1/30/18

2018 BMT Pharmacists Conference

New and Emerging Drugs

Arpita Gandhi, PharmD, BCOP Hematology/Oncology Clinical Pharmacy Specialist Augusta University Medical Center, Augusta, GA

Disclosure

• Arpita Gandhi has nothing to disclose concerning possible financial or personal relationships with commercial entities (or their competitors mentioned in this presentation).

Objectives

• Review new drug approvals and investigational new drugs relevant to the field of hematopoietic stem cell transplantation • Describe mechanisms of action and evaluate the toxicity profile of newly approved agents • Analyze clinical data supporting the approval and proposed benefit of these drugs • Identify clinical pearls and potential place in therapy for these novel agents

1 1/30/18

New Drug Approval Gemtuzumab (AML) Copanlisib (FL)

March-July August September October 2017 2017 2017 2017

Midostaurin CPX-351 (AML) Acalabrutinib (MCL) (AML) (AML) (HL) Inotuzumab (ALL) Oral glutamine AML: acute myeloid ALL: acute lymphocytic leukemia powder (SCD) FL: follicular HL: hodgkin’s lymphoma MCL: SCD: sickle cell disease

Outline

Expanded Sickle Cell Indications/ Leukemia Lymphoma HCT Disease Emerging Drugs

HCT: hematopoietic stem cell transplantation

Acute Myeloid Leukemia

2 1/30/18

Midostaurin: FLT3 inhibitor

Multi-targeted kinase inhibitor (VEGF, PDGFR, stem cell factor, and FLT3)

Approval: April 2017

Labeled indication: FLT3-positive AML

Dosage and administration: 50 mg oral twice daily WITH FOOD on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation cycle (in combination with high-dose cytarabine)

Hepatically metabolized, but no dosage adjustment required for baseline hepatic impairment (note: patients with bili > 2.5 x ULN were excluded from RATIFY study)

FLT: FMS-like tyrosine kinase; PDGFR: platelet derived growth factor; ULN: upper limit of normal; VEGF: vascular endothelial growth factor; Midostaurin (Rydapt® ). Package Insert. Novartis Pharmaceutical Corporation, East Hanover, NJ. Accessed Nov 2017

FLT3

• FLT3 gene Located on chromosome 13 and encodes for FLT3 , which is expressed on majority of the leukemic blasts Mutated gene: proteins that spontaneously dimerize causing factor independent growth and fatal myeloproliferative neoplasm in murine models • Mutations Internal tandem duplication (ITD) • 25-30% of de novo AML and 15% of MDS derived AML • Increased risk of relapse, reduced survival and inferior clinical course overall Tyrosine kinase domain (TKD) • 10% of de novo AML • Unclear if confers poor prognosis • Clinical outcomes better than FLT3-ITD AML, however less clear clinical implications

Stone RM, et al. N Engl J Med 2017;377:454-64 Stansfield LC, et al. Pharmacotherapy 2017 Oct 4 [Epub]

RATIFY: Midostaurin in FLT3+ AML

Patients Treatment Groups Results (n= 717) Placebo (n = 357) Induction (up to 2 cycles): 7+3 Overall survival (median): 25.6 Consolidation (4 cycles): HiDAC* months R Maintenance: placebo for twelve 28-day Phase III, A cycles 4 yr. OS: 44.3% randomized, double- N blind, placebo controlled study D O Midostaurin (n = 360) Age 18-59 years with Induction (up to 2 cycles): 7+3 + Overall survival newly diagnosed M midostaurin** days 8-21 (median): 74.7 AML (t-AML I Consolidation (4 cycles): HiDAC* + months excluded) with FLT3 Z midostaurin** days 8-21 4 yr OS: 51.4% mutation Maintenance: midostaurin* for twelve E 28-day cycles HR 0.78, p = 0.009

⁋ cytarabine 200 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3 *HiDAC: high dose cytarabine (3 gm/m2 IV q12H days 1, 3, 5) ** Midostaurin 50 mg PO BID Stone RM, et al. N Engl J Med 2017;377:454-64

3 1/30/18

RATIFY: Efficacy

Midostaurin + Placebo + Outcomes Chemotherapy P Value (n = 360) (n = 357) Median OS, mos (range)* 74.7 (31.7-NR) 25.6 (18.6-42.9) 0.009 4-yr OS, % (95% CI) § Uncensored 51.4 (46.0-57.0) 44.3 (39.0-50.0) 0.0074 § Censored for SCT 63.7 (56.0-71.0) 55.7 (47.0-63.0) 0.08 HCT, (%) § Any time 59 55 0.28 § CR1 only 28.1 22.7 0.10

CR (by day 60), % 59 54 0.15

Median EFS, mos 8.2 3.0 0.002 4-yr EFS rate, % 28.2 20.6 0.002 Median DFS, mos 26.7 15.5 0.01

CR: complete remission, DFS: disease free survival, EFS: event free survival, HCT: hematopoietic stem cell transplantation, NR: not reached, OS: overall survival * OS also longer in the midostaurin group compared with placebo among patients with a FLT3 TKD and FLT3 ITD mutation with either a high ratio (>0.7) or low ratio (0.05-0.7) of mutant to wild-type allele

Stone RM, et al. N Engl J Med 2017;377:454-64

RATIFY: Safety

Midostaurin + Placebo + Select Grade 3-4 Adverse Chemotherapy Chemotherapy P Value Events, % (n = 360) (n = 357) Thrombocytopenia 97 97 0.52 Neutropenia 95 96 0.82 Anemia 93 88 0.03 Febrile neutropenia 82 82 0.84 Infection 52 50 0.60 Diarrhea 16 15 0.92 Hypokalemia 14 17 0.25 Rash/desquamation 14 8 0.008 Increased alanine 13 9 0.19 aminotransferase Nausea 6 10 0.05

