrolizumab • OS update in 2017 confirmed superiority of pembrolizumab

Robert C, et al. N Engl J Med. 2015; 372:2521-2532. PFS, progression-free survival; ORR, overall response rate. CheckMate 067: Combined Nivolumab and Ipilimumab or Monotherapy

Primary end point: PFS and OS Secondary end points: ORR, PD-L1 expression, and safety

Outcomes Arm 1 (n = 316) Arm 2 (n = 314) Arm 3 (n = 315) Nivolumab 3 mg/kg q2 Nivolumab 1 mg/kg q3 weeks Ipilimumab 3 mg/kg weeks + placebo + ipilimumab 3 mg/kg q3 weeks x 4 q3 weeks doses, then nivo 3 mg/kg q2 weeks x 4 doses + placebo Median OS 37.6 mo NR 19.9 mo P <0.001 P <0.001 Median PFS 6.9 mo 11.5 mo 2.9 mo P <0.001 P <0.001 Grade 3 or 4 Toxicity 21% 59% 28%

Larkin J, et al. N Engl J Med. 2015;373(1):23-34; Wolchok JD, et al. N Engl J Med. 2017;377(14):1345-1456. Dabrafenib and Trametinib versus Dabrafenib for BRAF V600-Mutant Melanoma: COMBI-D • Primary end point: PFS • Secondary end point: OS, safety, duration of response • 3 year landmark efficacy and safety analysis confirmed initial results

Arm 1 (n = 211) Outcome Dabrafenib + Trametinib Dabrafenib Dabrafenib 150 mg twice daily Median PFS 11 months 8.8 months + trametinib 2 mg daily Median PFS at 3 years 22% 12% (PFS probability) Arm 2 (n = 212) Median OS 25.1 months 18.7 months Dabrafenib 150 mg twice daily Serious Adverse Events, 45% 38% + placebo updated at 3 years follow- (ex. >10% difference): (ex. >10% difference): up Pyrexia, chills, diarrhea, Hyperkeratosis, alopecia, vomiting, peripheral skin papilloma edema

Long GV, et al. Lancet. 2015;386(9992):444-451; Long GV et al. Ann Oncol. 2017;28(7):1631-1639. Combined Vemurafenib and Cobimetinib in BRAF-Mutated Melanoma: coBRIM • Primary end point: PFS • Secondary end points: OS, OR, duration of response (DOR), safety • Updated efficacy analysis confirmed interim data Arm 1 (n = 238) Outcome Vemurafenib + Vemurafenib + Vemurafenib 960 mg twice daily Cobimetinib placebo Inclusion Criteria + cobimetinib 60 mg daily Median PFS 12.3 months 7.2 months • Unresectable Stage IIIC for 21 days, then 7 days off P <0.001 or IV • V600 E/K mutation positive Median OS 22.3 months 17.4 months • Previously UNTREATED • ECOG 0 or 1 Arm 2 (n = 240) Serious 37% 28% Vemurafenib 960 mg twice Adverse (ex. CPK, LFTs, (ex. alopecia, daily + placebo Events photosensitivity, hyperkeratosis) nausea, diarrhea, retinopathy) Ascierto PA, et al. Lancet Oncol. 2016; 17(9):1248-60. Encorafenib plus Binimetinib versus Vemurafenib or Encorafenib in BRAF-Mutant Melanoma (COLUMBUS)

• Primary end point: PFS • Secondary end points: OS and safety

Outcome Encorafenib + Encorafenib Vemurafenib Arm 1 (N = 192) Binimetinib Arm 2 (N = 194) Encorafenib 450 mg daily Encorafenib 300 mg daily Median PFS 14.9 months 9.6 months 7.3 months + binimetinib 45 mg bid (significant vs. vemurafenib) Arm 3 (N = 191) Median OS 33.6 months 23.5 months 16.9 months Vemurafenib 960 mg bid (significant vs. vemurafenib) Key toxicities: nausea, vomiting, fatigue. Dummer R, et al. Lancet Oncol. 2018;19(5):603-615; Dummer R, et al. Lancet Oncol. 2018;19(10):1315-1327. T-VEC Improves Durable Response Rate in Patients With Advanced Melanoma Primary end point: Durable response rate (DRR) Secondary end points: OS, ORR Inclusion Criteria R Arm 1 (n = 295) • 18 years or older A T-VEC 10^6 pfu/mL x1 (seroconversion), • Stage IIIB or IV suitable for injection N then 10^8 pfu/mL 3 weeks later, • Measureable disease D • LDH ≤1.5 ULN then continue every 2 weeks O *max 4 mL per total treatment • ECOG ≤1 2:1 M I Exclusion Criteria • Chronic antiviral or high-dose steroid use Z A Arm 2 (n = 141) • Ocular or mucosal melanoma 2 • Active cerebral metastases T Sargramostim 125 mcg/m SC daily for 14 • >3 visceral metastases I days in 28-day cycles • Patients with history of autoimmune disease O N Andtbacka RH, et al. J Clin Oncol. 2015;33(25):2780-2788. IV, intravenous; SC, subcutaneous; ULN, upper limit of normal. T-VEC Improves DRR in Patients With Advanced Melanoma

Precautions T-VEC Sargramostim P-value • Avoid direct contact to the injection site or dressing N = 295 N = 141 • Blood should be considered potentially infectious DRR 16.3% 2.1% P <0.001 • Urine can be infectious on the day of the injection

Patient Counseling ORR 26.4% 5.7% Not • Avoid direct contact with treatment sites, dressings, available or body fluids Median OS 23.3 mo 18.9 mo P = 0.051 • Wear gloves when changing dressings and keep covered for at least 1 week following treatment • AEs included fatigue, chills, and pyrexia. Dispose of all used dressings and cleaning materials in a sealed plastic bag before throwing in the garbage

Andtbacka RH, et al. J Clin Oncol. 2015;33(25):2780-2788; Imlygic [prescribing information]. Thousand Oaks, CA: Amgen; 2018. A Note About Brain Metastases in Melanoma

