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Hematological toxicities of anti-cancer agentsManagement strategies

Presenter: Dr Pranav SoporyDepartment of Pharmacology

All India Institute of Medical SciencesNew Delhi

Mob: 9999-491-690email: pranav.sopory@gmail.com

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Contents

PART I

Epidemiology of cancer

Classification of anti-cancer drugs

PART II

Chemotherapy induced neutropenia

Chemotherapy induced thrombocytopenia

Chemotherapy induced anemia

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Epidemiology of cancer in India (2016)

Prevalence of Cancer 2.5 millionIncidence 700,000/year

Cancer related deaths 556,000/year

Cancerindia.gov

Top 5 malignancies in India (2016)

Men WomenOral cavity (12%) Breast (27%)

Lung CervixStomach Colorectum

Colorectum OvaryPharynx Oral Cavity

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Anti-cancer agents

Goodman & Gilman's The Pharmacological Basis of Therapeutics

1. CYTOTOXIC DRUGSClass Examples

Alkylating agents Mechlormethamine, Mitomycin, Melphalan, Cyclophosphomide, Ifosphomide, Procarbazine, Nitrosourea, Busulfan

Platinum compounds Cisplatin, Carboplatin, Oxaliplatin

Anti-metabolites (S) DHFR#: Methotrexate, Pemetrexate.Purine Analogues: 6-MP, 6-TG, Cladaribine, Fludaribine.

Pyrimidine Analogue: 5-FU, Capecitabine, Gemcitabine, Cytarabine.Microtubule damaging agent (M) Formation#: Vincristine, Vinblastine

Breakdown#: Paclitaxel, DocetaxelTopoisomerase-1 inhibitors Topotecan, Irenotecan

Topoisomerase-2 inhibitors Etoposide, Doxorubicin, Daunorubicin

Antibiotics Bleomycin, L-Asparginase,.

Miscellaneous Arsenic Trioxide, Thalidomide

2. TARGETED DRUGSClass Examples

Tyrosine Kinase inhibitors Imatinib, Dasatinib, Nilotinib.EGF receptor inhibitors Gefitinib, Erlotinib.Angiogenesis Inhibitors BevacizumabProteosome inhibitors BortezomibMonoclonal antibody Rituximab, Trastuzumab

3. HORMONAL DRUGSClass ExampleSERM Tamoxifen

SERD Fulvestrant

Aromatase inhibitors Letrozole, Anastrozole

Antiandrogen Flutamide

5- reductase inhibitors Finastride

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Myelosupressive chemotherapy

Smith RE. Trends in recommendations for myelosuppressive chemotherapy for the treatment of solid tumors. J Natl Compr Canc Netw. 2006 Aug

Drug Disease setting Neutropenia (%)

Thrombocyto-penia (%)

Anemia (%)

Pemetrexed NSCLC 5 2 8

Paclitaxel Ca Breast 28 3 4

Vinorelbine NSCLC 58 0 0

Docetaxel Ca Breast 88 0 8

Gemcitabine NSCLC 57 50 25

Irinotecan Colorectal Ca 31 2 5

Topotecan SCLC 70 29 42

Epirubicin Ca Breast 67 5 6

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Bone Marrow sparing agents

1. Cytotoxic agents:

• Vincristine, Bleomycin, L-Asparginase

2. Hormonal Agents

Goodman & Gilman's The Pharmacological Basis of Therapeutics

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Neutropenia associated with chemotherapy

NCCN guidelines 2015 8

Neutropenia associated with chemotherapy• Causes of neutropenia other than anti-cancer agents:

1. Cancers causing neutropenia

• Solid tumors with bone marrow involvement

• Chronic Lymphocytic Leukemia, Hairy cell leukemia

2. Other drugs causing neutropenia

• Penicillin (beta-lactams)

• Anti-psychotics

• Risk Factors for developing neutropenia

1. Age>65 years

2. Concurrent Chemo-radiotherapy

3. Previous cycle associated with neutropenia

4. Poor liver and renal function tests

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Neutropenia associated with chemotherapy

TLC

DLC

path.upmc.edu/cases/case679.html

ANC

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Calculating ANC: Absolute Neutrophil Count

• ANC is a measure total neutrophils

• i.e. mature neutrophils (PMNs) and immature neutrophils(bands).