Stone RM, et al. N Engl J Med 2017;377:454-64

Midostaurin Key Points

• Midostaurin added to standard chemo • Interaction with strong CYP3A4 in patients with newly diagnosed inhibitors FLT3-mutated AML 1.44 fold increase in midostaurin Improved OS and EFS, regardless of exposure; no notable increase in ITD/TKD stratification group midostaurin related AEs Reduced risk of death by 23% compared with placebo • Interaction with NPM1 mutation EFS and OS benefit most pronounced in • Benefit derived early in therapy NPM1wt/FLT3-ITD high group (median exposure: 42 days) • Take with food; Anti-emetic • Not approved for use as maintenance prophylaxis recommended therapy • QTc prolongation 11% vs. 6% in • Age/Gender placebo (consider interval assessment of QTc if taken in combination with No age restriction in FDA labeling medications that can prolong QT Differences in outcomes based on gender interval) • Cons • Area of ongoing investigation How to best combine midostaurin with Lack of IV formulation other agents Midostaurin combined with Role of maintenance therapy in high-risk daunorubicin 60 mg/m2 instead of 90 patients mg/m2 Concurrent vs. sequential therapy

Midostaurin (Rydapt® ). Package Insert. Novartis Pharmaceutical Corporation, East Hanover, NJ. Accessed Nov 2017 Taoufik O, et al. ASH 2017, Abstract 3814

4 1/30/18

CPX-351 A Nanoscale Delivery Complex

Liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio

Approval: August 2017

Labeled indication: treatment of adults with newly diagnosed therapy related AML or AML with myelodysplasia-related changes

• Dosing and administration: • Induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 liposome via intravenous infusion over 90 minutes on days 1, 3, and 5 and on days 1 and 3 for subsequent cycles of induction, if needed • Consolidation: daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 liposome via intravenous infusion over 90 minutes on days 1 and 3 • Hepatic/renal impairment: not studied in patients with T.bili > 3 mg/dL, GFR < 30 mL/min and end stage renal disease

• Full course: 1-2 cycles of induction and up to 2 cycles of consolidation

Vyxeos® . Jazz Pharmaceuticals, Inc. Palo Alto, CA. Accessed November 2017

CPX-351 A Nanoscale Delivery Complex Liposomal Formulation • Synergistic effect at killing leukemia cells in-vitro and murine models • Liposome retains drug in the synergistic ratio, minimizes first pass metabolism and delivers drugs preferentially at tumor site • Effective drug exposure of leukemia cell extended by days beyond what’s possible with conventional chemotherapy

Image credit: clinicaloptions.com Raut LS, et al. South Asian J Cancer 2015;4(1):38-40

CPX-351: Clinical Data

Patients Treatment Groups Results (n= 309) 7+3 (n = 156) 1st induction: 7+3 à cytarabine 100 Overall survival Phase III, mg/m2 + daunorubicin 60 mg/m2 (median): 9.6 randomized, open- R 2nd induction AND consolidation: 5+2 months label study (cytarabine 100 mg/m2 + daunorubicin A 2 Age 60-75 years with N 60 mg/m ) sAML (t-AML, antecedent MDS or D CMML, AML with O CPX-351 (n = 153) MDS-related 1st induction: 100 units/m2 on Overall survival cytogenetic M days 1, 3, 5 (median): 5.9 abnormalities) I 2nd induction: 100 unit/m2 on months Z days 1 and 3 Consolidation: 65 unit/m2 on day • t-AML (20%) • AML with antecedent E 1 and 3 HR 0.69, p = 0.005 hematological disorder (54%) • De novo AML with MDS related cytogenetic abnormalities (25%)

CMML: chronic myelomonocytic AML, MDS: myelodysplastic syndrome, sAML: secondary 1 unit = 1 mg cytarabine + 0.44 mg daunorubicin AML, t-AML: therapy related AML, Lancet JE, et al. ASCO 2016. Abstract 7000.

5 1/30/18

CPX-351: Outcomes

CPX-351 7+3 Outcomes P Value (n = 153) (n = 156) Median overall survival, mos 9.56 5.95 0.005 Complete remission, % 38 26 0.036 CR + CRi, % 47.7 33.3 0.016 Event free survival Data not reported Data not reported 0.021 Rate of transplantation, % 34 29 -

OS post-transplantation, mos Not reached 10.25 0.0046

Prolonged thrombocytopenia* (grade 3-5) - During induction 28 13 - - During consolidation 25 16 (with 5+2) Prolonged neutropenia* (grade 3-5) - During induction 17 3 - - During consolidation 10 3

CRi: complete remission with incomplete count recovery;*defined as PLT < 50K, ANC < 500 lasting past cycle day 42 in the absence of leukemia

Lancet JE, et al. J Clin Oncol 2016;24: Abstract 7000 Vyxeos® . Jazz Pharmaceuticals, Inc. Palo Alto, CA. Accessed November 2017

CPX-351: Key Points

1.0 De novo AML • CPX-351 superior to 7 + 3 for OS, EFS, CR, CR + CRi sAML, MDS 30- and 60-day mortality rates lower with CPX-351 0.8 sAML, non-MDS OS after transplantation improved tAML with CPX-351 vs 7 + 3 • High frequency of sAML in older 0.6 population; CPX-351 new standard for older, fit, patients with previously untreated high- risk AML 0.4

• An effective bridge to HCT Probability Survival • Can not be substituted for 0.2 standard 7+3 • 1 unit = 1 mg cytarabine + 0.44 mg daunorubicin 0 1 3 5 7 9 11 13 • Substantially longer half life compared with non-liposomal Yrs Since AML Diagnosis formulations likely leading to longer time to neutrophil (36 vs. 32 days) and platelet recovery Image credit: clinicaloptions.com Feldman EJ, et al. J Clin Oncol. 2011;29(8):979-985 (37 vs. 28 days) Granfeldt Ostgard LS, et al. J Clin Oncol. 2015;33:3641-3649.