• Frequent event in advanced disease • Common site of therapeutic failure • Generally excluded from clinical trials • Historically very poor prognosis • Cause of death in majority of patients • Median OS: ≈5 months

Davies MA, et al. Cancer. 2011;117(8):1687-1696; Flanigan JC, et al. Curr Probl Cancer. 2011;35(4):200-210. Brain Metastases in Melanoma

Trial Prior Treatment Arms Extracranial Intracranial PFS Median OS Systemic RR RR (mo) Median Therapy (mo) CheckMate 17% Nivo + ipi, then nivo 50% 55% NR NR 204 (n = 94) Break-MB ≥26% Dab (n = 89) 38% 39% 3.8 7.7

≥42% Dab (n = 83) 3.9 7.3 COMBI-MB 22% A = Dab + Tram (n = 76) 55% 58% 5.6 10.8 B = Dab + Tram (n = 16) 44% 56% 7.2 24.3 31% C = Dab + Tram (n = 16) 75% 44% 4.2 10.2 D = Dab + Tram (n = 17) 41% 59% 5.5 11.5

RR, relative risk.

Tawbi HA, et al. ASCO 2017: Abstract 9507; Long GV, et al. Lancet Oncol. 2012;13(11):1087-1095; Davies MA, et al. Lancet. 2017;18(7):863-873. Metastatic or Unresectable Disease Treatment Summary First-Line Second-Line or Subsequent Therapy Therapy • Pembrolizumab, Nivolumab (category 1) • First-line therapy options not already used • For BRAF-positive patients (category 1) • Ipilimumab • High-dose interleukin 2 (IL-2) (special NOTE: shorter time to onset of response vs circumstances) immunotherapy • Ipilimumab/intralesional T-VEC (category 2B) • Dabrafenib + trametinib • Cytotoxic agents (eg, dacarbazine, • Vemurafenib + cobimetinib temozolomide, taxane) • Encorafenib + binimetinib • Imatinib for cKIT tumors • Nivolumab/ipilimumab (category 1 for certain • Consider BSC for poor performance status circumstances) BSC, best supportive care. NCCN Clinical Practice Guidelines Melanoma, v2.2019. Summary of Available BRAF Inhibitors

Dabrafenib Vemurafenib Encorafenib Dosing 150 mg orally BID (empty 960 mg orally BID with or without 450 mg orally once daily with stomach) food or without food

Drug–drug Avoid strong inhibitors of Avoid strong inhibitors of CYP3A4. Avoid strong AND moderate interactions CYP3A4 (ex. voriconazole) If giving with strong CYP3A4 CYP3A4 inhibitors—dose and CYP2C8. inducer, may increase dose 240mg reductions required! (see PI)

May reduce efficacy of May reduce efficacy of CYP1A2 May reduce efficacy of CYP3A4 or CYP2C9 substrates or narrow therapeutic CYP3A4 substrates substrates (ex. warfarin) Pgp substrates (ex. digoxin)

Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; 2019; Zelboraf [prescribing information]. South San Francisco, CA: Genentech; 2017; Braftovi [prescribing information]. Boulder, CO: Array BioPharma; 2018. Summary of Available MEK Inhibitors

Trametinib Cobimetinib Binimetinib Dosing 2 mg orally once daily 1 hour 60 mg once daily, days 45 mg twice daily with or before or 2 hours after a 1-21, then 7 days off without food meal (empty stomach) with or without food Decrease to 30 mg bid for T. bili >1.5 x ULN Drug–drug Substrate of P-gp, likely not Avoid strong, moderate Substrate of P-gp, likely interactions significant, CYP2C8 inhibitor CYP3A4 inducers or not significant inhibitors (dose reduction to 20 mg)

Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; 2019; Cotellic [prescribing information]. South San Francisco, CA: Genentech; 2018; Mektovi [prescribing information]. Boulder, CO: Array BioPharma; 2018. Comparison of BRAF/MEK AEs

Dabrafenib/Trametinib Vemurafenib/Cobimetinib Encorafenib/Binimetinib General Symptoms Pyrexia +++ ++ ++ Headache + + ++ Fatigue ++ +++ ++ Peripheral edema + -- ++ Diarrhea + +++ ++ Nausea + + ++ Vomiting + ++ ++ Other Symptoms Rash -- +++ ++ Hypertension +++ +++ +++ ALT/AST increase ++ +++ ++ CPK increase -- +++ +++ Anemia -- ++ +++ Photosensitivity -- ++ ++

NCCN Clinical Practice Guidelines Melanoma, v2.2019; Tafinlar [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; 2019; Zelboraf [prescribing information]. South San Francisco, CA: Genentech; 2017; Braftovi [prescribing information]. Boulder, CO: Array BioPharma; 2018; Mekinist [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals; 2019; Cotellic [prescribing information]. South San Francisco, CA: Genentech; 2018; Mektovi [prescribing information]. Boulder, CO: Array BioPharma; 2018. Managing BRAF/MEK Inhibitor Adverse Effects

• General: gastrointestinal • Antiemetics, loperamide for diarrhea, dose reductions for severe or refractory issues • Dabrafenib/trametinib: pyrexia • Dose interruption at first sign of fever; after 24 hours, can resume same doses • May consider dose reduction if subsequent episode, use of acetaminophen or NSAID with fever symptoms and prophylaxis • Low dose prednisone 10 mg/day for 5 days can help prevent recurrent pyrexia or for fever not responding to acetaminophen or NSAID after 3 days • Vemurafenib/cobimetinib: photosensitivity (severe sunburns/blistering with exposure to UV-A light) • Patient education on use of sunscreen (even in winter), protective clothing/covering, hats, etc. • Rash: Dose interruption and dose reduction if higher than grade 2 toxicity • Encorafenib/binimetinib: gastrointestinal • Manage as recommended above Daud A, et al. Oncologist. 2017;22(7):823-833. Summary of Checkpoint Inhibitors Ipilimumab Nivolumab Pembrolizumab Mechanism Anti-CTLA4 Anti–PD-1 Anti–PD-1

