sign in sign up
<<
Home , Pegfilgrastim, Sargramostim

Friends in Low Places: A Clinical Review of Hematopoietic Growth Factors

Sabrina Schneider, PharmD PGY-2 Oncology Resident Sabrina Schneider, PharmD Huntsman Cancer Institute at University of Utah Health November 12, 2020 [email protected]

1 2

Poll Everywhere Audience Response Disclosures

• ACPE requires active learning during presentation -- We are using PollEverywhere software for this • Relevant Financial Conflicts of Interest process. • CE Presenter, Sabrina Schneider, PharmD: • You may participate via 3 different options: • None • Web Browser: Go to PollEv.com/ushp • PollEverywhere app: Download the PollEverywhere app and join “USHP presentation” • CE mentor, Jeffrey Gilreath, PharmD: • Text Messaging: Text USHP to 22333 • None • We recommend using the PollEverywhere app or web browser – easier real-time response • Off-Label Uses of • For each question, please select the correct answer in the Web Browser or App, or text the correct • Stimulating Agents (ESAs) for use in patient populations answer to 22333 who refuse blood transfusions • Additional off-label uses will be discussed to elaborate on why they are inappropriate

3 4

1 Learning Objectives Introduction to Hematopoietic Growth Factors Pharmacist Objectives: • The bone marrow is a very important organ for maintaining normal function 1. Develop an appropriate therapeutic management and monitoring plan for each class of hematopoietic growth factors based on a patient case. • Home to the pluripotent stem cells that eventually become all blood cells! 2. Review the normal physiology of hematopoiesis and describe the mechanism of • Clinical diseases & treatments can lead us to some low places with cell counts action for each class of hematopoietic growth factors. 3. Distinguish between appropriate and inappropriate uses for hematopoietic growth Anemia Thrombocytopenia factors in common clinical settings. Technician Objectives: • The “biologics boom” has led to the development of medications that mimic 1. Compare and contrast the different classes of hematopoietic growth factors and and/or replace endogenous signals to stimulate growth of specific cell lines determine which cell lineage each agent stimulates to grow. Erythropoietin 2. Define the term “” and provide examples of both biosimilar hematopoietic growth factors and their originator product. • Knowing when to use certain growth factors may help improve clinical status and quality of life 3. Identify brand and generic names of common hematopoietic growth factors.

5 Ciesla B. Hematology in Practice. 2007. 6

Normal Hematopoiesis: Overview White Blood Cells (WBCs)

Myeloid differentiation • (40-75% of WBCs) • Held in marrow “storage” for 7-10 days • Lifespan: Active in tissues for 2-5 days • Monocytes (0-10% of WBCs) • Variable lifespan, dependent on inflammation & “on-off” apoptosis • Macrophages (0-10% of WBCs) • Lifespan: Weeks-months • Only spend hours in peripheral blood – on their way to the tissues

Ciesla B. Hematology in Practice. 2007. Ciesla B. Hematology in Practice. 2007. 7 Image: Flikr. “Neutrophils” 8

2 White Blood Cells (continued) Red Blood Cells (Erythrocytes)

Lymphoid differentiation • Pronormoblasts • From the thymus and the marrow • Erythropoietin has greatest effect here • 1 pronormoblast  16 mature red cells • Maturation & activation are dependent on presence of antigens • Reticulocytes • T-Lymphocytes (60-80% of lymphoid cells) • Final step before mature erythrocytes – still some genetic material present • B-Lymphocytes (10-20% of lymphoid cells) • Erythrocytes • Natural Killer (NK) cells (<10% of lymphoid cells) • Carry oxygen via hemoglobin around the body • Do not need antigenic stimulation • Lifespan: 120 days • Lifespan: Unclear, possibly up to 4 years

Ciesla B. Hematology in Practice. 2007. Ciesla B. Hematology in Practice. 2007. 9 10

Platelets

Megakaryocytes • 1 can produce up to 2,000 platelets! • Thrombopoietin – produced in the liver Low Place #1: • Stimulated by presence of “old” platelets Platelets: the first responder to vessel injury Neutropenia • No “platelet reserve” in the marrow ® • 80% in circulation, 20% in spleen “WHERE THE [WHITE CELLS] DROWN, AND THE [NEUPOGEN ] CHASES MY BLUES AWAY…” • Lifespan: 7-10 days

