friends in low places: a clinical review of hematopoietic
TRANSCRIPT
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Sabrina Schneider, PharmD
November 12, 2020
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Friends in Low Places: A Clinical Review of
Hematopoietic Growth Factors
Sabrina Schneider, PharmD
PGY-2 Oncology Resident
Huntsman Cancer Institute at University of Utah Health
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Disclosures
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• Relevant Financial Conflicts of Interest
• CE Presenter, Sabrina Schneider, PharmD:
• None
• CE mentor, Jeffrey Gilreath, PharmD:
• None
• Off-Label Uses of Medications
• Erythropoietin Stimulating Agents (ESAs) for use in patient populations
who refuse blood transfusions
• Additional off-label uses will be discussed to elaborate on why they are
inappropriate
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Learning Objectives
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Pharmacist Objectives:
1. Develop an appropriate therapeutic management and monitoring plan for each class of hematopoietic growth factors based on a patient case.
2. Review the normal physiology of hematopoiesis and describe the mechanism of action for each class of hematopoietic growth factors.
3. Distinguish between appropriate and inappropriate uses for hematopoietic growth factors in common clinical settings.
Technician Objectives:
1. Compare and contrast the different classes of hematopoietic growth factors and determine which cell lineage each agent stimulates to grow.
2. Define the term “biosimilar” and provide examples of both biosimilar hematopoietic growth factors and their originator product.
3. Identify brand and generic names of common hematopoietic growth factors.
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Introduction to Hematopoietic Growth Factors
• The bone marrow is a very important organ for maintaining normal function
• Home to the pluripotent stem cells that eventually become all blood cells!
• Clinical diseases & treatments can lead us to some low places with cell counts
• The “biologics boom” has led to the development of medications that mimic and/or replace endogenous signals to stimulate growth of specific cell lines
• Knowing when to use certain growth factors may help improve clinical statusand quality of life
Neutropenia Anemia Thrombocytopenia
Ciesla B. Hematology in Practice. 2007.
Filgrastim Erythropoietin Thrombopoietin
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Normal Hematopoiesis: Overview
Ciesla B. Hematology in Practice. 2007. 8
White Blood Cells (WBCs)
Myeloid differentiation
• Neutrophils (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.
Image: Flikr. “Neutrophils”
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White Blood Cells (continued)
Lymphoid differentiation
• From the thymus and the marrow
• Maturation & activation are dependent on presence of antigens
• T-Lymphocytes (60-80% of lymphoid cells)
• B-Lymphocytes (10-20% of lymphoid cells)
• Natural Killer (NK) cells (<10% of lymphoid cells)
• Do not need antigenic stimulation
• Lifespan: Unclear, possibly up to 4 years
Ciesla B. Hematology in Practice. 2007.10
Red Blood Cells (Erythrocytes)
• Pronormoblasts
• Erythropoietin has greatest effect here
• 1 pronormoblast 16 mature red cells
• Reticulocytes
• Final step before mature erythrocytes – still some genetic
material present
• Erythrocytes
• Carry oxygen via hemoglobin around the body
• Lifespan: 120 days
Ciesla B. Hematology in Practice. 2007.
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Platelets
Megakaryocytes
• 1 megakaryocyte can produce up to 2,000 platelets!
• Thrombopoietin – produced in the liver
• Stimulated by presence of “old” platelets
Platelets: the first responder to vessel injury
• No “platelet reserve” in the marrow
• 80% in circulation, 20% in spleen
• Lifespan: 7-10 days
Ciesla B. Hematology in Practice. 2007.
Low Place #1: Neutropenia“WHERE THE [WHITE CELLS] DROWN, AND THE [NEUPOGEN®] CHASES MY BLUES AWAY…”
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Patient Case
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• 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 other significant past medical history and has a good performance score (ECOG = 0). Per NCCN: febrile neutropenia risk = 10-20%.
• Should SR receive G-CSF to prevent infection with this chemotherapy regimen?
Let’s discuss to find out!