Dose 3 mg/kg every 3 weeks for 240 mg IV every 2 weeks or 200 mg IV every 3 4 doses 480 mg IV every 4 weeks weeks Combination ipi and nivo: • Ipi 3 mg/kg with nivo 1 mg/kg every 3 weeks x 4 doses, then nivo standard dosing • CheckMate 511 (not yet FDA approved): nivo 3 mg/kg with ipi 1 mg/kg every 3 weeks x 4 doses then nivo standard dosing

Yervoy [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2019; Opdivo [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; 2019; Keytruda [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2019; Lebbé C, et al. J Clin Oncol. 2019;37(11):867-875. Managing Immunotherapy: Timing of IRAEs

Toxicity Clinical Effects Time Frame Skin Rash, vitiligo, 2-3 weeks pruritus Gastrointestinal Diarrhea, colitis 6-7 weeks Liver Elevated enzymes, 6-7 weeks bilirubin, hepatitis Endocrine Hypophysitis, After 9 weeks hypothyroidism

Weber JS, et al. J Clin Oncol. 2012;30(21):2691-2697. IRAEs

• Early recognition and intervention is key • Steroids are primary therapy for most organ toxicities • Steroids do NOT reduce efficacy of immunotherapy • For doses >20 mg daily of prednisone, can consider PJP prophylaxis (if >4 weeks) and fungal prophylaxis (if >6-8 weeks) • In general: • Grade 1 – Checkpoint inhibitor therapy continued with close monitoring • Grade 2 – Checkpoint inhibitor therapy should be held and give steroids • Grade 3 and 4 – Checkpoint inhibitors should be held or permanently discontinued • High-dose corticosteroids (prednisone 1-2 mg/kg/d or methylprednisolone 1-2 mg/kg/d), continued until resolution to Grade 1, THEN tapered over at least 4-6 weeks • Exception of endocrinopathies that have been controlled by hormone replacement

NCCN Guidelines Management of Immunotherapy-Related Toxicities, V2.2019; Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-1768. Dermatologic IRAE Management

• Topical emollients and/or mild-moderate potency topical Continue immune Grade 1 corticosteroids checkpoint inhibitor • Avoid skin irritants and sun exposure (ICPI) therapy

• Consider initiating prednisone (or equivalent) at 1 mg/kg, tapering Consider holding over at least 4 weeks Grade 2 ICPI, monitor weekly • Treat with topical emollients, oral antihistamines, and medium to for improvement high potency topical corticosteroids

• Initiate (methyl)prednisolone (or equivalent) 1-2 mg/kg, tapering over at least 4 weeks Hold ICPI, consult Grade 3 • Treat with topical emollients, oral antihistamines, and high- dermatology for potency topical corticosteroids resumption

• Initiate IV (methyl)prednisolone (or equivalent) 1-2 mg/kg, Hold ICPI indefinitely Grade 4 with slow tapering unless benefits outweigh risks

Brahmer JE, et al. J Clin Oncol. 2018;36:1714-1768. Gastrointestinal IRAE Management

• Mild • Hydration, antidiarrheals • Moderate to Severe • Corticosteroids (prednisone 1-2 mg/kg daily, give IV if hospitalized) • If no response in 2-3 days, give 1 dose of infliximab (5 mg/kg) • If no response to infliximab, give 1 dose vedolizumab • Colectomy for extremely serious or persistent cases

NCCN Guidelines Management of Immunotherapy-Related Toxicities, V2.2019; Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-1768. Hepatic IRAE Management

• Mild: monitor closely • Moderate to Severe: • Prednisone 1-2 mg/kg daily (or give IV if hospitalized) • Refer to hepatology • If no response in 3 days, give mycophenolate 500-1000 mg BID • DO NOT USE infliximab

NCCN Guidelines Management of Immunotherapy-Related Toxicities. V2.2019; Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-1768. Endocrine IRAE Management

• Not reversible • Hypothyroidism • Thyroid supplement (ex. levothyroxine 1.6 mcg/kg, can use lower dose for elderly patients) • Adrenal insufficiency • Hydrocortisone 20 mg QAM/10 mg QPM or Prednisone 10 mg daily • Then add fludrocortisone 0.1 mg titrate based on symptoms/assessment

NCCN Guidelines Management of Immunotherapy-Related Toxicities, V2.2019; Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-1768. IRAE Management: Steroid Taper Plan

Example steroid protocol Reduce by 10 mg weekly thereafter • Weight: 80 kg • 70 mg (7 tablets) by mouth daily x 1 week • Prednisone 1 mg/kg/day • 60 mg (6 tablets) by mouth daily x 1 week • Immediately start 80 mg (8 tablets) by • 50 mg (5 tablets) by mouth daily x 1 week mouth daily x 1 week or until resolves • 40 mg (4 tablets) by mouth daily x 1 week to Grade 1, then taper weekly over AT • 30 mg (3 tablets) by mouth daily x 1 week LEAST 4 weeks • 20 mg (2 tablets) by mouth daily x 1 week • 10 mg (1 tablet) by mouth daily x 1 week • 5 mg (0.5 tablet) by mouth daily x 1 week

Brahmer JR, et al. J Clin Oncol. 2018;36(17):1714-1768. Role of the Pharmacist

• Collaboration with health care providers • Patient education • Goals of therapy • Common AEs • Storage, disposal of medications • Adherence • Review for drug–drug interactions • Telephone follow-up adherence assessments • Symptom management • Survivorship care

Mackler E, et al. J Oncol Pract. 2019;15(4):e346-e355. Ongoing Challenges and Next Steps

• Which BRAF/MEK combination to use? • Toxicity, indication, access, cost, familiarity • Re-treatment after progression on previous BRAF? • Which immunotherapy agent or should combination be used? • Toxicity, performance status, access, cost • How long should patients be treated with immunotherapy in the metastatic setting? • Clinical trials were for 2 years, then what? • Use of neoadjuvant treatment in earlier stage disease • Other T cell targets for immunotherapy medications • Vaccines Additional Resources