Ciesla B. Hematology in Practice. 2007. 11 12

3 Patient Case Definitions: ANC and Neutropenia

• SR is a 52-year old male with small cell lung cancer who receives carboplatin + Labs etoposide every 21 days for his initial treatment. He has no other significant • Low white blood cell (WBC) count past medical history and has a good performance score (ECOG = 0). Per NCCN: • Absolute count (ANC) <1500 cells/µL febrile neutropenia risk = 10-20%. • Should SR receive G-CSF to prevent infection with this regimen? How to calculate ANC • (Segmented neutrophil % + bands %) x WBC # = ANC • OR… (# segmented neutrophils + # bands) x 1000 = ANC Let’s discuss to find out! • Example: (30% + 3%) x 1.0 = 330 = ANC What does this mean?

• Neutrophils are our largest white cell population and are the “first line” defense against bacterial and fungal infection • “Nadir” periods often happen 7-10 days after chemotherapy/radiation

Ciesla B. Hematology in Practice. 2007; Kurtin S. J Adv Pract Oncol. 2012; 3: 209-24. 13 NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020 14

Pathophysiology Mechanism of Action ↆProduction ↑Destruction Loss • Granulocyte colony-stimulating factor • Neutrophil loss is rare (G-CSF) is an endogenous • Myelosuppressive chemotherapy • Myeloablative chemotherapy • Anthracyclines • High-dose alkylating agents • AKA: CSF3 • Taxanes • Radiation • Target: G-CSFR • Platinums • Topoisomerase 1 inhibitors • CLAG & FLAG • Downstream phosphorylation  • CDK4/6 inhibitors • Chemotherapy regimens increased myeloid differentiation & • Dose-dependent that contain G-CSF proliferation • Malignancy • Neutrophils “waiting in the wings” are • (AML) mobilized to the periphery • Myelodysplastic Syndrome • Rapid action (within 4-24h) (MDS) • Sustained elevation

Ciesla B. Hematology in Practice. 2007; Kurtin S. J Adv Pract Oncol. 2012; 3: 209-24. Panoupulos A, et al. Cytokine. 2008 June; 42(3): 277-88; Dwievedi P, et al. Exp Hematol. 2017 Feb; 46: 9-20. NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020 15 Ciesla B. Hematology in Practice. 2007 16

4 Granulocyte Colony Stimulating Factors (G-CSF) : Explained

Traditional G-CSFs Granulocyte Macrophage Colony- • Biologics are bioactive proteins produced in living cells Stimulating Factor (GM-CSF) • Neupogen® (filgrastim) • Aids in post-translational adjustments required for • Leukine® () • Granix® (tbo-filgrastim) protein to become biologically active • Promotes macrophage & neutrophil ® • Zarxio (filgrastim-sndz) production  increased antigen presenting • Biosimilar = Biologic products that are “highly similar” • Nivestym® (filgrastim-aafi)  increased immune activation with no clinically meaningful differences from an existing reference product Pegylated G-CSFs – Longer acting • Some megakaryocytic and erythroid stimulation ® • Reference Product = Usually the first FDA-approved • Neulasta () biologic • Udenyca® (pegfilgrastim-cbqv) • “Highly similar”= Small differences in clinically inactive • Fulphila® (pegfilgrastim-jmdb) substances that have no effect on safety, efficacy, purity, • Ziextenzo® (pegfilgrastim-bmez) and potency

Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine. FDA. Biosimilar and Interchangeable Products. Oct 2017. NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; Mehta H, et al. J Immunol. 2015 Aug; 195 (4): 1341-49. 17 FDA. Docket No. FDA-2015-N-0648. 18

Biosimilars: Explained (continued) Biosimilars: Explained (continued)

• Interchangeable products: the Biologics Price and Competition Act (2009) What’s with the 4 letter nonsense suffixes? adds an extra “tier” of biosimilarity • The FDA has rules on the naming of biosimilar products to help identify the • Must prove that product will produce the exact same clinical effect in any different products given patient 1) Core name • If a product is deemed interchangeable, product substitution can happen 2) Distinguishing random, 4-letter suffix that is devoid of meaning without any need for provider intervention • Three of the 4 letters must be different from other products • Utah Law: Pharmacy Practice Act 58-17b-605.5 • Upcoming changes: Zarxio® (filgrastim-sndz) & Granix® (tbo-filgrastim) will • Allowable to switch between interchangeable products without prescriber need new names. Reference products will need suffixes, too. approval provided prescriber is notified of changed product • For more information on naming: FDA Guidance on Biologic Naming