Gemtuzuamab Ozogamicin (GO)

Antibody-drug conjugate targeting CD33

Approval: September 2017

Labeled indications 1. In combination with daunorubicin and cytarabine in adults with newly diagnosed CD33-positive AML 2. As monotherapy for newly diagnosed CD33-positive AML in adults and as single-agent treatment of relapsed/refractory CD33- positive AML in adults and pediatric patients 2 years of age and older

• Dosing and administration: variable depending upon indication

• PREMEDICATE with an antihistamine and acetaminophen 1 hr PRIOR to GO and methylprednisolone 1 mg/kg or equivalent 30 min PRIOR to GO

Gemtuzumab-ozogamicin (Mylotarg). Package insert. Wyeth Pharmaceuticals a susidiary of Pfizer Inc. Philadelphia, PA. Accessed November 2017

6 1/30/18

GO

Growth Factors, Cytokines • CD33 expressed on 87-97% of CD33 AML GO Drug Transporter Target Activity • A humanized immunoglobulin G4 Survival antibody directed against CD33 Levels Signaling and conjugated via hydrolysable linker to the DNA toxin P13K/AKT calicheamicin MDR-1/MRP-1 MEK/ERK • GO/CD33 complexes JAK/STAT internalized into lysosomes, releasing calicheamicin and promoting single/double-strand GO-Induced GO-Induced breaks, leading to DNA Mitochondria Apoptosis Damage and Cell • Accelerated FDA approval in GO p-CHk2 c-Casp3 Death 2000 for treatment of CD33+ Internalization/ AML aged >60 yrs in first relapse Processing γH2AX c-PARP Increased induction mortality when compared with 7+3 (5.5% vs. 1.4%) without improving CR Cell Death or relapse-free survival Drug withdrawn from market in 2010 Image credit: clinicaloptions.com Andrea WH, et al. Blood 2017 130:2469-2474 Andrews RG, et al. J Exp Med 1989:169:1721-1731 Ehninger A, et al. Blood Cancer J 2014;4:e218 Petersdorf SH, et al. Blood 2013;121(24):4854-4860 Rosen DB, et al. PLoS One 2013;8:e53518

GO in Untreated AML Summary

Age Study N Treatment Results of GO vs Comparator (yrs) § No overall difference in response or OS Induction, consolidation, MRC AML15 § Improved 5 yr OS for favorable risk and some < 60 1113 maintenance w/ vs. w/o GO intermediate risk (3 mg/m2)a ***Daunorubicin dose: 50 mg/m2 x 3 days*** § Reduced 3-yr relapse risk, and superior OS MRC AML 16 GO (3 mg/m2) + either DA § No difference in TRM 51-84 1115 or DCLo **Daunorubicin dose: 50 mg/m2 x 3 days**

GO (6 mg/m2 on day 4) + § Increased TRM SWOG 0106 18-60 637 DAb § No difference in ORR, DFS, or OS Induction chemo w/ vs. w/o GO (3 mg/m2 days 1, 4, 7) § Improved EFS and RFS, however no ALPHA 0701 50-70 280 à consolidation w/ vs. w/o difference in response or OS GO (3 mg/m2 day 1) GOELAMS AML Induction chemo w/ vs. w/o § Improved EFS for non-HCT cohort, however 2006 IR 18-60 238 GO (6 mg/m2 on day 4) no difference in RFS or OS

DCLo: daunorubicin and clofarabine; RFS: relapse free survival; TRM: treatment related mortality a: induction with ADE (cytarabine, anthracycline and etoposide), DA (cytarabine and anthracycline) or FLAG-IDA (fludarabine, cytarabine, idarubicin, filgrastim); consolidation with amasacrine, cytarabine and etoposide or HiDAC b: daunorubicin 45 mg/m2 x 3 days if w/ GO or 60 mg/m2 if w/o GO; both + cytarabine 100 mg/m2 x 7 days

Lowenberg RJ, et al. Blood 2013; 121 (24): 4838-41

GO in AML Summary Trials OR and 95% CI (GO: Control) • GO reduced risk of relapse and Resistant disease 0.77 (67-0.90) improved RFS and OS for 2P = .0009 untreated AML; survival benefit Induction death 1.30 (1.04-1.63) most apparent in patients with 2P = .02 favorable or intermediate risk cytogenetics CR 0.93 (0.82-1.07) 2P = .3; NS standard induction and consolidation not utilized in most of the studies Favorable 0.46 (0.29-0.73) • FDA approval for R/R AML based 2P = .001 on a small phase II trial (n = 57, CR Favorable/intermediate 0.99 (0.69-1.40) 26%) 2P = .9; NS

• Monitoring Intermediate 0.89 (0.78-1.00) Hepatotoxicity/veno-occlusive 2P = .06 disease Adverse 1.00 (0.83-1.20) Thrombocytopenia/hemorrhage 2P = 1.0; NS Infusion reaction (transient) Fractionated dosing of GO à Total 0.90 (0.81-0.99) substantially improved safety profile 2P = .03

• Variation in CD33 expression 0 0.5 1.0 1.5 2.0 GO Better Control Better Applebaum FR, et al. Blood 2017;130(22):2373-76 Loke J, et al. Ann Hematol 2015;94:361-373 Taskin AL, et al. Leukemia 2007 Jan;21(1):66-71