• NCCN. Clinical Practice Guidelines – Management of Immunotherapy-Related Toxicities, v2.2019. Available at: www.nccn.org • NCCN Clinical Practice Guidelines – Melanoma, v2.2019. Available at: www.nccn.org Clinical Review of Recent Advances in Acute Myeloid Leukemia (AML) Therapy Larry W. Buie, PharmD, BCOP, FASHP Clinical Pharmacy Manager PGY2 Adult Residency Program Director Memorial Sloan Kettering Cancer Center New York, New York This activity is supported by educational grants from Agios Pharmaceuticals, Inc. and Jazz Pharmaceuticals. Educational Objectives

At the completion of this activity, the participants will be able to: • Select appropriate therapy for FLT3-positive patients based on treatment status • Identify IDH inhibitors used to treat AML • Examine appropriate therapy plans for older patients with AML with medical comorbidities Introduction to Patient KE

• 45-year-old woman • Presents to PCP with sore throat and prescribed 7-day course of antibiotics • Continued symptoms with increasing fatigue upon completion • CBC reveals WBC 90,000 and platelets of 75,000; KE is also slightly anemic • Concern for leukemia • Referral to ED • Flow PB: myeloid blasts CD13+, CD33+, CD34+, HLA-DR dim, CD117 dim, CD64 dim, CD4 dim, CD45 dim • BMBx reveals 79% myeloblasts in a hypercellular marrow • Cytogenetics reveal a normal karyotype • Molecular studies are pending • KE is started on 7+3 (daunorubicin 90 mg/m2 D1-3, cytarabine 100 mg/m2 CIV D1-7) Acute Myeloid Leukemia (AML) Overview

• Clonal expansion of myeloid blasts in peripheral blood, bone marrow, and/or other tissues • Leading cause of acute leukemia in adults • 21,450 new diagnoses in 2019 • 10,920 deaths • Median age is 67 years • Treatment outcomes are worse with progressively increasing age • Risk: antecedent hematologic malignancy, environmental exposures, or treatment-related risk • Chemotherapy, radiation, or immunosuppressant therapy

NCCN Guidelines Acute Myeloid Leukemia, Version 3.2019. Diagnosis and Risk Stratification: European LeukemiaNet Bone Marrow Blast Percent ≥20% blasts Current Risk Status Based on Presence of Validated Cytogenetics and Molecular Aberrations Risk Status: Risk Status: Risk Status: Poor/Adverse Favorable Intermediate • Complex (≥3 abnormalities) • Monosomal karyotype • Inv(16) or t(16;16) • Mutated NPM1 and FLT3-ITDhigh • -5, 5q-, -7, 7q-, -17/abn (17p) • t(8;21); RUNX1-RUNX1T1 • Wild-type NPM1 without FLT3-ITD • t(v;11q23); KMT2A rearranged low • Mutated NPM1 without FLT3-ITD or with FLT3-ITD • Inv(3), t(3;3) • FLT3-ITDlow • t(9;11); MLLT3-KMT2A • t(6;9); DEK-NUP214 • Biallelic mutated CEBPA • Other abnormalities not defined • t(9;22); BCR-ABL1 as favorable or adverse • Wild-type NPM1 and FLT3-ITDhigh 5-year Survival Rates 5-year Survival Rates • Mutated RUNX1, ASXL1, TP53 AML 10 65% 5-year Survival Rates AML 10 41% SWOG/ECOG 55% AML 10 14% SWOG/ECOG 38% CALGB 55% SWOG/ECOG 11% CALGB 24% CALGB 5% AML 11 34% AML 11 13% AML 11 2% NCCN Guidelines Acute Myeloid Leukemia, Version 3.2019. The Molecular Heterogeneity of the Intermediate-Risk Group Mutation Function Incidence in AML Notes

NPM1 Shuttle protein 28%-35% Improved EFS and OS compared with WT NPM1 FLT3 Receptor tyrosine kinase ITD 30% Associated with shorter duration of remission, decreased disease-free involved in hematopoiesis TKD 10% survival, and poorer outcomes CEBPA Transcription factor 7%-11% Favorable outcome (similar to CBF AML); OS improved in patients with biallelic mutation IDH1/2 Enzyme-decarboxylation of 6%-9% Conflicting prognostic information from clinical trials isocitrate DNMT3A Enzyme-DNA methylation 18%-22% Associated with poorer outcomes; prognostic information inconclusive KIT Receptor tyrosine kinase 20% Usually associated with CBF AML; may be associated with poorer prognosis in patients with t(8;21) RUNX1 Encodes myeloid 10% de novo Associated with older age, secondary AML; poorer risk group transcription factor ASXL Transcription factor 5%-36% de novo Associated with older age; lower EFS and OS TP53 mutations Tumor suppressor 12%-13% Most common in complex karyotype CBF, core-binding factor; EFS, event-free survival; ITD, internal tandem duplications; NCCN Guidelines Acute Myeloid Leukemia, Version 3.2019. OS, overall survival; TKD, tyrosine kinase domain; WT, wild-type. Response Criteria for AML

• Complete response (CR) Goals of Therapy: • Morphologic CR • Complete Remission • <5% blasts on BM aspirate • Absolute neutrophil count (ANC) >1000/mcL • Restoration of Normal • Platelets (Plt) >100,000/mcL Hematopoiesis • No residual extramedullary disease • No Evidence of Measurable • Cytogenetic CR – normal cytogenetics Residual Disease (MRD) • Molecular CR – negative molecular studies • Complete response with incomplete blood count recovery (CRi) • Transfusion independence with persistent cytopenia • Partial remission (PR) • Decrease in blast % by at least 50% and to 5%-25% in bone marrow aspirate and normalization of blood counts • Relapse – Reappearance of leukemic blasts, >5% blasts in bone marrow, or emergence of extramedullary disease • Induction failure – Failure to attain CR following at least 2 courses of induction NCCN Guidelines Acute Myeloid Leukemia Version 3.2019. AML Treatment Overview

Consolidation AML Diagnosis Induction Complete Post-remission Remission Therapy/Transplant