However, there are currently zero “interchangeable” biosimilar products

FDA. Biosimilar and Interchangeable Products. Oct 2017.; FDA. Docket No. FDA-2015-N-0648. FDA. Biosimilar and Interchangeable Products. Oct 2017. DOPL. Chapter 17b, 58-17b-605.5. Dec 2018.; FDA. Biosimilars and Interchangeable Biologics: More Treatment Choices. Mar 2020. 19 FDA. Docket No. FDA-2015-N-0648. 20

5 Check for Understanding G-CSFs: Labeled and Recommended Uses

Which of the following statements regarding biosimilars is true? • Used in high risk (>20%) or intermediate risk (10-20%) with risk factors A) The 4-letter suffix at the end of the name is a code to indicate a certain Chemotherapy ± radiation Bone marrow involvement Recent surgery manufacturer Prophylaxis Liver dysfunction Renal dysfunction Age >65 years HIV with low CD4 count History of transplantation Open wounds B) All biosimilar products are interchangeable with the reference product and never require a new prescription • Febrile neutropenia and infectious suspicion with expected neutropenia >10 days • Sepsis symptoms, age >65 years, ANC <100, history of febrile neutropenia C) Biosimilar products are considered “highly similar” and have no clinically meaningful differences from an existing FDA-approved reference product Pegfilgrastim 6mg x 1 dose Filgrastim 5mcg/kg/day D) Biosimilar products cannot have any differences in clinically inactive substances compared to a reference product • Severe chronic neutropenia Treatment • Cyclic, congenital, idiopathic Filgrastim 5mcg/kg/day Sargramostim 250mg/m2/day

Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine. 21 NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020 22

Expected (and Comparative) Onset Inappropriate Uses of G-CSFs

• Neutropenia but count recovery expected within 10 days and no other infectious concerns • Not every chemotherapy regimen requires prophylaxis with G-CSFs – check guidelines!

• Similar nadirs, similar time to recovery Pegfilgrastim Pearls: • Pegfilgrastim usually lasts about 12 days – no benefit to extra G-CSF within this time frame • Not for use with weekly chemotherapy regimens = Pegfilgrastim administered

= Filgrastim administered • Not technically labeled for stem cell mobilization for HSCT

= ANC following filgrastim • Some data to suggest benefit in auto-HSCT mobilization

= ANC following peg-filgrastim • Don’t reach for long-acting first – try shorter-acting filgrastim • Less costly and lower incidence of bone pain Clinical Controversy: • Concern with stimulating leukemic growth when using G-CSF in patients with myelodysplastic syndrome (MDS), a disease that commonly precedes acute myeloid leukemia

Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine. Kubo K, et al. BJH. 2016 Apr; 174: 563-570. 23 NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; Kim MG, et al. Bone Marrow Transplantation. 2015; 50: 523-30. 24

6 Adverse Effects of G-CSF and GM-CSF Patient Case: Check for Understanding

Filgrastim & Pegfilgrastim • SR is a 52-year old male with small cell lung cancer who receives carboplatin + etoposide every 21 days for his initial treatment. He has no • Bone pain other significant past medical history and has a good performance score • Can consider loratadine (Claritin) +/- NSAIDs (if clinically appropriate) (ECOG = 0). Per NCCN: febrile neutropenia risk = 10-20%. • Which G-CSF should SR receive with his chemotherapy? Sargramostim A) Pegfilgrastim (Neulasta®) 6 mg subQ 24h after last chemotherapy • Fluid retention, respiratory distress, supraventricular arrhythmias B) Filgrastim (Neupogen®) 5 mcg/kg/day subQ until ANC >1000 NCCN-Specific Warnings C) Sargramostim (Leukine®) 250 mcg/m2/day subQ until ANC >1000

• Acute respiratory distress syndrome (ARDS), pulmonary toxicity or D) No growth factor is indicated for this patient hemorrhage, splenic rupture, allergic reactions

Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine. NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020 25 26

Patient Case

NR is a 36-year old female with early stage, ER+ breast cancer treated with left lumpectomy and radiation, currently on tamoxifen. She also has a medical history of unresolved iron deficiency anemia and a deep vein thrombosis (DVT) Low Place #2: 3 years prior. She presents to clinic with the following lab values: • Hgb 8.2 g/dL, hematocrit 24.6% Based on the information above, should NR receive an erythropoietin Anemia stimulating agent to help with her anemia? “…I’M NOT BIG ON [OXYGEN DELIVERY] GRACES…” Let’s discuss to find out!