7 1/30/18

Enasidenib

• Approved in August 2017 for the treatment of relapsed or refractory AML in patients with isocitrate dehydrogenase-2 (IDH2) mutation • IDH2 mutation: ~ 12% patients with AML enriched in patients with normal karyotype and increases in frequency with age

↑ R-2- Histone and DNA Blocked myeloid hydroxyglutarate hypermethylation differentiation

• Enasidenib induced inhibition of mutated IDH2 à ↓ 2-HG by 90%, reduced abnormal histone hypermethylation and restored myeloid differentiation • Differentiating agent and not cytotoxic

Stein EM, et al. Blood 2017;130:722-31 Wei AH, et al. Blood 2017 130:2469-247

Enasidenib in R/R AML Clinical Trial

• Multi-center, open-label, phase I/II study in patients with mutant-IDH2 advanced myeloid malignancies • Enasidenib 100 mg PO daily selected for dose expansion based on PK/PD and efficacy R/R AML Endpoint 100 mg/d R/R AML (n = 109) Demographics 100 mg/d Overall response rate, n (%) 42 (38.5) (n = 109) Best response, n (%) § CR 22 (20.2) Age (median), yrs 67 § CRi/CRp 7 (6.4) Refractory to initial induction or re- 32 Median time to first response, mos induction treatment, % (range) 1.9 (0.5-9.4) Relapsed/refractory to > 2 cycles of Median DoR, mos (95% CI) 5.6 (3.8-9.7) 1st line lower-intensity tx, % 23 Median OS, mos 9.3 ECOG 0-1, % 93 Transfusion independence 34% (transfusion dependent prior to tx)

CR: complete remission; CRi: CR with incomplete hematologic recovery; CRp: CR with incomplete platelet recovery; PK: pharmacokinetic, PD: pharmacodynamic Stein EM, et al. Blood 2017;130:722-31

Enasidenib in R/R AML Clinical Trial

• Most common ADRs • Differentiation syndrome (DS) Nausea, vomiting, diarrhea, Overall: 10%, Grade 3-4: 6% Typically occurs 3-4 months decreased appetite, elevated following therapy bili • Median time to onset: 48 days Treatment related R/R AML Management: dexamethasone adverse events of 10 mg IV q12H grade 3 or 4 n (%) • If severe (i.e. pulmonary/renal failure), hold therapy Hyperbilirubinemia 13 (8) • Leukocytosis IDH differentiation Initiate hydroxyurea if WBC > syndrome 11 (7) 30K Anemia 10 (7) Within first two cycles Thrombocytopenia 8 (5) Not necessarily accompanied by DS Tumor lysis syndrome 5 (3) • Dose adjust for ↑ bili and any Decreased appetite 3 (2) other grade > 2 events Leukocytosis 2 (1)

Stein EM, et al. Blood 2017;130:722-31

8 1/30/18

Audience Response Question RM is a relatively healthy 45 YOM with PMH significant for stage 2 hypertension. He initially complained of symptoms consistent with an upper respiratory tract infection 4 week ago and was treated with a 10 day course of an antibiotic (abx). Since symptoms did not resolve after completion of abx, a blood test was done. Labs to note: WBC 42 x 109/L, blasts 65%, platelet 30K. Upon review of these results, she was admitted emergently to the hospital for further evaluation. Bone marrow biopsy revealed 80% blasts and complex cytogenetics. Next generation sequencing revealed FLT3-ITD mutation with high allelic burden. Which of the following represents the best evidence-based induction treatment strategy for CD33 neg, FLT3-mutated AML?

A. CPX-351 and midostaurin B. 7+3 and midostaurin C. Enasidenib and midostaurin D. and midostaurin

PMH: past medical history; YOM: year old male

Audience Response Question

Since RM has FLT3-mutated AML, he will receive midostaurin during his induction and consolidation therapy. Which adverse events should RM be closely monitored for?

A. Nausea and vomiting B. QTc prolongation C. Rash D. All of the above

Acute Lymphocytic Leukemia

9 1/30/18

Inotuzumab Ozogamicin (IO)

• Approved in august 2017 for treatment of adults with relapsed or refractory B-cell precursor ALL Tumor cell

• Antibody-antigen complex rapidly internalized upon binding to CD22 Nucleus 1.

• Cytotoxin calicheamicin released inside the tumor cell Calicheamicin binds • Calicheamicin binds to DNA, inducing double- Internalization 2. stranded DNA breaks to DNA

• DNA break development followed by apoptosis of CD22 3. tumor cell

Inotuzumab ozogamicin • Dosage and administration: 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8 and 15; reduce day 1 dose to 0.5 mg/m2 once in CR

Image credit: clinicaloptions.com Kantarjian H, et al. Cancer. 2013;119:2728-2736 Advani AS, et al. ASH 2014. Abstract 2255

INO-VATE: IO in R/R Ph(-) or Ph(+) ALL

Patients Treatment Groups Results (n= 326) IO (n = 109) 1.8 mg/m2/cycle (0.8 mg/m2 on Phase III, day 1, 0.5 mg/m2 on days 8 and CR/CRi: 80.7% randomized, open- R 15 of a 21-28 day cycle) for up to Overall survival: 7.7 label study A 6 cycles mo. Age > 18 years with N **dose reduced to 0.5 mg/m2 on relapsed or day 1 once in CR** refractory CD22+, D Ph- or Ph+ ALL as O first or second M salvage therapy Standard of care (n = 109 ) I CR/CRi:29.4% FLAG or cytarabine + Overall survival: 6.7 Stratification by duration of Z mitoxantrone or HiDAC for up to 4 mo. first remission (>12 vs <12 cycles mos), salvage therapy (2 E vs 1), age (> 55 vs < 55 p-value for CR/CRi: < 0.001 yrs) Patients achieving CR could undergo p-value for OS: 0.04 HCT at investigator discretion

Baseline characteristics: Most patients with one prior salvage therapy (64- 68%), about 20% of patients in each arm with prior HCT; about 70% of patients with > 50% blasts in bone marrow; Ph+ status (13-17%) Kantarjian HM, et al. N Engl J Med 2016;375:740-753

INO-VATE Trial: Efficacy

IO Standard of care Outcomes P Value (n = 109) (n = 109) Bone marrow blast results below threshold for minimal residual disease 78.4 28.1 < 0.001 in patients with CR or CRi, % Median duration of response in 4.6 3.1 0.03 responders (CR or CRi), mo.