Robbins Pathologic Basis of Disease

ANC Grade Nominal Grading

4,000-1,500/uL IMild1,499-1,000/uL II

999-500/uL III Moderate

<500/uL IV Severe

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Febrile Neutropenia

Single oral temperature of >38.3 C (101.4 F) OR

Oral temperature of >38 C (101 F) for over 1 hour

AND

ANC < 500/uL OR

ANC < 1000/uL predicted to decrease in the next 48 hours

Indian Society of Medical and Pediatric Oncology. Indian Guidelines— Febrile Neutropenia. 2013

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Consequence of febrile neutropenia

• Classified as a “Medical Emergency”

i.e. requires IPD admission and prompt empirical antibiotic administration

• Risk of Opportunistic infection:

1. M/C: Gram –ve rods: E. Coli, K. Pnuemonie, P. Aueroginosa

2. Gram +ve cocci: Staphylococcus, Streptococcus, Enterococcus

3. Fungal infection: Candida, Aspergillus, Pnuemocystis Carinii

• Mortality associated with Febrile Neutropenia

1. Solid tumors: 5%

2. Hematological tumors: 11%Indian Society of Medical and Pediatric Oncology. Indian Guidelines— Febrile Neutropenia. 2002

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Management: Granulocyte-Colony Stimulating Factors (G-CSF)

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G-CSF analogue: Filgrastim

• 175 amino-acid long protein

• Produced by recombinant DNA technology (E.Coli)

• Difference from human G-CSF:

• Addition of methionine at N-terminal

• Necessary for expression in E.Coli

• Scientifically: r-met-Hu-GCSF

• FDA approval: 1996

• India: 2001

accessdata.fda.gov

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G-CSF analogue: Filgrastim

• Pharmacokinetics:

• Follows first order kinetics

• t ½ : 3.5 hours

• Dose: 5 mcg/kg B.W. (300mcg in a 60 kg man)

• Administration: S/C injections

• Supply: Prefilled syringe

http://accessdata.fda.gov

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G-CSF analogue: Filgrastim

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Filgrastim Vs. Placebo (1991)

Crawford J, Ozer et.al Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991 Jul

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Filgrastim Vs. Placebo (1991)

Crawford J, Ozer et.al Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991 Jul

• Randomized, double-blinded, placebo-controlled, phase 3 trial

• Small Cell Lung Cancer

• Chemotherapy: DEC protocol (3 day regimen)

• Total: 5 cycles of chemotherapy

• Day +4 post chemotherapy: s/c Filgrastim (n=99) compared with placebo(n=111)

• Primary endpoint:

• Incidence of febrile neutropenia (after first cycle of chemotherapy)

• Secondary endpoints:

• Incidence of severe neutropenia (ANC <500/uL)

• Median ANC nadir

• Median duration of severe neutropenia and febrile neutropenia (in days)

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Filgrastim Vs. Placebo

Crawford J, Ozer et.al Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med. 1991 Jul

Indicators Placebo G-CSFPrimary endpoint

Incidence of febrile neutropenia 57% 28%Secondary endpoints

Incidence of severe neutropenia 98% 84% Median neutrophil nadir 36/uL 68/uL

Median duration of severe neutropenia

6 days 3 days

Median duration of febrile neutropenia

5 days 4 days

NCCN 2015 20

Disadvantages of Filgrastim

1. Allergic reactions: skin rashes, respiratory and CVS symptoms

• Incidence: 1/4000 patients

• Occurs more frequently in IV dosing (so now given s.c.)

2. Hemoptysis

• Idiopathic alveolar hemorrhage

3. Musculoskeletal pain (M/C)

• Since the drug acts in the bone marrow

NCCN 2015 21

Contraindications of Filgrastim

1. Hypersensitivity to E. Coli proteins

• Derived from E. Coli

2. Sickle Cell Anemia

• Causes sickle cell crisis

1. Splenic rupture

2. Sweets Syndrome (Acute febrile neutrophillic dermatosis)

3. Osteoporosis in pediatric oncology patients

Phase IV trials: Serious adverse effects

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Uses of Filgrastim (2017)

1. Cancer patients receiving myelosupressive chemotherapy

2. AML patients receiving initiation and consolidation chemotherapy

3. Severe chronic neutropenia

• Idiopathic

• Congenital (Kostman Syndrome)

4. Peripheral Stem Cell collection and therapy

accessdata.fda.gov

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Administration of Filgrastim

* sensitivity of chemotherapy to rapidly acting myeloid cells decreases

accessdata.fda.gov

Indication Dose Initiation Discontinuation

Cancer patients 5 mcg/kg B.W. 24 hours after last dose of

chemotherapy*

1. Till ANC >10,000/uL

2. For 2 weeks

Febrile Neutropenia 5 mcg/kg B.W. Immediately Till ANC >1,000/uL for 3 consecutive days showing an increasing

trend

Stem Cell collection 10 mcg/kg B.W. Stem cell mobilization 21 X 10 6 Stem cells/kg B.W.

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PEGylation

• PEGylation refers to the attachment of polyethylene glycol polymer chains to a

drug.

• The covalent attachment of PEG to a drug can

1. "mask" the agent from the host's immune system

(reduced immunogenicity and antigenicity),

2. increase the hydrodynamic size (size in solution) of the agent which prolongs its

circulatory time by reducing renal clearance.