27 28

7 Definitions: Anemia Pathophysiology ↓ Production ↑ Destruction • Iron deficiency anemia (IDA) ↑ Loss Labs • Hemolytic anemia • Folate and/or B12 deficiency • Disseminated • Bleeding! • Low hemoglobin (Hb) and hematocrit (Hct) • Anemia of chronic disease intravascular • Frequent lab draws • Hb < 13 g/dL (men) or <12 g/dL (women) coagulopathy (DIC) • Kidney disease • Surgery What does this mean? • Autoimmune disorders • Possible drug-related • Cancer-related anemia (CRA) • Dapsone • Inadequate supply of RBCs leads to inadequate oxygen carrying ability and • Myelosuppression due to • B-lactams (rare) oxygen delivery chemotherapy, radiation, • Identifying the reason for the anemia is necessary to select appropriate treatment inflammation • Rule out other causes before thinking of starting erythropoietin-stimulating • MDS, AML agents • Thalassemia (genetic)

Ciesla B. Hematology in Practice. 2007. Ciesla B. Hematology in Practice. 2007. 29 Gilreath JA, et al. AJH. 2014; 89: 203-12; Gilreath JA, Rodgers GM. Blood. 2020; 136(7): 801-13. 30

Mechanism of Action Erythropoietin Stimulating Agents (ESAs)

• Erythropoietin (EPO) is a • Epogen® () Which product should I choose? hormone that binds to • Retacrit® (epoetin alfa-epbx) Head-to-head comparisons of darbepoetin vs external receptors on epoetin alfa are inconclusive and do not show a pronormoblasts • Aranesp® () clear benefit of one product over the other • EPO is produced by the Go with the one the insurance covers! kidneys Erythrocyte production! Dosing (cancer) – subcutaneous only • Phosphorylation & • Epoetin alfa 150 units/kg three times weekly or 40,000 units weekly downstream signaling  • Darbepoetin 2.25 mcg/kg weekly or 300-500 mcg every 3 weeks increased erythrocyte Dosing (kidney disease) – subcutaneous or intravenous division • Epoetin alfa 20-50 u/kg three times weekly • Darbepoetin 0.45 mcg/kg weekly or 0.75 mcg/kg every 2 weeks

Goal: Reach a Hb level that will minimize transfusions (generally ≤11.5 g/dL)

Ciesla B. Hematology in Practice. 2007. Package inserts: Epogen, Aranesp, Retacrit. Gilreath JA, et al. AJH. 2014; 89: 203-12; Gilreath JA, Rodgers GM. Blood. 2020; 136(7): 801-13. 31 NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012. 32

8 Expected Onset ESAs: Labeled and Recommended Uses Epoetin alfa: Darbepoetin: • Likely will not see any benefit for 4-8 weeks 1) Treatment of anemia in chronic kidney 1) Treatment of anemia in CKD • There is no immediate effect disease (CKD) 2) Treatment of anemia related to • Benefits are seen with repeated dosing 2) Treatment of anemia related to myelosuppressive chemotherapy myelosuppressive chemotherapy • What effect do we expect to see? 1) NOT hormonal, biologic, or radiotherapy 1) NOT hormonal, biologic, or radiotherapy • 45-90% response rate 2) Palliative chemotherapy only 2) Palliative chemotherapy only • “Response” = Hb increase by 1-2 g/dL or reduction in transfusions 3) Reduction of perioperative transfusions • Approximately 55-65% response in ESA alone 4) Treatment of anemia in zidovudine-treated NCCN Off-Label Recommended Use: HIV patients Patients who refuse blood transfusions • 80% response in ESA + intravenous iron replacement

KDIGO ESA Guidelines (2012) “We recommend using ESA therapy with great caution, if at all, in CKD patients with active malignancy – in particular when cure is the anticipated outcome… or a history of malignancy.”