Incomplete Disease Response Relapse

Incomplete Response Re-induction Salvage Therapy Refractory Disease Allogeneic Stem Cell Transplantation

• CBF AML without KIT mutation • Insufficient data to support allogeneic stem cell transplantation in first CR • Intermediate-risk cytogenetics and/or molecular abnormalities • Consider transplant when the relapse incidence estimated at >35%-40% • Treatment-related AML or unfavorable cytogenetics and/or molecular abnormalities • Strong consideration should be given to allogeneic stem cell transplantation • Primary refractory disease • Allogeneic stem cell transplant is only curative option

NCCN Guidelines Acute Myeloid Leukemia, Version 3.2019; Dohner H, et al. Blood. 2016;129(4):424-447. Considerations When Frontline Therapy Fails…

Duration of FLT3? Clinical Trial CR1

Fitness of Molecular Patient Profiling

Salvage Chemotherapy IDH? and Transplant

Age Cytogenetics

Thol F, et al. Blood. 2015;126(3):319-327. FMS-Like Tyrosine Kinase (FLT3) Inhibition FLT3 Inhibitors in AML

• FMS-related tyrosine kinase 3 • Expressed on hematopoietic progenitors and leukemic blasts • One of the most common genomic alterations in AML • One-third of adult patients with de novo AML have FLT3 mutations • Leukocytosis, increased blast percent • Enriched in normal karyotype • Later event in leukemogenesis • Typically, patients are <70 years • 2 major mutations: • Internal tandem duplications (ITD) 20%-25% • Tyrosine kinase domain point mutations (TKD) 5%-10% • FLT3 ligand increased 2- to 3-fold during chemotherapy-induced aplasia

Grunwald MR, Levis MJ. Int J Hematology. 2013;97(6):683-694; Short NJ, et al. Ther Adv Hematol. 2019;10:1-18; Pratz KW, et al. Blood. 2017;129(5):565-571. Prognostic Impact of FLT3 Mutations

• Type of mutation • ITD mutations associated with increased relapse and worse survival compared with wild-type disease Risk stratification is critical! • Allelic ratio • FractionAllelic of leukemia ratios cells that harbor may the FLT3be mutation unreliable with • AUC of FLT3 mutation/AUC FLT3–wild-type • Ratios ≥0.5 are associatedlimited with worse survivalavailability. • Co-mutations may alter prognosis • NPM1 mutation improves prognosis • FLT3-ITD at relapse is associated with very short survival • Chemotherapy resistant with upregulation of pro-survival factors in leukemic blasts Midostaurin—RATIFY Trial Prospective,Midostaurin phase 3, multicenter,Placebo randomized, P-value CR 58.9%double-blind, placebo-controlled53.5% trial 0.15 OS 74.7 months 25.6 months 0.009

Allogeneic SCT in first CR 28.1% Cytarabine 3 g/m2 q12h22.7% N = 360 D1,3,5 Midostaurin EFS Daunorubicin 608.2 mg/m months2 D1-3 3 months50 mg PO bid D1-28 0.002 2 Midostaurin 50 mg Cytarabine 200 mg/m /d D1-7 (n = 120) Primary End Point: DFS Midostaurin 50 mg26.7 PO bid months D8-21 PO bid D8-21 15.5 months 0.01 N = 717 • OS •AgeSignificant 18-60 years adverse reactions: nausea, vomiting, rash. (n = 231) •Newly diagnosed •FLT3-mutated AML Secondary End Point: N = 357 Cytarabine Daunorubicin 60 mg/m2 D1-3 3Bottom g/m2 over 3hLine: q12h Placebo • EFS Cytarabine 200 mg/m2/d IVCI D1-7 D1,3,5 D1-28 Addition of midostaurinPlacebo D8to-21 standard chemotherapyPlacebo D8-21 results (nin = significantly 85) improved OS among patients with FLT3 mutation. Survival(n = 210) benefit was not seen with maintenance.

Stone RM, et al. N Engl J Med. 2017;377(5):454-464; Stone RM, et al. ASH 2015. Abstract 6. Gilteritinib in R/R AML: ADMIRAL Trial End Point Gilteritinib Salvage Chemotherapy HR, P-value Prospective,(N = 247) randomized,(N = 124) multicenter, OS, months 9.3 phase 3 clinical5.6 trial 0.637, P = 0.0007

Survival at 1 year 37.1% 16.7%

CR 21.1% Gilteritinib 12010.5% mg/day CRhN = 371 12.9% N = 2474.8% •Age 18-85 years EFS 2.8 months 0.7 months 0.793, P = 0.0830OS •R/R AML CR/CRi •FLT3-mutated≥ Grade 3 ITD AEsor Anemia, febrileSalvage neutropenia, Chemotherapy thrombocytopenia TKD LDAC BottomAZA Line: Gilteritinib is a potent FLT3 inhibitor that resultsMEC in longer OS and higher response rates compared AZA, azacitadine; FLAG-IDA, fludarabine, cytarabine, with traditional salvage chemotherapy and shouldFLAG be-IDA considered a newidarubicin standard with GCSF; of LDAC, care low in-dose R/R cytarabine; AML. MEC, mitoxantrone, etoposide, cytarabine; Perl AE, et al. AACR Annual Meeting 2019. Abstract CT184. N = 124 R/R, relapsed/refractory. Treatment Algorithm for FLT3-Mutated Patients

NO NO Newly diagnosed ITD/TKD: 7+3 (cytarabine/anthracycline) Clinical Trial Gilteritinib Midostaurin D 8-21 or Clinical Trial Azacitidine/ Sorafenib Complete remission? Complete remission? YES YES

Maintenance?