3. Enhance its protection from proteolytic degradation

Hamidi M, Azadi A, Rafiei P. Pharmacokinetic consequences of pegylation. Drug Deliv. 2006 Nov-Dec

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Peg-Filgrastim

• Chemical nature: 20kDA PEG molecule attached to Filgrastim

• Pharmacokinetics:

• Follows first order kinetics

• t ½ : 15 hours

• Dose: 100 mcg/kg B.W. (6mg in a 60 kg man)

• Administration: S/C injections

• Supply: Prefilled syringe

• FDA approval: 2002

• India: 2011

accessdata.fda.gov

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Peg-Filgrastim

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Peg-Filgrastim Vs. Filgrastim (2003)

Green MD, Koelbl H, et. al. International Pegfilgrastim 749 Study Group.. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003 Jan

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Peg-Filgrastim Vs. Filgrastim (2003)

• Randomized, double-blinded, placebo-controlled, phase 3 trial

• Adenocarcinoma Breast (n=157)

• Chemotherapy: Doxorubicin (60mg/m2) & Docetaxel (75mg/m2) – Single Day Regimen followed 3 weekly

• Total: 4 cycles of chemotherapy

• Doses:

• Filgrastim: 300 mcg s.c. from Day +2 given daily till ANC >10,000/uL or a maximum of 14 days (standard protocol)

• Peg-Filgrastim: 6 mg s.c. single dose on Day +2

• Primary endpoint:

• Duration of Grade 4 Neutropenia

• Secondary endpoints:

• Incidence of Febrile neutropenia

• Time to recovery (ANC > 20,000/ uL)

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Peg-Filgrastim Vs. Filgrastim

Green MD, Koelbl H, et. al. International Pegfilgrastim 749 Study Group.. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003 Jan

Indicator Peg-Filgrastim (n=80) Filgrastim (n=77)Primary endpoint

Duration of Grade 4 Neutropenia (days)Cycle 1 1.8 1.6Cycle 2 1.1 0.9Cycle 3 1.1 0.9Cycle 4 1.0 1.0

Secondary endpointsIncidence of Febrile neutropenia

(over 4 cycles) 10 patients (13%) 15 patients (20%)

Time to recovery (ANC > 20,000/uL) 9 days 9 days

Not clinically significant

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Advantages over Filgrastim• Single dose• Better compliance• Easier for out of city patients

• Cost: Rs. 33,000/- per vial vs. Rs. 2,300/- for Filgrastim

accessdata.fda.gov

Disadvantage over Filgrastim

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Management of febrile neutropenia

• IPD admission

• Blood withdrawal for CBC+Diff. and Culture

• CT-Scan/Bronchial wash (if respiratory symptoms observed)

• Stool and Urine culture (if infection suspected)

• Start empirical antibiotics

1. Inj. Piperacillin+Tazobactum (4.5gm q6h)

2. Inj. Amikacin (1gm q24h )

Indian Society of Medical and Pediatric Oncology. Indian Guidelines— Febrile Neutropenia. 2013

Gram +ve

Gram -ve

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Sargramostim : GM-CSF analogue

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Sargramostim

• 127 amino-acid long protein

• Produced by recombinant DNA technology (yeast: S. cerevisiae)

• Molgramostim (E.Coli derived): Withdrawn due to reports of fluid retention,

dyspepsia, hypotension and hypoxia.

• Difference from human GM-CSF:

• substitution of leucine at position 23

• Scientifically: r-Hu-GMCSF

• FDA approval: 1991

accessdata.fda.gov

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Sargramostim

• Follows first order kinetics

• t ½ : 2 hours

• Dose: 250 mcg/m2 BSA, IV, 24 hours after chemotherapy until

ANC >1,500/uL for 3 consecutive days

accessdata.fda.gov

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Sargramostim Vs. Filgrastim

Milkovich G, Moleski RJ, et.al. Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy. 2000

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Sargramostim Vs. Filgrastim (2000)

Milkovich G, Moleski RJ, et.al. Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy. 2000

• Retrospective review of 10 US oncology centers

• 490 patients treated for lymphoma, lung, breast, ovarian malignancies

• Measurement:

• The frequency and severity of adverse events

• Conclusion:

• More frequent adverse effects noted with Sargramostim

• Esp. Fever with unproven bacteremia (42% vs 14%)

• Cost: same as Filgrastim

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Thrombocytopenia associated with chemotherapy

NCCN 38

Thrombocytopenia related guidelines

Platelet count Grade Guideline

<150,000 I Safe to give chemotherapy if counts are stable

<100,000 II Chemotherapy allowed only in cases of bone marrow involvement and hematological

malignancies.<50,000 III

Chemotherapy not allowed<25,000 IV

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Clinical approach to thrombocytopenia in cancer