Package inserts: Epogen, Aranesp, Retacrit. Package inserts: Epogen, Aranesp, Retacrit. NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012. 33 NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012. 34

Inappropriate Uses of ESAs ESAs in Non-myelosuppressive Therapy

• Immediate resolution of anemia needed – will not work in time! • Cancer-related anemia but not receiving myelosuppressive chemotherapy! • Examples: vincristine, hormonal treatments, biologics, no treatment • Patients with cancer-related • Anemia related to myelosuppressive chemotherapy with a curative intent anemia NOT receiving • Examples: early-stage breast cancer, , non-Hodgkin’s lymphomas, testicular chemotherapy or radiation cancer, early-stage non-small cell lung cancer, small cell lung cancer, acute leukemia • N= 989 • Phase III, randomized trial • History of stroke or venous thromboembolism (VTE) from 2004-2006 NCCN specifications: Use of ESAs in these patients may be harmful • Non-statistically significant • Metastatic breast cancer – decreased progression-free survival decrease in transfusions • ESA use outside of 6-week window of treatment completion – concern for decreased survival, black box warning Key Takeaway: No benefit KDIGO specifications: Do not start ESA if Hb >10 g/dL

Package inserts: Epogen, Aranesp, Retacrit.NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012. 35 36 Leyland-Jones B, et al. JCO. 2005; 23: 5960-72. Leyland-Jones B, et al. JCO. 2016: 34; 1197-1207. Gilreath JA, Rodgers GM. Blood. 2020. Smith Jr RE, et al. JCO. 2008; 26: 1040-50.

9 Adverse Effects of ESAs Patient Case: Check for Understanding NR is a 36-year old female with early stage, ER+ breast cancer treated with left Thrombosis lumpectomy and radiation, currently on tamoxifen. She also has a medical • Increased absolute & relative stroke risk compared to no treatment history of unresolved iron deficiency anemia and a deep vein thrombosis (DVT) • VTE in cancer patients – meta-analyses = ~5% increase in relative risk from baseline 3 years prior. She presents to clinic with the following lab values: • Unclear if risk is still elevated when patients are on anticoagulation • Hgb 8.2 g/dL, hematocrit 24.6%

Hypertension Based on the information above, which patient characteristics are reasons NR should not receive an ESA for treatment of her anemia? • Control blood pressure (<140/90 mmHg) before starting and while on treatment A) Not on myelosuppressive treatment Pure red cell aplasia (PRCA) B) Uncorrected iron deficiency anemia • Antibody development against specific ESA product C) History of DVT • Decreased ESA and EPO effect D) All of the above

Package inserts: Epogen, Aranesp, Retacrit. NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012. Bohlius J, et al. JNCI. 2005; 97 (7): 489-98. Glaspy J, et al. BJC. 2010; 102: 301-15. Bennett CL, et al. JAMA. 2008; 299 (8): 914-24. 37 38

Check for Understanding

Which of the following cell lines does Aranesp® (darbepoetin) work on? A) Neutrophils B) Red blood cells Low Place #3: C) Neutrophils and macrophages D) Platelets Thrombocytopenia “…THINK I’LL SLIP ON DOWN TO THE [THROMBOPOIETIN] OASIS…”

39 40

10 Patient Case Definitions: Thrombocytopenia

BB is a 50-year old male with chronic idiopathic thrombocytopenia (cITP). He has been on prednisone 40 mg daily for the past 12 months and has received Labs one dose of rituximab for treatment. Today, his platelets are still low at 25 x 103/mL. He has a phobia of needles and confined spaces and would ideally like • Low platelets (<150 x 103/mL) to avoid surgery. Which thrombopoietin receptor agonist would be the most appropriate to initiate? How would you monitor for efficacy? What does this mean? • Inadequate ability to form primary and secondary Let’s discuss to find out! clots, allowing for increased bleeding • Petechial bleeds, purpura, mucosal bleeding

Ciesla B. Hematology in Practice. 2007. 41 Mitchell WB, Bussel JB. Blood. 2013; 121 (24): 4817-4818. 42