HCT directly after treatment, (%) 41 11 < 0.001

HCT after achieving CR/CRi, % 38 9 < 0.001

Median PFS, mo. 5 1.8 < 0.001

CR or CRi significantly better with IO regardless of bone marrow blasts, CD22 expression, karyotype or prior HCT

Kantarjian HM, et al. N Engl J Med. 2016;375:740-753

10 1/30/18

INO-VATE Trial: Safety

• Common ADRs (any grade): myelosuppression (30-45%), febrile neutropenia and pyrexia (27% each), fatigue (22%), gastrointestinal (17%), hypokalemia (17%), ↑ AST (20%), ↑ GGT (17%), ↑ bili (15%)

IO Standard therapy Select grade 3-5 AEs, % (n = 139) (n = 120) Thrombocytopenia 37 61 Neutropenia 46 42 Anemia 19 40 Febrile neutropenia 24 49 AST increased 5 3 GGT increased 9 4 Hyperbilirubinemia 4 3 ALT increased 3 3 Lipase increased 4 0

AST: aspartate aminotransferase; ALT: alanine aminotransferase, GGT: gamma-glutamyltransferase Kantarjian HM, et al. N Engl J Med 2016;375:740-753

INO-VATE Focus on Sinusoidal Obstructive Syndrome (SOS)

Parameter IO Standard of care Overall SOS incidence, % 11 1 SOS incidence during study treatment, % (n/N) 3 (5*/164) -- Post-study HCT, % (n/N) 47 (77/164) 20 (33/162) Post-HSCT SOS, % (n/N) 22 (17†/77) -- Median time to post-HSCT SOS, days (range) 15 (3-57) --

*2/5 pts with prestudy HSCT. †5/17 pts with prestudy HCT.

Multivariate analysis of factors associated with post-HCT SOS Factors Associated With Post-HCT SOS OR (95% CI) P Value Alkylator conditioning: dual vs single 7.6 (1.7-33.8) .008 Age: ≥ 55 yrs vs < 55 yrs 4.8 (1.0-22.0) .043

Kantarjian HM, et al. N Engl J Med. 2016;375:740-753

IO Place in Therapy

Targeting CD19 vs. CD22 in R/R B-ALL

Blinatumomab IO - Response rate affected by baseline - Response rate NOT affected by blasts % baseline blasts % - 28-day continuous infusion - Short IV infusions once weekly - Inpatient admission for first cycle - Most common toxicity: myelosuppression - Serious toxicities: cytokine release syndrome and CNS disorders - Most serious toxicity: SOS, primarily - Frequent clinic visits for monitoring associated with allogeneic HCT neurological signs and symptoms - Can be used for Ph+ disease - Distance from cancer center - No difference in CR for patients with - Can be used for Ph+ disease Ph+ disease or t(11;14) when compared with standard of care

Bridge to HCT

11 1/30/18

Audience Response Question

AB was diagnosed with Ph-neg ALL a few weeks ago. He completed HyperCVAD cycle 1B five weeks ago and did not show up for his scheduled cycle 2A. He now presents to the ER following a minor motor vehicle accident. Physical examination revealed splenomegaly, slight hepatomegaly, and lymphadenopathy. Labs revealed WBC of 80 x 109/L, PLT 30K, and LDH of 1500 units/L. Bone marrow biopsy revealed 70% blasts. Which of the following represents the best treatment option for relapsed/refractory Ph-neg ALL for AB? A. Inotuzumab ozogamicin B. C. Any of the above D. None of the above

Audience Response Question

AB has been initiated on inotuzumab ozogamicin (IO). Donor search is currently ongoing for allogeneic HCT once he is in remission. Which of the following have been shown to increase the risk of IO related veno-occlusive disease/sinusoidal obstructive syndrome? A. Conditioning therapy with an alkylating agent B. Age > 55 yrs C. A and B D. None of the above

Lymphoma

12 1/30/18

Copanlisib

Pan class I phosphatidylinositol-3 kinase (PI3K) Different chemical inhibitor with predominant inhibitory activity against structure than PI3K-ɑ and PI3K-δ isoform idelalisib, which only targets δ Accelerated approval: September 2017 isoform

Labeled indication: Treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies

Dosage and administration: 60 mg administered as a 1-hour intravenous infusion on Days 1, 8, and 15 of a 28-day treatment cycle

Drug interactions: avoid concomitant use with strong CYP3A4 inducers; reduce dose to 45 mg when concomitantly administered with strong CYP3A4 inhibitors

Warnings: start treatment once optimal blood sugar achieved; withhold treatment until SBP < 150 mmHg and diastolic BP < 90 mmHg achieved

Copanlisib (Aliqopa® ). Package Insert. Bayer Healthcare Pharmaceutical Inc, Whippany, NJ. Accessed Nov 2017

CHRONOS-1: Copanlisib in R/R Indolent B-cell

• Open-label, uncontrolled, phase II study in heavily pretreated patients with relapsed or refractory, indolent B-cell lymphoma (n = 142)

