1. HAEMATOPOEITIC GROWTH
FACTORS
DR. VARUN GOEL
MEDICAL ONCOLOGIST
RAJIV GANDHI CANCER INSTITUTE,
DELHI

2. some of the important cytokines that determine which type of blood cell will be created.

3. INTRODUCTION
hematopoietic growth factors (HGFs)
• cytokines that govern hematopoiesis by
regulating
– proliferation,
– differentiation,
– maturation,
– function, and
– viability of the cellular components of blood
and their progenitor cells.
• production of HGFs is primarily by the cells of
the bone marrow except erythropoietin.

4. • Hematological toxicity is the most common
side effect of chemotherapy.
• Several hematopoietic growth factors are
currently available for clinical use
– And synthesized mainly by DNA recombinant
technology.

5. • four major HGFs currently used clinically:
• EPO,
• granulocyte colony-stimulating factor (G-CSF or CSF3),
• granulocyte-macrophage colony-stimulating factor
(GM-CSF), and
• interleukin-11 (IL-11).
• Thrombopoietin is also included, although the
currently available clinical agents are
thrombopoietin mimetics due to antigenicity of
the native cytokine.

6. • Recombinant human (rHu) HGFs are
commonly used for a variety of purposes
– attenuation of chemotherapy-induced
myelosuppression,
– treatment of hematopoietic malignancies, and
– management of decreased HGF production in
malignancy.
• Six rHu HGFs are approved by the U.S. Food
and Drug Administration (FDA) for use in the
United States

7. Hematopoietic
Generic Name Brand Names
Growth Factor
EPO Epoetin alfa Epogen, Procrit
Darbepoetin Aranesp
CSF3 Filgrastim Neupogen
Pegfilgrastim Neulasta
GM-CSF Sargramostim Leukine
IL-11 Oprelvekin Neumega

8. • The effects of HGFs are mediated through
receptors (JAK-STAT pathway) located on both
hematopoietic and nonhematopoietic cells.
– physiologic effects of HGFs are numerous and not
confined to hematopoiesis.

9. ERYTHROPOIETIN

10. ERYTHROPOIETIN
• primary regulator of red blood cell production
• primarily produced in the kidney
– interstitial fibroblasts and proximal tubular cells
• Normal serum EPO levels ~ 4 to 30 U/L
• Endogenous EPO levels are depressed in
cancer patients
– chronic anemia

11. • A recombinant form of human EPO first
became available in 1989
• currently three different forms are
commercially available.
– epoetin alfa
– identical amino acid sequence to endogenous human EPO
– T1/2 ~ 3 to 10 hours
– IV
– darbepoetin alfa
– addition of two N-glycosylation sites to produce
– longer half-life ~ threefold greater
– epoetin beta
– identical amino acid sequence to endogenous human EPO but
with a different glycosylation pattern than epoetin alfa.

12. Clinical Use of Erythropoietin in
Cancer Therapy
• Anemia secondary to malignancy or
chemotherapy - common and important
clinical problem with a negative impact on
quality of life (QOL)
• Until the 1990s, transfusion was the only
treatment option for anemia.
• 1993 - Epogen approved: anemia
associated with cancer chemotherapy

13. Benefits of ESAs
• Use of ESAs reduced proportion of pts receiving
RBC transfusions & their concomitant risks
– by an average of 62%
• Effect of rHu EPOs administration starts after 2
weeks of continuous dosing and may take up to
8 weeks.
• The updated ASCO/ASH guidelines recommend
epoetin therapy for chemotherapy-induced
anemia if the Hb has declined to 10 g/dL or less

14. DOSES
Epoetin alfa
• a starting dose of 150 U/kg three times weekly
for a minimum of 4 weeks
• After 4 weeks, a dose increase to 300 U/kg for
an additional 8 weeks in nonresponders
• (less than 1 g/dL improvement by week 4)
• weekly dosing (40,000 U/wk) is commonly
applied in clinical practice

15. Darbepoetin
• Start at 2.25 mcg/kg SC weekly or
500 mcg SC Q3W
• Escalate dose to 4.5 mcg/kg if Hb rises <1g/dl
after 6 wk.

16. • The optimal duration of therapy in patients
who respond to epoetin therapy is not defined.
• withhold the dose of ESA when Hb reaches 12 g/dL
• In nonresponders (patients achieving a less
than 1 to 2 g/dL rise in Hb), dosing beyond 6 to
8 weeks does not appear to be beneficial.