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Definitions: ANC and Neutropenia
• Low white blood cell (WBC) count
• Absolute neutrophil count (ANC) <1500 cells/µL
Labs
• (Segmented neutrophil % + bands %) x WBC # = ANC
• OR… (# segmented neutrophils + # bands) x 1000 = ANC
• Example: (30% + 3%) x 1.0 = 330 = ANC
How to calculate ANC
• 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
What does this mean?
Ciesla B. Hematology in Practice. 2007; Kurtin S. J Adv Pract Oncol. 2012; 3: 209-24.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020
Pathophysiology
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ↆProduction• Myelosuppressive chemotherapy
• Anthracyclines
• Taxanes
• Platinums
• Topoisomerase 1 inhibitors
• CDK4/6 inhibitors
• Dose-dependent
• Malignancy
• Acute myeloid leukemia (AML)
• Myelodysplastic Syndrome (MDS)
↑Destruction
• Myeloablative chemotherapy
• High-dose alkylating agents
• Radiation
• CLAG & FLAG
• Chemotherapy regimens
that contain G-CSF
Loss
• Neutrophil loss is rare
Ciesla B. Hematology in Practice. 2007; Kurtin S. J Adv Pract Oncol. 2012; 3: 209-24.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020 16
Mechanism of Action
• Granulocyte colony-stimulating factor (G-CSF) is an endogenous cytokine
• AKA: CSF3
• Target: G-CSFR
• Downstream phosphorylation increased myeloid differentiation & proliferation
• Neutrophils “waiting in the wings” are mobilized to the periphery
• Rapid action (within 4-24h)
• Sustained elevation
Panoupulos A, et al. Cytokine. 2008 June; 42(3): 277-88; Dwievedi P, et al. Exp Hematol. 2017 Feb; 46: 9-20.
Ciesla B. Hematology in Practice. 2007
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Granulocyte Colony Stimulating Factors (G-CSF)
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Traditional G-CSFs
• Neupogen® (filgrastim)
• Granix® (tbo-filgrastim)
• Zarxio® (filgrastim-sndz)
• Nivestym® (filgrastim-aafi)
Pegylated G-CSFs – Longer acting
• Neulasta® (pegfilgrastim)
• Udenyca® (pegfilgrastim-cbqv)
• Fulphila® (pegfilgrastim-jmdb)
• Ziextenzo® (pegfilgrastim-bmez)
Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF)
• Leukine® (sargramostim)
• Promotes macrophage & neutrophil
production increased antigen presenting
increased immune activation
• Some megakaryocytic and erythroid
stimulation
Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; Mehta H, et al. J Immunol. 2015 Aug; 195 (4): 1341-49. 18
Biosimilars: Explained
• Biologics are bioactive proteins produced in living cells
• Aids in post-translational adjustments required for
protein to become biologically active
• Biosimilar = Biologic products that are “highly similar” with no clinically meaningful differences from an existing reference product
• Reference Product = Usually the first FDA-approved biologic
• “Highly similar”= Small differences in clinically inactive substances that have no effect on safety, efficacy, purity, and potency
FDA. Biosimilar and Interchangeable Products. Oct 2017.
FDA. Docket No. FDA-2015-N-0648.
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Biosimilars: Explained (continued)
• Interchangeable products: the Biologics Price and Competition Act (2009) adds an extra “tier” of biosimilarity
• Must prove that product will produce the exact same clinical effect in any
given patient
• If a product is deemed interchangeable, product substitution can happen
without any need for provider intervention
• Utah Law: Pharmacy Practice Act 58-17b-605.5
• Allowable to switch between interchangeable products without prescriber
approval provided prescriber is notified of changed product
FDA. Biosimilar and Interchangeable Products. Oct 2017.; FDA. Docket No. FDA-2015-N-0648.
DOPL. Chapter 17b, 58-17b-605.5. Dec 2018.; FDA. Biosimilars and Interchangeable Biologics: More Treatment Choices. Mar 2020.
However, there are currently zero “interchangeable” biosimilar products
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Biosimilars: Explained (continued)
What’s with the 4 letter nonsense suffixes?