Inclusion Grade 1-3a follicular lymphoma (FL), Exclusion Copanlisib 0.8 mg/kg IV marginal zone lymphoma, Prior treatment with PI3K over 1 hr on days 1, 8, lymphoplasmacytic lymphoma/WM or CLL inhibitors and allogeneic HCT relapsed or refractory to >2 prior therapies and 15 of a 28-day cycle (including and alkylating agents)

• Baseline characteristics: majority with FL (73%) and stage III/IV disease (80%) • Results (FL subgroup) ORR (59%), CR (14%), PR (44%), median PFS: 9.7 mo. Median time to response: 53 days; median duration of response: 12.8 months

Dreyling et al. Ann Oncol. 2017 Sep 1;28(9):2169-2178

CHRONOS-1 Trial: Safety and Summary

AE (grade > 3), % n = 142 • Overall transient hyperglycemia (49%), Hyperglycemia (blood sugar > 250 41 hypertension (HTN) [30%] mg/dL) Diarrhea 5 • Noninfectious pneumonitis (8%) Hypertension (> 160 mm Hg) 24 • Increased ALT (overall, 23%; mostly grade 1) Lung infection 16 • Increased AST (overall, 28%; mostly grade 1) Decreased neutrophil count 24 Decreased platelet 7 SUMMARY • Transient HTN and hyperglycemia due to ɑ target (BP and plasma glucose levels peak 1-2 hrs and 5-8 after start of infusion, respectively) • Comparison with idelalisib IV vs. oral Lower rate of pneumonitis (3.6%) compared with idelalisib (12-15%) • Unmet needs: predictive biomarkers, head to head comparision (phase III CHHRONOS 2-4 trials ongoing)

Dreyling et al. Ann Oncol. 2017 Sep 1;28(9):2169-2178 Falchi L, et al. Mediterr J Hematol Infect Dis. 2016; 8(1): e2016011

13 1/30/18

Acalabrutinib

Bruton Tyrosine Kinase (BTK) inhibitor A highly selective, potent, covalent, inhibitor of BTK with minimal off Accelerated approval: October 2017 target activity

Labeled indication: mantle cell lymphoma (MCL) following at least one prior therapy

Dosage and administration: - 100 mg oral every 12 hours (with or without food) - Avoid co-administration with proton pump inhibitors. Stagger dosing with histamine-2 receptor antagonist and antacids

Drug-Drug Interactions: avoid co-administration with strong CYP3A inducers and inhibitors

Acalabrutinib (Calquence® ). Package Insert. AstraZaneca Pharmaceuticals LP, Wilmington, DE. Accessed Nov 2017

ACE-LY 004: Acalabrutinib in R/R MCL

• Phase II trial (n = 124, age > 18 yrs), R/R MCL, median of 2 prior therapies • Notable exclusion: concomitant warfarin or equivalent • 100 mg PO twice daily

Efficacy Safety • CR 49%, PR 51% • Common ADEs: myelosuppression (36-44%), headache (38%), diarrhea (31%), fatigue (27%), myalgia (21%), • Median TTR: 1.9 mo. bruising (21%), rash (18%) • 12-mo. PFS: 67% • No cases of atrial fibrillation • 12-mo. OS: 87% • Common bleeding events (all grade 1/2 except one): contusion (13%), petechiae (9%) • Grade 3/4 ADEs: neutropenia (10%), anemia (9%), pneumonia (5%)

Favorable benefit-risk profile; a promising treatment option for R/R MCL

Acalabrutinib (Calquence® ). Package Insert. AstraZaneca Pharmaceuticals LP, Wilmington, DE. Accessed Nov 2017

Stem Cell Transplantation

14 1/30/18

Cytomegalovirus (CMV) post HCT

• Risk factors: positive CMV serostatus, T-cell depleted graft, receipt of antithymocyte globulin, and/or > 1 mg/kg prednisone or equivalent, GVHD, donor type (high risk: mismatched, haploidentical, and cord blood) • Preemptive therapy recommended by the NCCN

Prophylaxis Preemptive Therapy

§ Routine monitoring for CMV § Antivirals for all pts at risk prior to Description infection; treatment upon detection the onset of CMV infection of asymptomatic CMV infection

Pros § Prevents infection § Limits drug toxicity and side effects

§ Unnecessary drug administration in some patients § May not prevent indirect effects of Cons § Adverse events associated with CMV viremia medications

NCCN Guideline. Prevention and treatment of Cancer-Related Infections. V1.2018. Accessed December 1, 2017

Letermovir

Antiviral that inhibits CMV replication by binding to component of the terminase complex (UL51, UL56, UL89)

Approval: November 2017

Labeled indication: prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic HCT

Contraindicated in patients receiving pimozide and ergot alkaloids and in patients receiving pitavastatin or simvastatin when co-administered with cyclosporine.

Dosage and Administration: - 480 mg oral or IV (over 1 hour) through day 100 post-transplantation - Adjust dose to 240 mg PO or IV once daily if administered in combination with cyclosporine

In patients with GFR < 50 mL/min, accumulation of intravenous vehicle, hydroxypropyl betadex may occur

Letermovir not recommended in patients with severe hepatic impairment

PrevymisTM [Packager Insert]. 2017

Letermovir Phase III Trial

• Randomized, multicenter, double-blind, placebo-controlled phase III trial Primary endpoint: pts with clinically significant CMV infection** through post-HCT Wk 24

Post-HSCT Pts could start taking study medication by day 28 post- Wk 14 HCT

Randomization stratified by trial site Letermovir 480 mg PO or IV and CMV disease Dose reduced to 240 mg if concomitantly on Pts assessed through post-HSCT Wk 48; cyclosporine* Adult (age > 18 yrs), preemptive treatment (n = 376) CMV-seropositive, given per study allogeneic HCT recipients center guidelines with no CMV viremia Placebo (n = 570) (n = 194)

*due to drug interaction mediated by organic anion transporter **Clinically significant CMV infection: CMV disease occurrence or treatment with anti-CMV preemptive therapy (which occurred if confirmed CMV viremia and CMV disease risk). Preemptive treatment of CMV viremia if > 150 copies/mL in high-risk patients and > 300 copies/mL in low-risk patients through week 14 after transplantation and a threshold of > 300 copies/mL for all the patients thereafter.