17. • BUT Improved QOL, fatigue, and other
symptoms associated with anemia NOT
established in properly conducted,
randomized, double-blind, placebo-controlled
trials.
Straus DJ, et al. Cancer 2006;107(8):1909.
• Improved survival or improved tumor control
NOT established

18. Risks of ESAs
• Edema - minimal
• Increased thrombovascular events (TVEs)
– Increased Morbidity, Potential Increased Mortality
Bennett CL, et al. JAMA2008;299(8):914.
• Decreased Survival
• Increased Tumor Promotion
– Decreased Locoregional Control
– Decreased Progression-Free Survival?

19. Concern raised in 1993
• At the time of approval for treatment of
anemia associated with cancer chemotherapy,
the FDA noted that Epoetin Alfa (Procrit)
could potentially serve as a growth factor for
malignant tumors.

20. • Because of this concern, study (N93-004), was
designed to rule out a detrimental effect of
Procrit on the response rate in patients with
limited or extensive stage small cell lung
cancer.
• Results were inconclusive on the issue of
tumor promotion
Wright JR, et al. J Clin Oncol 2007;25(9):1027.

21. 2 other trials added to concerns
• BEST (Stg IV Breast Ca): ↓ survival for pts on ESA arm
• ENHANCE (Head/Neck Ca): ↓ survival &
↓ locoregional control for pts on ESA arm
• Leyland-Jones B, et al. J Clinl Oncol2005;23(25):5960.
• Henke M, et al. Lancet 2003;362(9392):1255.
• data continue to accumulate regarding the increased risks
of mortality and of possible tumor promotion from the
use of ESAs.
– Esp. when ESA treatment strategies were designed to achieve
and maintain hemoglobin levels above 12 g/dL.

22. • When ESAs are used, we still don’t know:
– If the risk of thrombovascular events outweigh the
benefit of not getting a transfusion
– If overall survival is decreased by use of ESAs
– If ESAs promote tumor growth

23. FDA Update 2007
• No use of ESAs when HgB > 12
• Use minimum ESA possible to increase HgB
• Clear statement that data does not exist which
shows ESAs are safe when HgB levels are
between 10 and 12.
http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf

24. MYELOID GROWTH FACTORS

25. • filgrastim(G-CSF) and sargramostim(GM-CSF)
• Among these two myeloid growth factors, there
is no firm evidence indicating the superiority of
one over another.
• Both increases ANC but side effects different.

26. • Filgrastim(G-CSF) • Sargramostim(GM-CSF)
– Neutrophil production- – Monocyte and
most specific eosinophils production
– Immunomodulatory in addition to
effect on lymphocyte, neutrophils
monocyte and – Enhances chemotaxis,
macrophages. phagocytosis, antibody
– Anti-inflammatory dependent cellular
effects cytotoxicity.

27. Granulocyte Colony-Stimulating
Factor - CSF3
• Regulates the production, maturation, and
function of the neutrophil lineage
• CSF3 ~ 20 to 100 pg/mL
• Serum concentrations vary inversely with
blood neutrophil concentrations.

28. • rHu CSF3 is currently available commercially in
four forms,
– filgrastim
– produced in Escherichia coli,
– has an amino acid sequence identical to endogenous CSF3, with
the exception of the addition of an N-terminal methionine and
absence of glycosylation.
– The half-life ~ 3.5 hours
– IV or subcutaneous (SC) dosing
– pegfilgrastim
– polyethylene glycol-conjugated version of filgrastim
– The half-life ~ 33 hours
– lenograstim
– a glycosylated recombinant CSF3 derived from a mammalian cell
system (Chinese hamster ovaries)
– nartograstim
– an N-terminal–mutated recombinant CSF3 produced in E. coli.

29. • After administration of CSF3, neutrophils
show morphologic changes consistent with
activation
• including Döhle’s inclusion bodies,
• toxic granulation, and
• increase in band forms.
• CSF3 enhances
• chemotaxis,
• phagocytosis, and
• the oxidative burst of mature neutrophils in vitro
• increases antibody-dependent cellular cytotoxicity in
vivo.