• The FDA has rules on the naming of biosimilar products to help identify the different products
1) Core name
2) Distinguishing random, 4-letter suffix that is devoid of meaning
• Three of the 4 letters must be different from other products
• Upcoming changes: Zarxio® (filgrastim-sndz) & Granix® (tbo-filgrastim) will need new names. Reference products will need suffixes, too.
• For more information on naming: FDA Guidance on Biologic Naming
FDA. Biosimilar and Interchangeable Products. Oct 2017.
FDA. Docket No. FDA-2015-N-0648.
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Check for Understanding
Which of the following statements regarding biosimilars is true?
A) The 4-letter suffix at the end of the name is a code to indicate a certain manufacturer
B) All biosimilar products are interchangeable with the reference product and never require a new prescription
C) Biosimilar products are considered “highly similar” and have no clinically meaningful differences from an existing FDA-approved reference product
D) Biosimilar products cannot have any differences in clinically inactive substances compared to a reference product
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G-CSFs: Labeled and Recommended Uses
• Used in high risk (>20%) or intermediate risk (10-20%) with risk factors
• Febrile neutropenia and infectious suspicion with expected neutropenia >10 days
• Sepsis symptoms, age >65 years, ANC <100, history of febrile neutropenia
• Severe chronic neutropenia
• Cyclic, congenital, idiopathic
Chemotherapy ± radiation Bone marrow involvement Recent surgery
Liver dysfunction Renal dysfunction Age >65 years
HIV with low CD4 count History of transplantation Open wounds
Prophylaxis
Treatment
Pegfilgrastim 6mg x 1 dose Filgrastim 5mcg/kg/day
Sargramostim 250mg/m2/day
Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020
Filgrastim 5mcg/kg/day
Expected (and Comparative) Onset
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• Similar nadirs, similar
time to recovery
= Pegfilgrastim administered
= Filgrastim administered
= ANC following filgrastim
= ANC following peg-filgrastim
Kubo K, et al. BJH. 2016 Apr; 174: 563-570.
Inappropriate Uses of G-CSFs
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• Neutropenia but count recovery expected within 10 days and no other infectious concerns
• Not every chemotherapy regimen requires prophylaxis with G-CSFs – check guidelines!
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
• Not technically labeled for stem cell mobilization for HSCT
• Some data to suggest benefit in auto-HSCT mobilization
• 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.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; Kim MG, et al. Bone Marrow Transplantation. 2015; 50: 523-30.
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Adverse Effects of G-CSF and GM-CSF
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• Bone pain
• Can consider loratadine (Claritin) +/- NSAIDs (if clinically appropriate)
Filgrastim & Pegfilgrastim
• Fluid retention, respiratory distress, supraventricular arrhythmias
Sargramostim
• Acute respiratory distress syndrome (ARDS), pulmonary toxicity or
hemorrhage, splenic rupture, allergic reactions
NCCN-Specific Warnings
Package inserts: Neupogen, Granix, Zarxio, Nivestym, Neulasta, Udenyca, Fulphila, Ziextenzo, Leukine.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020
Patient Case: Check for Understanding
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• 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 other significant past medical history and has a good performance score (ECOG = 0). Per NCCN: febrile neutropenia risk = 10-20%.
• Which G-CSF should SR receive with his chemotherapy?
A) Pegfilgrastim (Neulasta®) 6 mg subQ 24h after last chemotherapy
B) Filgrastim (Neupogen®) 5 mcg/kg/day subQ until ANC >1000
C) Sargramostim (Leukine®) 250 mcg/m2/day subQ until ANC >1000
D) No growth factor is indicated for this patient
Low Place #2: Anemia“…I’M NOT BIG ON [OXYGEN DELIVERY] GRACES…”
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Patient Case
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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) 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 stimulating agent to help with her anemia?
Let’s discuss to find out!
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Definitions: Anemia
• Low hemoglobin (Hb) and hematocrit (Hct)
• Hb < 13 g/dL (men) or <12 g/dL (women)
Labs
• Inadequate supply of RBCs leads to inadequate oxygen carrying ability and
oxygen delivery
• Identifying the reason for the anemia is necessary to select appropriate treatment
• Rule out other causes before thinking of starting erythropoietin-stimulating
agents
What does this mean?