Pathophysiology Mechanism of Action ↓ Production ↑ Destruction ↑ Loss • Bleeding • Thrombopoietin (TPO) binds • Myelosuppression related • Antibody-mediated to megakaryocyte surface to anticancer treatment • Idiopathic thrombocytopenic • Medications receptor purpura (ITP) • Aspirin • Malignancy • Hemolytic uremic syndrome • Sulfa antibiotics • JAK2/STATs pathway activated • AML, MDS (HUS) • Quinine  increased proliferation • Thrombotic thrombocytopenic • Viral infections purpura (TTP) • Medications have two • HIV, Hepatitis C • Disseminated intravascular available binding sites: • Chronic alcohol use coagulation 1. Directly at receptor site • Heparin-induced thrombocytopenia • Liver dysfunction (HIT) 2. Trans-membrane site • Non-alcoholic fatty liver disease

Ciesla B. Hematology in Practice. 2007. Ciesla B. Hematology in Practice. 2007. Lim MY, Gilreath JA. Blood Adv. 2020; 4(18): 4438-4441. 43 Ghanima W, et al. Haematologica. 2019; 104 (6). 44

11 Agonists (TPO-RAs) Expected Onset

• (Nplate®) - peptibody • Subcutaneous injection, 1 mcg/kg weekly TPO-RA First Effect Peak Effect • Pearls: reconstitution required, small volumes (0.3mL) Which product should I choose? Romiplostim (Nplate®) 4-9 days 12-16 days ® • (Promacta ) – small molecule 1) Patient preference Eltrombopag (Promacta®) Effect seen within 7-14 days • Oral capsule & suspension, 50-75 mg daily 2) Insurance coverage • Take doses on an empty stomach Avatrombopag (Doptelet®) 3-5 days 10-13 days • Avatrombopag (Doptelet®) – small molecule • Oral tablets, 20-40 mg daily Also, a 4th TPO-RA: May take longer to see effect in certain patients Lusutrombopag (Mulpleta®) – • High levels of peripheral platelet destruction • Take doses with food Small molecule, oral tablets Goal: Maintain platelets > 50 x 103/mL Niche indication, not used much • Low bone marrow myeloid stem cell reserves

Package inserts: Nplate, Promacta, Doptelet, Mulpleta. Wormann B. Transfus Med Hemother. 2013; 40: 319-25. Package inserts: Nplate, Promacta, Doptelet. Ghanima W, et al. Haematologica. 2019; 104 (6). Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP. 45 Wolters Kluwer. Lexicomp. Nplate, Promacta, Doptelet. 46

TPO-RAs: Labeled and Recommended Uses Inappropriate Uses of TPO-RAs

Romiplostim Eltrombopag Avatrombopag • Chemotherapy-induced thrombocytopenia – No FDA approved treatments (yet!) • Immune • ITP with insufficient • ITP with insufficient • Avatrombopag – FDA granted orphan drug designation for chemotherapy-induced response to thrombocytopenia thrombocytopenia corticosteroids, response to previous (ITP) with insufficient immunoglobulins, or treatment • Phase 3 trial (NCT03451078) ongoing response to splenectomy • Pre-operative platelet • Romiplostim – Phase 2 placebo-controlled trial found effective in correcting corticosteroids, chemotherapy-induced thrombocytopenia (93% vs 12.5%) immunoglobulins, or • Severe aplastic anemia management in chronic splenectomy with insufficient liver disease response to • Not for correcting thrombocytopenia related to MDS or other malignancies immunosuppression • Concern that can increase blast counts  AML! Lusutrombopag (Mulpleta®) • Hepatitis C-related • Only initiate if platelets <50 x 103/mL and clinical condition increases bleed risk thrombocytopenia to Only for use in liver disease allow for use with upcoming procedure • Not necessarily a platelet-transfusion replacement modality (antiquated indication)

Package inserts: Nplate, Promacta, Doptelet, Mulpleta. Wormann B. Transfus Med Hemother. 2013; 40: 319-25. Package inserts: Nplate, Promacta, Doptelet. Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP. Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP. 47 Duffy S.. 2020 Jan 13. MPR: Drugs in the Pipeline. Soff GA, et al. JCO. 2019; 37: 2892-98. 48