Consolidation: HiDAC + midostaurin Consider participation in Allogeneic HSCT if appropriate post-transplant TKI clinical trial Treatment Options in FLT3-Mutated AML Agent Mechanism of Action Highlights Sorafenib ITD Available off-label Off-target: c-KIT, PDGFR, Dose: 400 mg PO bid without food RAF, VEGFR Warnings: CV events, bleeding, hypertension, GI perforation, QT prolongation, hepatotoxicity Drug Interactions: 3A4 inducers; sorafenib inhibits UGT1A1, 1A9 and P-glycoprotein Midostaurin ITD and TKD FDA approved April 28, 2017—induction and consolidation Off-target: c-KIT, PKC, Dose: 50 mg PO bid PDGFR, VEGFR Warnings: Pulmonary toxicity Drug Interactions: 3A4 inhibitors and inducers Gilteritinib ITD and TKD Improved OS in R/R AML Off-target: AXL FDA approved November 28, 2018—R/R AML with FLT3 mutation Dose: 120 mg PO daily Warnings: Posterior reversible encephalopathy syndrome (PRES), QT prolongation, pancreatitis Drug Interactions: P-glycoprotein inducers; 3A inducers and inhibitors Quizartinib ITD only FDA Oncology Drug Advisory Committee (ODAC) voted against approval Off-target: c-KIT Internal FDA analysis did not show EFS benefit Dose: 60 mg daily Warnings: Cardiac toxicity and QT prolongation Crenolanib ITD and TKD Investigational Off target: PDGFR Dose: up to 200 mg/m2 PO tid; 100 mg PO tid in combination with chemotherapy Warnings: Elevated transaminases, diarrhea, n/v Adapted from Short NJ, et al. Ther Adv Hematol. 2019;10:1-18. Isocitrate Dehydrogenase (IDH) 1/2 Mutations Isocitrate Dehydrogenase (IDH) in AML

• IDH converts isocitrate to α-ketoglutarate (α-KG) • 2 predominant forms of IDH mutations • IDH1 (cytosolic): 7%-14% in adult AML • IDH2 (mitochondria): 8%-19 % in adult AML • Mutations lead to increased production to β-hydroxyglutarate (2-HG) • 2-HG poisons TET → epigenetic changes that block differentiation

Buege MJ, et al. Cancer. 2018;10(6):187; Levis M. Blood. 2013;122(16):2770-2771; Image republished with permission of American Society of Hematology, from “Targeting IDH: the next big thing in AML,” Blood, Levis M, 122(16) © 2013; permission conveyed through Copyright Clearance TET, ten eleven translocation. Center, Inc. IDH2 Mutation: Enasidenib Prospective, phaseResponse 1/2, R/R open AML (N label,= 176) dose escalation ORR 40.3% CR and expansion trial 19.3% CRp/CRi 6.8% MLFS 8% PR ≥60 years with R/R AML; relapse 6.3% Time to first response, months after transplant 1.9 Time to CR, months 3.8 N = 239 Median OS, months 9.3 Safety <60 years with R/R AML • ResponseAdvanced duration, myeloid months 5.6 MTD Transplantmalignancy rate 10% Response rates • ECOG 0-2 ≥60Safety years Gradewith untreated 3-4 AML and • HyperbilirubinemiaIDH2 mutation ineligible 12%for induction chemo Nausea 2%

IDH inhibitor-associated differentiation syndrome 6% Expansion dose: 100 mg PO daily. Leukocytosis Ineligible for3% other expansion arms MTD, maximum tolerated dose. Stein EM, et al. Blood. 2017;130(6):722-731. Bottom Line: Cri, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet Enasidenib induces hematologic responses inrecovery; patients mCR with, marrow R/R recovery; AML MLFS,and morphologicIDH2 mutation. leukemia-free state. IDH1 Mutation: Ivosidenib Treatment-related Grade 3 or Higher AEs Occurring in >1% of Overall Population Prospective, phase 1,Number open of-label, Patients dose (%) escalation and Event End Point R/RdoseEfficacy AML expansion (N = Population179) trial OverallResponse Population (NR/R = 258) AML ≥1 event grade 3 or higher 37 (20.7) (N = 125) 66 (25.6) (N = 179) QT interval prolongation 14 (7.8) 18 (7.0) ORR 41.6 % 39.1 % IDH Differentiation Syndrome 7 (3.9) 12 (4.7) CR 21.6 % 21.8 % Anemia 4 (2.2) 6 (2.3) CRh N = 179 Ivosidenib12.8 %dose escalation 11.7 % Thrombocytopenia 3 (1.7) 5 (1.9) Safety • Median≥18 years time to CR/CRi 2.7 monthsMTD not reached 2.0 months • ECOGLeukocytosis 0-2 3 (1.7)500 mg used as expansion dose3 (1.2) Response rates • MedianMyeloidFebrile duration malignancy neutropenia of CR/CRi 1 (0.6) 8.2 months 3 (1.2) 6.5 monthsPK/PD • IDH1 mutation MedianDiarrhea time to first response 1 (0.6) 1.9 months 3 (1.2) 1.9 months Hypoxia 2 (1.1) 3 (1.2) OS Bottom8.8 months Line: Ivosidenib induces durable remissions in patients with R/R AML and IDH1 mutation. DiNardo CD, et al. N Engl J Med. 2018;378(25):2386-2398. Untreated Mutated IDH AML Not Eligible for Intensive Chemotherapy Ivosidenib (N = 34) Enasidenib (N = 39) Patients Median age Patients Median age 77 years, 76.5 years, 79% 59% antecedent secondary AML malignancy ORR 55.0 % ORR 30.8% CR/CRi 42.0 % CR 18% Transplant rate 8.8 % Transplant rate 8%