Baseline characteristics (overall): high risk of CMV (31%), haploidentical donors (14%), mismatched, unrelated donor (14%), use of ATG (25%)

Marty F, et al. N Engl J Med 2017 [Epub]

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Letermovir Phase III Trial Efficacy

Letermovir Placebo Outcomes, % P-value (n = 325) (n = 170)

37.5 60.6 < 0.001 Failure of therapy at wk 24 Clinically significant CMV infection at week 24 17.5 41.8 § Started preemptive therapy 16.0 40 § CMV disease 1.5 1.8 All-cause mortality at week 24 10.2 15.9 0.03 Nonrelapse mortality at week 24 6.5 10.6 All cause mortality at week 48 20.9 25.5 0.12 Clinically significant CMV infection at week 14 19.1 50 < 0.001 after HCT § In pts with undetectable CMV DNA at baseline, letermovir associated with significant benefit in terms of time to clinically significant CMV infection and all-cause mortality vs placebo through week 24 § For all subgroups assessed, letermovir associated with less clinically significant CMV infection through week 14 vs. placebo

Marty F, et al. N Engl J Med 2017 [Epub]

Letermovir: Phase III Trial Safety

Safety Outcome During Letermovir Placebo • GVHD was the most common Treatment Phase, % (n = 373) (n = 192) AE of any severity (39% in both Any AE 97.9 100 groups) Drug-related AE 16.9 12.0 Diarrhea, nausea, fever, and Vomiting 18.5 13.5 rash also occurred in > 20% Cough 14.2 10.4 of patients in both groups Peripheral edema 14.5 9.4 with similar frequency Headache 13.9 9.4 Acute kidney injury 9.7 13 Dyspnea 8 3.1 Myalgia 5.1 1.6 Atrial fibrillation/flutter 4.6 1 ALT > 5 x ULN 3.5 1.6 Hyperkalemia 7.2 2.1 Discontinuation due to AE 19.3 51.0 § CMV treatment 6.2 39.1 § Other 13.1 12.0

Marty F, et al. N Engl J Med 2017 [Epub]

Letermovir Key Points • Letermovir prophylaxis beginning at a median of 9 days after HCT and administered through week 14 is highly effective and prevents clinically significant CMV infection in CMV+ patients and yields mortality benefit compared with placebo • Patients considered to be high risk for CMV disease benefited mostly from letermovir prophylaxis

- Availability of IV - Activity limited PROS formulation to CMV - Favorable safety - Caution use of profile IV formulation in renal impairment - Absence of myelotoxicity and - Data limited to CONS nephrotoxicity prophylaxis setting

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Ibrutinib for Marginal Zone Lymphoma (MZL)

• Bruton tyrosine kinase (BTK) inhibitor • Approved in Feb 2017 for the treatment of patients with relapsed or refractory MZL who require systemic therapy and have had at least one prior anti-CD20 therapy

MZL who received ORR: 48% Phase II (n = 63) one or more prior CR (3%) 560 mg therapy including at least one CD20 Median time to initial PO daily monoclonal antibody response: 4.5 months

• Most common ADEs: diarrhea, anemia, nausea, thrombocytopenia, peripheral edema, cough, arthralgia, dyspnea, upper respiratory tract infection • Most common grade 3/4 ADEs: ↓ hemoglobin (13%), ↓ neutrophil (13%), pneumonia (10%)

Noy E, et al. Blood 2017:blood-2016-10-747345

Ibrutinib for Chronic GVHD

• First FDA approved drug for treating graft versus host disease (GVHD) • Approved in August 2017 for adults with chronic GVHD (cGVHD) who have failed on one or more lines of prior systemic therapy • BTK mediates BCR and chemokine signaling, driving B- cell adhesion, migration, proliferation, and survival • B-cell signaling pathway implicated in cGVHD pathophysiology

Advani RH, et al. J Clin Oncol. 2013;31:88-94 Byrd JC, et al. N Engl J Med. 2013;369:32-42 Ibrutinib (Imbruvica® ). Package Insert. Pharmacyclics, Inc. Sunnyvale, CA. Accessed Nov 2017

Ibrutinib: Phase II Trial

100 Best cGVHD Response Patients with steroid- (N = 42) dependent/refractory 80 cGVHD (> 25% BSA Ibrutinib 420 mg PO daily “erythematous rash” or CR > 4 total mouth score) 60 PR 9 (N = 42) 40

Response (%) 19 • cGVHD response per NIH 2005 response 20 criteria -> ORR: 67%, CR 21%, PR 45% 7 2 • Median time to response: 87 days; 30 days 0 ORR SD PD after protocol amendment for earlier response • Mean reduction in steroid dose (0.29 • 71% had a sustained response of at least mg/kg/day to 0.12 mg/kg/day) 20 weeks • AEs are consistent with those previously • Similar response rate across all affected reported for ibrutinib and those observed in organs pts with cGVHD on concomitant corticosteroids • Patients with multiple organ involvement generally showed responses in 2 or more organs Slide credit: clinicaloptions.com Miklos D, et al. Blood. 2017;130:2243-2250.