12 Adverse Effects of TPO-RAs Patient Case: Check for Understanding

Thrombosis BB is a 50-year old male with chronic idiopathic thrombocytopenia (cITP). He has been on prednisone 40 mg daily for the past 12 months and has received one dose • Increasing platelet counts may have increased thrombogenic potential of rituximab for treatment. Today, his platelets are still low at 25 x 103/mL. He has a • Chronic liver disease: portal vein thrombosis phobia of needles and confined spaces and would ideally like to avoid surgery. Which would be the most appropriate treatment to initiate? How would you Bone marrow fibrosis monitor for efficacy? ® • Related to increased reticulin deposition A) Romiplostim (Nplate ) 1 mcg/kg subcutaneously weekly; recheck platelets in 2 • Appears to reverse with cessation of treatment weeks B) Eltrombopag (Promacta®) 50 mg by mouth daily; recheck platelets in 2 weeks General other effects C) Romiplostim (Nplate®) 1 mcg/kg subcutaneously weekly; recheck hemoglobin in 2 weeks • Headache, nausea/vomiting, elevations in liver transaminases ® • Avatrombopag: Claims lower LFT abnormalities than eltrombopag D) Eltrombopag (Promacta ) 50 mg by mouth daily; recheck hemoglobin in 2 weeks

Package inserts: Nplate, Promacta, Doptelet. Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP. 49 50

Check for Understanding Recap: Putting it all together

Which of the following is the brand name for eltrombopag? • In many cases, hematopoietic growth factors can be life-saving treatments A) Nplate® • However, it is important to recognize when the use of growth factors is appropriate per guideline recommendations and FDA labeled indications B) Promacta® • Use of growth factors for inappropriate uses can be harmful and may ® C) Doptelet cloud the clinical picture D) Granix® • Not all growth factors are “friends in low places!” • Pharmacists and technicians can work together to find the most appropriate (and financially feasible) options for each patient • Biosimilar products help to keep costs competitive