Pollyea DA, et al. Leukemia. Published online April 9, 2019. doi: 10.1038/s41375-019-0472-2; Roboz GJ, et al. J Clin Oncol. 2019;37(15 suppl):7028. Treatment Options for IDH-Mutated AML Drug Mechanism of Highlights Action Enasidenib IDH2 inhibitor FDA approved: August 1, 2017 Indications: Adult patients with R/R AML with an IDH2 mutation as detected by an FDA- approved test Dose: 100 mg PO daily with or without food Warnings: Differentiation syndrome (DS) Drug interactions: Enasidenib and its metabolite AGI-16903 in vitro inhibitors of CYP1A, - 2B, -2C, -2D, -3A; UGT1A1, P-gp, BCRP, and organic anion transporters; enasidenib induces CYPB2B6 and 3A4 Ivosidenib IDH1 inhibitor FDA approved: July 20, 2018 Indication: Newly diagnosed patients with AML ≥75 years with comorbidities that preclude use of intensive chemotherapy or R/R AML (both with IDH1 mutation as detected by an FDA-approved test) Dose: 500 mg PO daily; avoid high-fat meal Warnings: QT prolongation, Guillain-Barré syndrome, DS Drug interactions: 3A4 inhibitors and inducers; avoid concomitant use of sensitive 3A4 substrates or QT prolonging medications Idhifa [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; 2017; Tibsovo [prescribing information]. Cambridge, MA: Agios Pharmaceuticals; 2019. A Closer Look at IDH-DS Management

Drug-induced differentiation can lead to changes in cytokine levels, producing inflammation and tissue damage: Onset varies! Signs and Symptoms of DS Supportive Care Measures • Dyspnea • Glucocorticoids • Fever • Broad-spectrum antibiotics • Rash • Cytoreductive therapy if leukocytosis • Pulmonary infiltrates present • Pleural effusion • Monitor for tumor lysis syndrome • Renal dysfunction IDH-DS can be effectively managed! Goal is to resume therapy if IDH1 or IDH2 Abou Dalle I, DiNardo CD. Ther Adv Hematol. 2018;9(7):163-173; Fathi AT, et al. JAMA Oncol. 2018;4(8):1106-1110. inhibitor is held. Options for Elderly Patients With Comorbidities Age Is Suboptimal Criterion for Allocation to Intensive Induction Therapy • NCCN has separate guidelines for patients >60 years •OlderPoor outcomesadults with with intact standard functional treatment status, minimal comorbidity, • Increasede novo in AML unfavorable without karyotypes unfavorable cytogenetics or molecular markers,• Increase inwithout mutations antecedent hematologic disorder, and without • Decreasetherapy -inrelated the number AML of may favorable benefit CBF from translocations intensive cytarabine- • Multidrugbased resistance therapy protein regardless expression of chronological age. • Treatment-related mortality increases

CBF, core binding factor. Novel Chemotherapeutics in AML Reformulating 7+3: Liposomal Daunorubicin/Cytarabine (CPX-351) • Daunorubicin and cytarabine in 1:5 molar ratio • Ensures that synergistic therapeutic drug ratios are constant • Each unit contains: • 1 mg cytarabine • 0.44 mg daunorubicin Cycle* Liposomal Daunorubicin/Cytarabine Dose/Schedule Units First Induction Daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 D1,3, and 5 100 units/m2 Second Induction Daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 D1 and 3 100 units/m2 (if needed) Consolidation Daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 D1 and 3 65 units/m2 *All infusions are over 90 minutes. Stein EM, Tallman MS. Blood. 2016;127(1):71-78; Vyxeos [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals; 2019. Liposomal Daunorubicin/Cytarabine in Elderly Patients

Phase 3, open-label, multicenter, randomized clinical trial

N = 153 N = 309 CPX-351 100 units/m2 60-75 years old Days 1,3,5 tAML sAML OS De novo AML with MDS- related cytogenetic N = 156 abnormalities Daunorubicin 60 mg/m2 IV push D1-3 Cytarabine 100 mg/m2 CI D1-7 Lancet JE, et al. J Clin Oncol. 2018;36(26):2684-2692. Liposomal Daunorubicin/Cytarabine: Survival Analysis Efficacy (N = 309) Outcome CPX-351 (n = 153) 7+3 (n = 156) HR, P-value 1-year survival 41.5 % 27.6 % 2-year survival 31.1 % 12.3 % ORR 47.7 % 33.3 % P = 0.016 CR 37.3 % 25.6 % P = 0.040 EFS 2.53 months 1.31 months 0.74, P = 0.021 Median duration of remission 6.93 months 6.11 months P = 0.291 Safety Increased time to neutrophil and platelet recovery; increased bleeding events; early mortality rates were acceptable Bottom Line: Liposomal daunorubicin/cytarabine improves OS irrespective of age, WT FLT3, t-AML, sAML in both favorable and intermediate risk subgroups.

Image reproduced from Lancet JE, et al. J Clin Oncol. 2018;36(26):2684-2692. © American Society of Clinical Oncology under a Creative Commons Attribution 4.0 License. Venetoclax: Inducing Apoptosis in Leukemia Cells • B-cell leukemia/lymphoma-2 (BCL-2) is a pro-survival molecule within the cell and key regulator of mitochondrial pathway • Venetoclax is an orally bioavailable, highly selective inhibitor of BCL-2 (BH3 mimetic) • Frees proapoptotic proteins to induce apoptosis • Venetoclax has been shown to induce death in AML cell lines • May be useful in eliminating chemoresistant disease • Major substrate of CYP3A4 and P-gp

Konopleva M, et al. Cancer Discov. 2016;6(10):1106-1117. Venetoclax + LDAC

N = 82 ≥60 years old Response rates Untreated AML Venetoclax 600 mg PO daily Duration of Unfit for standard LDAC 20 mg/m2 SC D1-10 response induction Safety

CR/CRi rate 54% Safety • 1.4 months to best response • Febrile neutropenia • Duration of remission 8.1 months • Myelosuppression Median OS: 10.1 months • Pneumonia Transfusion independence: 46% • Sepsis