Ciesla B. Hematology in Practice. 2007.
Pathophysiology
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↓ Production• Iron deficiency anemia (IDA)
• Folate and/or B12 deficiency
• Anemia of chronic disease
• Kidney disease
• Autoimmune disorders
• Cancer-related anemia (CRA)
• Myelosuppression due to chemotherapy, radiation, inflammation
• MDS, AML
• Thalassemia (genetic)
↑ Destruction
• Hemolytic anemia
• Disseminated intravascular coagulopathy (DIC)
• Possible drug-related
• Dapsone
• B-lactams (rare)
↑ Loss• Bleeding!
• Frequent lab draws
• Surgery
Ciesla B. Hematology in Practice. 2007.
Gilreath JA, et al. AJH. 2014; 89: 203-12; Gilreath JA, Rodgers GM. Blood. 2020; 136(7): 801-13.
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Mechanism of Action
• Erythropoietin (EPO) is a hormone that binds to external receptors on pronormoblasts
• EPO is produced by the kidneys
• Phosphorylation & downstream signaling increased erythrocyte division
Erythrocyte production!
Ciesla B. Hematology in Practice. 2007.
Gilreath JA, et al. AJH. 2014; 89: 203-12; Gilreath JA, Rodgers GM. Blood. 2020; 136(7): 801-13.
Erythropoietin Stimulating Agents (ESAs)
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• Epogen® (epoetin alfa)
• Retacrit® (epoetin alfa-epbx)
• Aranesp® (darbepoetin alfa)
Which product should I choose?
Head-to-head comparisons of darbepoetin vs epoetin alfa are inconclusive and do not show a clear benefit of one product over the other
Go with the one the insurance covers!
Dosing (cancer) – subcutaneous only
• Epoetin alfa 150 units/kg three times weekly or 40,000 units weekly
• Darbepoetin 2.25 mcg/kg weekly or 300-500 mcg every 3 weeks
Dosing (kidney disease) – subcutaneous or intravenous
• 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)
Package inserts: Epogen, Aranesp, Retacrit.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012.
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Expected Onset
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• Likely will not see any benefit for 4-8 weeks
• There is no immediate effect
• Benefits are seen with repeated dosing
• What effect do we expect to see?
• 45-90% response rate
• “Response” = Hb increase by 1-2 g/dL or reduction in transfusions
• Approximately 55-65% response in ESA alone
• 80% response in ESA + intravenous iron replacement
Package inserts: Epogen, Aranesp, Retacrit.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012.
ESAs: Labeled and Recommended Uses
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Epoetin alfa:
1) Treatment of anemia in chronic kidney disease (CKD)
2) Treatment of anemia related to myelosuppressive chemotherapy
1) NOT hormonal, biologic, or radiotherapy
2) Palliative chemotherapy only
3) Reduction of perioperative transfusions
4) Treatment of anemia in zidovudine-treated HIV patients
Darbepoetin:
1) Treatment of anemia in CKD
2) Treatment of anemia related to myelosuppressive chemotherapy
1) NOT hormonal, biologic, or radiotherapy
2) Palliative chemotherapy only
NCCN Off-Label Recommended Use:
Patients who refuse blood transfusions
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.
NCCN Guidelines: Hematopoietic Growth Factors. V 2.2020; KDIGO. Anemia in CKD. 2012.
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Inappropriate Uses of ESAs
• 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
• Anemia related to myelosuppressive chemotherapy with a curative intent
• Examples: early-stage breast cancer, Hodgkin lymphoma, non-Hodgkin’s lymphomas, testicular
cancer, early-stage non-small cell lung cancer, small cell lung cancer, acute leukemia
• History of stroke or venous thromboembolism (VTE)
NCCN specifications: Use of ESAs in these patients may be harmful
• Metastatic breast cancer – decreased progression-free survival
• ESA use outside of 6-week window of treatment completion – concern for decreased survival,
black box warning
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.
