This document provides a summary of hematological toxicities caused by anti-cancer agents and their management strategies. It discusses chemotherapy-induced neutropenia, thrombocytopenia, and anemia. It describes common chemotherapy drugs that cause these side effects and their frequencies. Management strategies for neutropenia include use of granulocyte colony-stimulating factors like filgrastim and pegfilgrastim. Febrile neutropenia is discussed as a medical emergency requiring prompt treatment. Thrombocytopenia caused by chemotherapy is also summarized.

1. Hematological toxicities of anti-cancer agents
Management strategies
Presenter: Dr Pranav Sopory
Department of Pharmacology
All India Institute of Medical Sciences
New Delhi
Mob: 9999-491-690
email: pranav.sopory@gmail.com
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2. Contents
PART I
Epidemiology of cancer
Classification of anti-cancer drugs
PART II
Chemotherapy induced neutropenia
Chemotherapy induced thrombocytopenia
Chemotherapy induced anemia
2

3. Epidemiology of cancer in India (2016)
Prevalence of Cancer 2.5 million
Incidence 700,000/year
Cancer related deaths 556,000/year
3Cancerindia.gov
Top 5 malignancies in India (2016)
Men Women
Oral cavity (12%) Breast (27%)
Lung Cervix
Stomach Colorectum
Colorectum Ovary
Pharynx Oral Cavity

4. Anti-cancer agents
Goodman & Gilman's The Pharmacological Basis of Therapeutics
1. CYTOTOXIC DRUGS
Class 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, Docetaxel
Topoisomerase-1 inhibitors Topotecan, Irenotecan
Topoisomerase-2 inhibitors Etoposide, Doxorubicin, Daunorubicin
Antibiotics Bleomycin, L-Asparginase,.
Miscellaneous Arsenic Trioxide, Thalidomide
2. TARGETED DRUGS
Class Examples
Tyrosine Kinase inhibitors Imatinib, Dasatinib, Nilotinib.
EGF receptor inhibitors Gefitinib, Erlotinib.
Angiogenesis Inhibitors Bevacizumab
Proteosome inhibitors Bortezomib
Monoclonal antibody Rituximab, Trastuzumab
3. HORMONAL DRUGS
Class Example
SERM Tamoxifen
SERD Fulvestrant
Aromatase inhibitors Letrozole, Anastrozole
Antiandrogen Flutamide
5- reductase inhibitors Finastride
4

5. Myelosupressive chemotherapy
Smith RE. Trends in recommendations for myelosuppressive chemotherapy for the treatment of solid tumors. J Natl Compr Canc Netw. 2006 Aug 5
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

6. Bone Marrow sparing agents
1. Cytotoxic agents:
• Vincristine, Bleomycin, L-Asparginase
2. Hormonal Agents
Goodman & Gilman's The Pharmacological Basis of Therapeutics
6

7. Neutropenia associated with
chemotherapy
7

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
NCCN guidelines 2015 8

9. Neutropenia associated with chemotherapy
TLC
DLC
path.upmc.edu/cases/case679.html 9
ANC

10. 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 10
ANC Grade Nominal Grading
4,000-1,500/uL I
Mild
1,499-1,000/uL II
999-500/uL III Moderate
<500/uL IV Severe

11. 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
11

12. 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
12

13. Management: Granulocyte-Colony Stimulating Factors (G-CSF)
13

14. 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 14

15. 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 15

16. G-CSF analogue: Filgrastim
16

17. 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 17

18. 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)
18

19. 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-CSF
Primary 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
19

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 20

21. Contraindications of Filgrastim
1. Hypersensitivity to E. Coli proteins
• Derived from E. Coli
2. Sickle Cell Anemia
• Causes sickle cell crisis
NCCN 2015
1. Splenic rupture
2. Sweets Syndrome (Acute febrile neutrophillic dermatosis)
3. Osteoporosis in pediatric oncology patients
Phase IV trials: Serious adverse effects
21

22. 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 22

23. 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.
23

24. 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 24

25. 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 25

26. Peg-Filgrastim
26

27. 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
27

28. 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)
28

29. 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 1.6
Cycle 2 1.1 0.9
Cycle 3 1.1 0.9
Cycle 4 1.0 1.0
Secondary endpoints
Incidence 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
29

30. 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
30

31. 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
31

32. Sargramostim : GM-CSF analogue
32

33. 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 33

34. 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 34

35. Sargramostim Vs. Filgrastim
Milkovich G, Moleski RJ, et.al. Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy. 200035

36. 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
36

37. Thrombocytopenia associated
with chemotherapy
37

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
NCCN 38

39. 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 39

40. Clinical approach to thrombocytopenia in cancer
40

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
NCCN 41

42. 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 42

43. 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
• FDAApproval: 2010
• Adverse effect: Increased risk of DVT
• Current use:
1. ITP
2. Hep-C with thrombocytopenia
accessdata.fda.gov 43

44. 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)
44

45. 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
45

46. Anemia associated with
chemotherapy
46

47. 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 47

48. Management: EPO analogue
48

49. 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 49

50. 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 50

51. 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 51
Managing Anemia in chemotherapy
• Management of choice: Blood transfusion
• AIM: maintain Hb > 10g/dL

52. Conclusion
52
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

53. Thank You
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