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Sickle Cell Disease

Oral Glutamine Powder

• Sickle cell disease: continuous oxidative stress à sickle cell crises and organ damage • L-glutamine: a precursor for synthesis of essential metabolic redox cofactors; depletion linked with oxidative stress

• A phase III, randomized, double blind, • Median number of sickle cell crises lower placebo controlled study (n = 230) for L-glutamine (3 vs. 4, p < 0.01) • Inclusion: sickle cell anemia and β0- • Common ADRs: constipation, nausea, thalassemia who had two or more headache, abdominal pain, cough, pain in painful crises within the 12 months prior extremity, back pain, and chest pain. to enrollment • Intervention: L-glutamine or placebo for Dose: 10 grams to 30 grams per day (based on 48 weeks followed by three weeks of body weight) taken orally, twice daily. Each dose drug tapering. should be mixed in 8 oz. (240 mL) of cold or room temperature beverage or 4 to 6 oz. of food before ingestion.

*A sickle cell crisis was defined as an emergency room/medical facility visit for sickle cell disease-related pain treated with a parenteral narcotic or parenteral ketorolac. Niihara Y, et eal. Blood 2016 128:1318 L-glutamine oral powder (Endari® ). Package Insert. Emmaus Medical, Inc.. Torrace, CA. Accessed Nov 2017

Expanded indications/New Approvals Relevant to HCT Medication Indication Pembrolizumab (E) Adults and pediatric patients with refractory classical HL and relapsed > 3 prior lines of therapy March 2017 (E) For use in combination with pomalidomide and dexamethasone for the third-line treatment of patients with MM who received prior therapy with June 2017 lenalidomide and a proteasome inhibitor Rituximab/hyaluronidase (N) Subcutaneous administration of rituximab for adults with FL, DLBCL, and CLL June 2017 Blinatumomab (E) Regular approval granted and indication expanded to include Ph+ ALL based on results of TOWER (phase 3 trial in R/R, B-precursor, Ph-neg ALL July 2017 with 3.7 mo. OS benefit) study (E) For use in combination with chemotherapy, followed by obinutuzumab alone for November 2017 1. Treatment of R/R FL (after previous rituximab) 2. Treatment of stage II-IV FL in patients achieving at least a partial remission

CLL: chronic lymphocytic leukemia, DLBCL: diffuse large Blinatumomab (Blincyto®). Package insert. Amgen Inc. Thousand Oaks, CA. Accessed Nov 2017 B cell lymphoma, MM: multiple myeloma Daratumomab (Darzalex®). Package insert. Janssen Biotech, Inc. Horsham, PA. Accessed Nov 2017 (E): expanded indication Pembrolizumab (Keytruda®). Package insert. Merck & Co., Inc. Whitehouse station, NJ. Accessed Nov 2017 (N): new indication Obinutuzumab (Gazyva®). Packager insert. Genentech, Inc. South San Francisco, CA. Accessed Nov 2017 Rituximab and hyaluronidase (Rituxan Hycela®). Package Insert. Genentech, Inc. South San Francisco, CA. Accessed Nov 2017

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Expanded indications/New Approvals Relevant to HCT

Medication Indication

Axicabtagene Chimeric antigen receptor T cell immunotherapy approved for treatment of adult ciloleucel (N) patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy October 2017 • Approval based on single-arm multicenter trial (n = 108) of adults with aggressive B-cell lymphoma; ORR: 72%, CR: 51% • Common ADRs grade > 3: febrile neutropenia, fever, cytokine release syndrome, encephalopathy, infections, hypotension, hypoxia (E) Regular approval granted for treatment of pediatric patients with Ph+ CML in chronic phase November 2017 • Approval based on phase 1 and phase 2, open-label trial • Population: N= 51 with newly diagnosed chronic phase CML and n = 46 for resistant or intolerant to • Outcomes: After 24 months of treatment, 96.1% of newly diagnosed patients and 82.6% of imatinib resistant/intolerant patients had complete cytogenic response (CCyR). • No new safety signals noted

Axicabtagene ciloleucel (Yescarta®). Package insert. Kite Pharma, Inc. Santa Monica, CA. Accessed Dec 2017 Dasatinib (Sprycel®). Package insert. Bristol-Myers Squibb Company Inc. Princeton, NJ. Accessed Nov 2017

Emerging Therapies relevant to HCT

Medication Indication/Clinical Data

Ivosidenib (IDH-1 In a phase 1 trial of with mutated IDH1 hematologic malignancies, CR was 22% inhibitor)

Gilteritinib CHRYSALIS: first study to demonstrate molecular responses (25%) in patients (FLT3/AXL inhibitor) with AML treated with a FLT3 inhibitor

Brentuximab vedotin In a phase 3 Echelon 1 study, brentuximab + AVD (doxorubicin, vinblastine, (Antibody drug dacarbazine) yielded superior PFS compared with ABVD in previously conjugate targeting untreated advanced stage HL CD30)

Venetoclax + rituximab superior to bendamustine + rituximab in R/R CLL (bcl-2 inhibitor) (phase 3 Murrano study)

Venetoclax + low-dose cytarabine in older previously untreated patients with AML à CR 62% Venotoclax + azacytidine in older previously untreated patients with AML à CR 58%

Altman JK, et al. ASCO 2017. Abstract 7003 Connors JM, et al. ASCO 2017 DiNardo CD, et al. ASCO 2017. Abstract 725 Seymours JF, et al. ASCO 2017. LBA-2

2018 BMT Pharmacists Conference

New and Emerging Drugs

Arpita Gandhi, PharmD, BCOP Hematology/Oncology Clinical Pharmacy Specialist Augusta University Medical Center, Augusta, GA

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