Wei AH, et al. J Clin Oncol. 2019;37(15):1277-1284. LDAC, low-dose cytarabine. Venetoclax + HMA in Treatment-Naïve, Elderly Patients Results Patient characteristics PhaseMedian age:1b, 74open years-label, dose escalation trial 49% high-risk cytogenetics 25% secondary AML Safety Grade 3/4 AEs: febrile neutropenia,N=73 anemia, leukopenia, thrombocytopenia, N = 145 neutropenia, and pneumoniaVenetoclax* ≥65 years old No TLS reported Decitabine 20 mg/m2 D1-5 ORR Untreated AML 47% patients had AE that led to dose interruption OS Efficacy ECOG 0-2 ORR 68% Duration of response Unfit for standard inductionOverall leukemia response rate 83% Safety Median time to best response 2.1N=72 months Similar results withBottom differing venetoclaxVenetoclax* Line: doses and HMAs Median DOR 11.3 monthsAzacitidine in all patients; 75 mg/m 12.52 monthsD1-7 if CR Venetoclax, in combination with LDAC or HMA, is an option*Dose for escalation, front 400-line mg PO Median OS 17.5 months daily is approved dose. MRDDiNardo negativity CD,treatment et al. Blood. 2019;133(1):7 of-29%17 elderly MRD less patients than 10-3 and those who have significantHMA, hypomethylating agent. comorbidities that preclude use of intensive induction chemotherapy. Glasdegib-Hedgehog Pathway Inhibition

• Hedgehog signaling is essential to embryonic development • Aberrant signaling implicated in leukemogenesis and leukemia stem cell survival • Overexpression of hedgehog signaling is often seen in chemotherapy- resistant cells • Glasdegib binds smoothened, interrupting hedgehog signaling

Cortes JE, et al. Leukemia. 2019;33(2):379-389. Glasdegib in Elderly Patients With AML

Phase 2, open-label, multicenter, randomized clinical trial

N = 144 N = 88 ≥55 years old Glasdegib 100 mg daily Newly diagnosed LDAC 20 mg SC bid D1-10 Untreated AML OS High-risk MDS Unfit for intensive N = 44 chemotherapy LDAC 20 mg SC bid D1-10 ECOG 0-1

Cortes JE, et al. Leukemia. 2019;33(2):379-389. Glasdegib + LDAC: Overall Survival End Point Glasdegib/LDAC LDAC Alone HR, P-value OS 8.8 months 4.9 months 0.51, P = .0004 Alive at 6 months 59.8 % 39.5 % Alive at 12 months 38.2 % 9.5 % CR 17 % 2.3 % P <.05 DOR 9.9 months Safety QT prolongation, myelosuppression, pneumonia, fatigue, dyspnea; dysgeusia, alopecia, and muscle spasms were mostly low grade Patients With AML Glasdegib/LDAC LDAC Alone HR, P-value (n = 116) OS 8.3 months Bottom4.3 Line: months 0.46, P = .0002 ORRGlasdegib + LDAC is26.9 a new% front-line option5.3 % for patients with AML who cannot

Image reproduced from Cortes JE, et al. Leukemia. 2019;33(2):379tolerate-389, intensive under a Creative Commonschemotherapy. Attribution 4.0 International License. https://creativecommons.org/licenses/by/4.0/. Options for the Elderly Patient With AML Agent Mechanism of Action Highlights Liposomal Liposomal drug delivery with FDA approved August 3, 2017 daunorubicin/ daunorubicin:cytarabine Indication: Newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related cytarabine molar ratio 1:5 changes (AML-MRC) Induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 Consolidation: daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 Warnings: Hemorrhage, cardiotoxicity, tissue necrosis Drug Interactions: Monitor closely with cardiotoxic or hepatotoxic medications Venetoclax BCL-2 inhibitor FDA Approved November 21, 2018 Indication: In combination with azacitidine or decitabine or low-dose cytarabine for treatment of newly-diagnosed AML in adults who are ≥75 years or who have comorbidities that preclude the use of intensive induction chemotherapy Dosage: 400 mg daily with HMA; 600 mg daily with LDAC—take with food Warnings: Neutropenia, infections Drug interactions: 3A inhibitors, inducers, and P-glycoprotein inhibitors Glasdegib Hedgehog pathway inhibitor FDA Approved November 21, 2018 Indication: Used in combination with low-dose cytarabine for the treatment of newly-diagnosed AML in adult patients who are ≥75 years or who have comorbidities that preclude use of intensive induction chemotherapy Dosage: 100 mg PO daily Warnings: Embryo-fetal toxicity, blood donation, QT prolongation Drug interactions: 3A4 inhibitors and inducers, QT prolonging medications Vyxeos [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals; 2019; Venclexta [prescribing information]. South San Francisco, CA: Genentech USA; 2019; Daurismo [prescribing information]. New York, NY: Pfizer; 2018. Investigational Therapies

Agent Mechanism of Action Suggested Patient Population Vosaroxin Topoisomerase II inhibitor R/R AML Guadecitabine Hypomethylating agent Unfit for intensive chemotherapy resistant to deamination Volasertib Novel PLK1 inhibitor Combination with hypomethylating agent versus conventional induction EPZ-5676 DOT1L inhibitor MLL rearranged OTX-015 Bet inhibitor Ongoing investigation Pracinostat HDAC inhibitor Ongoing investigation Anti-CD33 BiTE Bispecific T-Cell Engager Ongoing investigation Many others Vaccines, immunotherapy, antibody drug conjugates

Stein EM, Tallman MS. Blood. 2016;127(1):71-78; Ravandi F, et al. Blood. 2018;1325:25. Conclusion

• AML is a heterogenous disease • Improved molecular understanding is increasing our ability to predict outcomes in AML and improve treatment options • Targeted therapies may improve outcomes when combined with conventional therapies • Patient selection for intensive therapy is multifactorial and not age dependent • Less intensive combination therapy is available for unfit patients • For patients with high risk disease, hematopoietic stem cell transplantation should be considered at CR1 • When possible, patients should be offered a clinical trial Additional Resources

• NCCN Clinical Practice Guidelines in Oncology • Provides an overview of AML, with emphasis on diagnosis and treatment recommendations • https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf

• Diagnosis and Management of AML in Adults: 2017 ELN Recommendations from an International Expert Panel • Döhner H, et al. Blood. 2017;129(4):424-447

• Clinical Considerations for the Use of FLT3 Inhibitors in Acute Myeloid Leukemia • Weis TM, et al. Crit Rev Oncol Hematol. 2019;141:125-138

• Can We Incorporate MRD Assessment into Clinical Practice in AML? • Ossenkoppele G, et al. Best Pract Res Clin Haematol. 2019;32:186-191