Filgrastim Erythropoietin Thrombopoietin

51 52

13 References

1) Ciesla B. Hematology in Practice. E.A. Davis Company. Philadelphia, PA. 2007. ISBN-10: 0-8036-1526-4. 2) Parihar A, Eubank TD, Doseff AI. Monocytes and Macrophages Regulate Immunity through Dynamic Networks of Survival and Cell Death. J Innate Immun. 2010;2(3):204-215. doi:10.1159/000296507 3) Wolters Kluwer. Lexicomp [database online]. Updated 2020 Oct. Accessed 2020 Oct. 4) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Hematopoietic Growth Factors. Version 2.2020. Updated 2020 Jan 27. Accessed 2020 Oct. 5) Kurtin, RN, MS, AOCN®, ANP-C SE. Myeloid Toxicity of Cancer Treatment. JADPRO. 2012;3(4). doi:10.6004/jadpro.2012.3.4.2 6) Inc. Neupogen (filgrastim). Package insert. Revised 9/2013. Accessed 2020 Oct. 7) Amgen Inc. Neulasta (pegfilgrastim). Package insert. Revised 1/2020. Accessed 2020 Oct. 8) -Aventis. Leukine (sargramostim). Package insert. Revised 2/2017. Accessed 2020 Oct. 9) Dwivedi P, Greis KD. Granulocyte colony-stimulating factor receptor signaling in severe congenital neutropenia, chronic neutrophilic leukemia, and related malignancies. Experimental Hematology. 2017;46:9-20. doi:10.1016/j.exphem.2016.10.008 10) Panopoulos AD, Watowich SS. Granulocyte colony-stimulating factor: Molecular mechanisms of action during steady state and ‘emergency’ hematopoiesis. Cytokine. 2008;42(3):277-288. doi:10.1016/j.cyto.2008.03.002 11) Mehta HM, Malandra M, Corey SJ. G-CSF and GM-CSF in Neutropenia. JI. 2015;195(4):1341-1349. doi:10.4049/jimmunol.1500861 12) Designation of Official Names and Proper Names for.pdf. Accessed October 9, 2020. https://www.fda.gov/media/93748/download 13) Research C for DE and. Biosimilar and Interchangeable Products. FDA. Published online February 9, 2019. Accessed October 9, 2020. https://www.fda.gov/drugs/biosimilars/biosimilar-and-interchangeable-products 14) Department of Occupational and Professional Licensing. Pharmacy Practice Act.. Chapter 17b, 58-17b-605.5. Dec 2018. Accessed 2020 Oct. 15) Kubo K, Miyazaki Y, Murayama T, et al. A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma. Br J Haematol. 2016;174(4):563-570. doi:10.1111/bjh.14088 16) Kim MG, Han N, Lee E-K, Kim T. Pegfilgrastim vs filgrastim in PBSC mobilization for autologous hematopoietic SCT: a systematic review and meta-analysis. Bone Marrow Transplant. 2015;50(4):523-530. doi:10.1038/bmt.2014.297 17) Gilreath JA, Stenehjem DD, Rodgers GM. Diagnosis and treatment of cancer-related anemia: Diagnosis and treatment of cancer-related anemia. Am J Hematol. 2014;89(2):203-212. doi:10.1002/ajh.23628 18) Gilreath JA, Rodgers GM. How I treat cancer-associated anemia. Blood. 2020;136(7):801-813. doi:10.1182/blood.2019004017 19) KDIGO. Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Journ Int Society of Nephrology. 2012. Accessed 2020 Oct. 20) Amgen Inc. Epogen (epoetin alfa). Package insert. Revised 5/2012. Accessed 2020 Oct. 21) Pfizer Inc. Retacrit (epoetin alfa-epbx). Package insert. Revised 5/2018. Accessed 2020 Oct. 22) Amgen Inc. Aranesp (darbepoetin alfa). Package insert. Revised 6/2011. Accessed 2020 Oct. Questions? 23) Leyland-Jones B, Bondarenko I, Nemsadze G, et al. A Randomized, Open-Label, Multicenter, Phase III Study of Epoetin Alfa Versus Best Standard of Care in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy. JCO. 2016;34(11):1197-1207. doi:10.1200/JCO.2015.63.5649 24) Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining Normal Hemoglobin Levels With Epoetin Alfa in Mainly Nonanemic Patients With Metastatic Breast Cancer Receiving First-Line Chemotherapy: A Survival Study. JCO. 2005;23(25):5960-5972. doi:10.1200/JCO.2005.06.150 25) Smith RE, Aapro MS, Ludwig H, et al. Darbepoetin Alfa for the Treatment of Anemia in Patients With Active Cancer Not Receiving Chemotherapy or Radiotherapy: Results of a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. JCO. 2008;26(7):1040-1050. doi:10.1200/JCO.2007.14.2885 Thank you for listening! 26) Bohlius J, Langensiepen S, Schwarzer G, et al. Recombinant Human Erythropoietin and Overall Survival in Cancer Patients: Results of a Comprehensive Meta-analysis. JNCI Journal of the National Cancer Institute. 2005;97(7):489-498. doi:10.1093/jnci/dji087 27) Bennett CL. Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia. JAMA. 2008;299(8):914. doi:10.1001/jama.299.8.914 28) Glaspy J, Crawford J, Vansteenkiste J, et al. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010;102(2):301-315. doi:10.1038/sj.bjc.6605498 [email protected] 29) Mitchell WB, Bussel JB. How Low Can You Go? Blood. 2013 June; 121 (24): 4817-18. 30) Amgen Inc. Nplate (romiplostim). Package insert. Revised 10/2019. Accessed 2020 Oct. 31) GlaxoSmithKline. Promacta (eltrombopag). Package insert. Revised 8/2015. Accessed 2020 Oct. 32) Dova Pharmaceuticals. Doptelet (avatrombopag). Package insert. Revised 6/2019. Accessed 2020 Oct. 33) Shionogi Inc. Mulpleta (lusutrombopag). Package Insert. Revised 7/2018. Accessed 2020 Oct. 34) Neunert C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Advances. 2019;3(23):3829-3866. doi:10.1182/bloodadvances.2019000966 35) Wormann B. Clinical Indications for Thombopoietin and Thrombopoietin-Receptor Agonists. Transfus Med Hemother. 2013; 40: 319-25. 36) Lim MY, Gilreath JA. Periprocedural use of avatrombopag for neurosurgical interventions: a strategy to avoid platelet utilization. Blood Advances. 2020;4(18):4438-4441. doi:10.1182/bloodadvances.2020003045 37) Soff GA, Miao Y, Bendheim G, et al. Romiplostim Treatment of Chemotherapy-Induced Thrombocytopenia. JCO. 2019;37(31):2892-2898. doi:10.1200/JCO.18.01931

53 54

14