30. Goal of G-CSF
• Overall survival
• Response rate
• Treatment related mortality
• Antibiotics course and hospital days

31. Clinical Situations
• Primary prophylaxis
• Secondary prophylaxis
• Therapy of patient with neutropenia
• CSF to increase chemotherapy dose
density and intensity
• In older patients
• Other situations

32. Primary prophylaxis
• Current evidence indicates that primary
prophylaxis with a CSF results in a relative risk
reduction of FN by approximately 50% to 90%,
depending on the type of cancer and
chemotherapy regimen used.
• use of primary prophylaxis in those
chemotherapy regimens in which the risk of
FN is approximately 20% or higher

33. • Also recommended for the prevention of
febrile neutropenia(FN) in patients who have
a high risk of FN based on age, medical
history, disease characteristics and
myelotoxicity of chemotherapy regimen.
• Special circumstances: relative nonmylelo-
suppressive chemotherapy but who have
potential risk factors for febrile neutropenia or
infection because of bone marrow
compromise or comorbidity.
JCO 2006;24:3187-3205

36. • When available, alternative regimens
offering equivalent efficacy, but not
requiring CSF support, should be utilized.

37. Secondary prophylaxis
• Recommended for patients who
experienced a neutropenic complication
from a prior cycle of chemotherapy, IN
which a reduced dose may compromise
disease-free or overall survival or
treatment outcome.

38. • Re-evaluate the goal of chemotherapy. Dose
reduction or delay remains an appropriate
strategy for the palliative treatment of cancer.
• No definite conclusion can be drawn
regarding the benefits of secondary
prophylaxis on survival, quality of life, or cost.

39. Patient with neutropenia
• Afebrile neutropenia
Should NOT be routinely used for patients
with neutropenia who are afebrile.
• Febrile neutropenia
Should NOT be routinely use as
adjunctive treatment with antibiotic therapy
for patients with fever and neutropenia.

40. Febrile neutropenia
• Randomized control trial: G-CSF recipients had
a shorter period of grade 4 neutropenia (2 vs 3
days), antibiotic therapy (5 vs 6 days), and
hospital stay (5 vs 7 days). No survival benefit.
• Meta-analysis: CSF recipients had less
prolonged neutropenia, less prolonged
hospitalization, marginally less infection-related
mortality, no significant difference in overall
mortality.

41. Febrile neutropenia
• CSF is recommended in patient with high-risk
feature.
– Expected prolonged (10 days) and profound
(100/ml) neutropenia,
– age greater than 65 years,
– uncontrolled primary disease,
– pneumonia,
– hypotension and
– multi-organ dysfunction (sepsis syndrome),
– invasive fungal infection, or
– being hospitalized at the time of the development
of fever.

42. CSF to increase chemotherapy dose
density and intensity
• In a few specific settings, use of dose-
dense (but not dose-intese) regimen with
CSF support have survival benefit.
• CSF allows a modest to moderate
increase in dose-density and/or dose-
intensity of chemotherapy regimens

43. Specific settings
• Adjuvant therapy for node positive breast
cancer
– Dose-dense chemotherapy with CSF support
has better disease-free and overall survival.
• no justification exists for the use of CSFs to
increase chemotherapy dose intensity outside
a clinical trial

44. In older patients
• Prophylactic CSF use patients with diffuse
aggressive lymphoma aged 65 and older
treated with curative chemotherapy
(CHOP or more aggressive regimens)
should be given to reduce the incidence of
FN and infection.

45. • Age and risk of chemotherapy-induced
neutropenia
– Older patients have higher risk of neutropenic
infections
• Dose reduction
– Dose reduction has been associated with reduced
response rate and survival in lymphoma undergoing
curative therapy.
• Patient selection
– Insufficient evidence to support the use of
prophylactic CSFs in patients solely based on age

46. Other situations
• Stem cell transplantation
– CSF mobilize peripheral-blood progenitor cels
– In allogeneic transplantation, CSF may increase the
incidence of severe GVHD and reduce survival.
• AML
– CSF use following initial induction therapy is
reasonable, but no impact on remission rate, remission
duration, or survival
– Use of CSFs is not recommended
• In younger patients
• For priming effects
• Postconsolidation
• In relapsed disease

47. • ALL
– After initiation of induction or postremission
chemotherapy in an effort to reduce the duration
of neutropenia
– No impact on survival.
• MDS
– Routine use not recommended.