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. 36
ESAs in Non-myelosuppressive Therapy
• Patients with cancer-related
anemia NOT receiving
chemotherapy or radiation
• N= 989
• Phase III, randomized trial
from 2004-2006
• Non-statistically significant
decrease in transfusions
Key Takeaway: No benefit
Smith Jr RE, et al. JCO. 2008; 26: 1040-50.
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Adverse Effects of ESAs
• Increased absolute & relative stroke risk compared to no treatment
• VTE in cancer patients – meta-analyses = ~5% increase in relative risk from baseline
• Unclear if risk is still elevated when patients are on anticoagulation
Thrombosis
• Control blood pressure (<140/90 mmHg) before starting and while on treatment
Hypertension
• Antibody development against specific ESA product
• Decreased ESA and EPO effect
Pure red cell aplasia (PRCA)
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.
Patient Case: Check for Understanding
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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) 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, which patient characteristics are reasons NR should not receive an ESA for treatment of her anemia?
A) Not on myelosuppressive treatment
B) Uncorrected iron deficiency anemia
C) History of DVT
D) All of the above
Check for Understanding
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Which of the following cell lines does Aranesp® (darbepoetin) work on?
A) Neutrophils
B) Red blood cells
C) Neutrophils and macrophages
D) Platelets
Low Place #3: Thrombocytopenia“…THINK I’LL SLIP ON DOWN TO THE [THROMBOPOIETIN] OASIS…”
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Patient Case
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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 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 to avoid surgery.
Which thrombopoietin receptor agonist would be the most appropriate to initiate? How would you monitor for efficacy?
Let’s discuss to find out!
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Definitions: Thrombocytopenia
• Low platelets (<150 x 103/mL)
Labs
• Inadequate ability to form primary and secondary
clots, allowing for increased bleeding
• Petechial bleeds, purpura, mucosal bleeding
What does this mean?
Ciesla B. Hematology in Practice. 2007.
Mitchell WB, Bussel JB. Blood. 2013; 121 (24): 4817-4818.
Pathophysiology
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↓ Production
• Myelosuppression related to anticancer treatment
• Malignancy
• AML, MDS
• Viral infections
• HIV, Hepatitis C
• Chronic alcohol use
• Liver dysfunction
• Non-alcoholic fatty liver
disease
↑ Destruction• Antibody-mediated
• Idiopathic thrombocytopenic purpura (ITP)
• Hemolytic uremic syndrome (HUS)
• Thrombotic thrombocytopenic purpura (TTP)
• Disseminated intravascular coagulation
• Heparin-induced thrombocytopenia (HIT)
↑ Loss
• Bleeding
• Medications
• Aspirin
• Sulfa antibiotics
• Quinine
Ciesla B. Hematology in Practice. 2007.
Lim MY, Gilreath JA. Blood Adv. 2020; 4(18): 4438-4441. 44
Mechanism of Action
• Thrombopoietin (TPO) binds to megakaryocyte surface receptor
• JAK2/STATs pathway activated increased proliferation
• Medications have two available binding sites:
1. Directly at receptor site
2. Trans-membrane site
Ciesla B. Hematology in Practice. 2007.
Ghanima W, et al. Haematologica. 2019; 104 (6).
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Thrombopoietin Receptor Agonists (TPO-RAs)
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• Romiplostim (Nplate®) - peptibody
• Subcutaneous injection, 1 mcg/kg weekly • Pearls: reconstitution required, small volumes (0.3mL)
• Eltrombopag (Promacta®) – small molecule
• Oral capsule & suspension, 50-75 mg daily
• Take doses on an empty stomach
• Avatrombopag (Doptelet®) – small molecule
• Oral tablets, 20-40 mg daily
• Take doses with food
Goal: Maintain platelets > 50 x 103/mL
Which product should I choose?
1) Patient preference
2) Insurance coverage
Package inserts: Nplate, Promacta, Doptelet, Mulpleta. Wormann B. Transfus Med Hemother. 2013; 40: 319-25.
Ghanima W, et al. Haematologica. 2019; 104 (6). Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP.