1. Is the underlying disease the cause of thrombocytopenia

• Bone marrow aspiration+biopsy (hypercellular marrow)

2. Is there associated ITP?

• 1% of patients with Hodgkins disease

• 10% of patients with Chronic Lymphocytic Leukemia

• Treat as per ITP protocol

3. Recent history of febrile neutropenia?

• Suspect DIC

4. When was the last dose of chemotherapy?

• Platelets have a life-span of 8-10 days

• Drop starts at Day +7 and nadir reached at Day +14. Recovery by Day 28

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Clinical approach to thrombocytopenia in cancer

NCCN 41

Role of thrombopoietin

• Growth factor for platelet production

• Produced by the liver

• No physiological stimulus identified

• TPO independent growth factors: IL-3, IL-6 and IL-11

• TPO Receptors present in bone marrow

• 2 management strategies:

1. Recombinant TPO analogue

2. TRO Receptor agonist

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Recombinant human thrombopoetin (rH-TPO)

• 163 amino acid protein

• Developed in Chinese hamster ovary

• Phase 3 clinical trials in between 1995-2000

• Neutralizing IgG antibody production in patients

• Cross reactivity with endogenous TPO

• Further development stopped.

• Current status: ITP patients post splenectomy

accessdata.fda.gov

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TPO Receptor agonist: Eltrombopag

• 14 amino acid peptide

• Acts on the same receptor as TPO but in the transmembrane region

• i.e. receptors embedded inside the membranes of cells. Activation via cell signaling

• t1/2: 2-6 hours

• FDA Approval: 2010

• Adverse effect: Increased risk of DVT

• Current use:

1. ITP

2. Hep-C with thrombocytopenia

accessdata.fda.gov

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TPO Receptor agonist: Eltrombopag

Winer, Eric S et al. “Eltrombopag with Gemcitabine-Based Chemotherapy in Patients with Advanced Solid Tumors: A Randomized Phase I Study.” Cancer Medicine (2015)

Indicators Eltrombopag (n=12) Placebo (n=14)Nadir Platelet count (Gemcitabine alone)

143,000/uL 103,000/uL

Nadir Platelet count (Gemcitabine + Carboplatin/Cisplatin)

115,000/uL 53,000/uL

Dose: 50 mg p.o. X 10 days (D-5 to D-1 and D+2 to D+6)

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Eltrombopag: 2015 review

• Many studies published are challenging.

• Most cytotoxic regimens do not produce high rates of thrombocytopenia

• Efficacy of 3-4 days of platelet transfusions similar to 10 day regimen of

Eltrombopag

Kuter DJ. Managing thrombocytopenia associated with cancer chemotherapy. Oncology (Williston Park). 2015 Apr

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Anemia associated with chemotherapy

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Anemia in cancer patients

• Prevalence: 30 to 90%

• Causes of cancer other than Anti-cancer therapy

1. Bone marrow metastasis

2. Renal metastasis: ↓ EPO

3. Anemia of chronic disease (Hepcidin)

4. Decreased appetite (IDA)

5. Bleeding: Gynaecological malignancy & colorectal cancer

Rodgers GM 3rd, Becker PS et. al. Cancer- and chemotherapy-induced anemia. J Natl Compr Canc Netw. 2012 May;10

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Management: EPO analogue

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EPO analogue: Darbepoetin

• 165-amino acid protein.

• Produced by recombinant DNA technology  (Chinese hamster ovary

cells).

• Different from endogenous EPO: contains two extra oligosaccharide

chains.

• FDA approval: 2001

• India (2010)

Rodgers GM 3rd, Becker PS et. al. Cancer- and chemotherapy-induced anemia. J Natl Compr Canc Netw. 2012 May;10

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Darbepoetin: Trials in cancer patients

• Decreased overall survival in breast, NSCLC, lymphoid, and cervical

cancers 

1. Serious adverse events

• Myocardial infarction

• Thromboembolic events (Pulmonary embolism and stroke)

• Seizure

2. Tumor progression and recurrence

• Probable growth factor activity of darbepoetin

Rodgers GM 3rd, Becker PS et. al. Cancer- and chemotherapy-induced anemia. J Natl Compr Canc Netw. 2012 May;10

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Darbepoetin: Current Guidelines

• In CKD patients with anemia

• 0.45 mcg/kg B.W. weekly s.c. till Hb> 11g/dL

• In Cancer patients receiving chemotherapy

• Black Box Warning

accessdata.fda.gov

Managing Anemia in chemotherapy

• Management of choice: Blood transfusion

• AIM: maintain Hb > 10g/dL

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Conclusion

Management Aim

Neutropenia G-CSF, Peg G-CSF Maintain ANC > 10,000/uL

Thrombocytopenia Platelet transfusion Maintain platelet count> 100,000

Anemia Blood transfusion Maintain Hb > 10g/dL

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Thank You