Also, a 4th TPO-RA:
Lusutrombopag (Mulpleta®) –
Small molecule, oral tablets
Niche indication, not used much
Expected Onset
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May take longer to see effect in certain patients
• High levels of peripheral platelet destruction
• Low bone marrow myeloid stem cell reserves
TPO-RA First Effect Peak Effect
Romiplostim (Nplate®) 4-9 days 12-16 days
Eltrombopag (Promacta®) Effect seen within 7-14 days
Avatrombopag (Doptelet®) 3-5 days 10-13 days
Package inserts: Nplate, Promacta, Doptelet.
Wolters Kluwer. Lexicomp. Nplate, Promacta, Doptelet.
TPO-RAs: Labeled and Recommended Uses
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Romiplostim
• Immune thrombocytopenia (ITP) with insufficient response to corticosteroids, immunoglobulins, or splenectomy
Eltrombopag
• ITP with insufficient response to corticosteroids, immunoglobulins, or splenectomy
• Severe aplastic anemia with insufficient response to immunosuppression
• Hepatitis C-related thrombocytopenia to allow for interferon use (antiquated indication)
Avatrombopag
• ITP with insufficient response to previous treatment
• Pre-operative platelet management in chronic liver disease
Package inserts: Nplate, Promacta, Doptelet, Mulpleta. Wormann B. Transfus Med Hemother. 2013; 40: 319-25.
Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP.
Lusutrombopag (Mulpleta®)
Only for use in liver disease
with upcoming procedure
Inappropriate Uses of TPO-RAs
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• Chemotherapy-induced thrombocytopenia – No FDA approved treatments (yet!)
• Avatrombopag – FDA granted orphan drug designation for chemotherapy-induced
thrombocytopenia
• Phase 3 trial (NCT03451078) ongoing
• Romiplostim – Phase 2 placebo-controlled trial found effective in correcting
chemotherapy-induced thrombocytopenia (93% vs 12.5%)
• Not for correcting thrombocytopenia related to MDS or other malignancies
• Concern that can increase blast counts AML!
• Only initiate if platelets <50 x 103/mL and clinical condition increases bleed risk
• Not necessarily a platelet-transfusion replacement modality
.Package inserts: Nplate, Promacta, Doptelet. Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP.
Duffy S. 2020 Jan 13. MPR: Drugs in the Pipeline. Soff GA, et al. JCO. 2019; 37: 2892-98.
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Adverse Effects of TPO-RAs
• Increasing platelet counts may have increased thrombogenic potential
• Chronic liver disease: portal vein thrombosis
Thrombosis
• Related to increased reticulin deposition
• Appears to reverse with cessation of treatment
Bone marrow fibrosis
• Headache, nausea/vomiting, elevations in liver transaminases
• Avatrombopag: Claims lower LFT abnormalities than eltrombopag
General other effects
Package inserts: Nplate, Promacta, Doptelet.
Neunert C, et al. Blood Advances. ASH 2019 Guidelines for ITP. 50
Patient Case: Check for Understanding
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 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 to avoid surgery.
Which would be the most appropriate treatment to initiate? How would you monitor for efficacy?
A) Romiplostim (Nplate®) 1 mcg/kg subcutaneously weekly; recheck platelets in 2 weeks
B) Eltrombopag (Promacta®) 50 mg by mouth daily; recheck platelets in 2 weeks
C) Romiplostim (Nplate®) 1 mcg/kg subcutaneously weekly; recheck hemoglobin in 2 weeks
D) Eltrombopag (Promacta®) 50 mg by mouth daily; recheck hemoglobin in 2 weeks
Check for Understanding
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Which of the following is the brand name for eltrombopag?
A) Nplate®
B) Promacta®
C) Doptelet®
D) Granix®
Recap: Putting it all together
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• In many cases, hematopoietic growth factors can be life-saving treatments
• However, it is important to recognize when the use of growth factors is appropriate per guideline recommendations and FDA labeled indications
• Use of growth factors for inappropriate uses can be harmful and may
cloud the clinical picture
• 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 medication costs competitive
Filgrastim Erythropoietin Thrombopoietin
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Questions?Thank you for listening!
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References
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