48. dosage, duration
• CSF should be given 24-74 hrs after myelotoxic
chemotherapy
• G-CSF: 5μg/kg/day
• GM-CSF: 250μg/m2/day
• Pegylated G-CSF: 6mg once

49. • Transient increase in neutrophil count is
typically observed in first 1-2 days after
initiation of CSFs.
• But treatment should continue until post nadir
ANC reaches 10,000/mm3.
• For PBPC mobilization, a dose of 10 mcg/kg/d
for filgrastim
• Pegylated G-CSF shouldn’t be use for stem cell
mobilizatin

50. Adverse effect of CSF
 Common
 Gastrointestinal: Nausea and vomiting
 mild-to-moderate bone pain.
 Splenomegaly - reported in chronic use
 transient dyspnea and pulmonary infiltrates on chest
radiography.
 leukocytosis
typically treatment is discontinued when the neutrophil
count reaches 10,000 cells/mcL
Serious
allergic-type reactions
splenic rupture in persons receiving recombinant CSF3
for peripheral blood stem cell mobilization (including
healthy donors),
adult respiratory distress syndrome

51. Side effects of GM-CSF
• Flu like symptoms
• In vitro evidence that it may stimulate HIV
replication but clinical studies not
coroborating
• Syncope – esp. with liquid forms
withdrawn
This not seen with lyophilized formulation.

52. Side effects of G-CSF
• Better tolerated than GM-CSF
• Rarely cause sweet syndrome
• Antibodies to grwth factors have been
detected with some preparations, but not
neutralizing.

53. Precautions of CSF
• Avoid the simultaneous use of chemotherapy and
radiation therapy with filgrastim; DO NOT
administer within 24 hours before or after
cytotoxic chemotherapy
– Potential sensitivity of rapidly dividing myeloid cells to
cytotoxic chemotherapy.
• Possible growth stimulation of tumors
• Leukocytosis (monitoring twice weekly
recommended)

54. Precautions of CSF
• Risk of development of myelodysplastic
syndrome or acute myeloid leukemia when used
in patients with aplastic anemia treated with long
term CSF.
• Sickle cell disease, severe sickle cell crisis
(some resulting in death)
• Splenic rupture, some fatal

55. Impact on quality of life and health care
costs
• No difference in global quality of life
between the study arms.
• In a cost-benefit study in Netherland, G-
CSF as primary prophylaxis has higher
total hospital cost.
• When available, alternative regimens
offering equivalent efficacy, but not
requiring CSF support, should be utilized.

56. PLATELETS GROWTH FACTORS

57. • Thrombocytopenia- important clinical
problem in hematology/oncolgy
• Platelet transfusion - remains the primary
therapeutic modality

58. Thrombopoietin Agents
• Recombinant human thrombopoietin (rhTPO)
• glycosylated protein
• i/v
• pegylated human recombinant megakaryocyte
growth and development factor (PEG-rHuMGDF)
• nonglycosylated protein
• s/c

59. • Patients with solid tumors undergoing
chemotherapy, when treated with either PEG-
rHuMGDF or rhTPO, demonstrated
– shorter duration of thrombocytopenia and
– required fewer platelet transfusions.
• The peak platelet count after administration
of both agents occurred on day 12 to 18 in the
various series.

60. • Initial trials of both agents - no serious
adverse events.
• But later, a randomized study in which in 13
patients developed thrombocytopenia after
use of PEG-rHuMGDF
• An immunoglobulin-G (IgG) antibody to PEG-rHuMGDF
that cross reacted with the thrombopoietin receptor
was detected.
• So further development of PEG-rHuMGDF and
rhTPO was halted.

61. Second-generation thrombopoietin mimetics
1) Romiplostim- subcutaneous
• human TPO receptor-binding peptide joined by disulfide
bonds to an immunoglobulin Fc fragment
• no homology to endogenous thrombopoietin
• No cross-reactivity
• FDA approved for patients with ITP.
2) Eltrombopag
• oral TPO agonist
• FDA approved for patients with ITP.
• Both are currently being studied in patients
with chemotherapy-induced
thrombocytopenia.
3) AKR-501 - another oral TPO receptor agonist

62. Endogenous IL-11 - Oprelvekin
• Endogenous IL-11 stimulates proliferation of
megakaryocyte progenitor cells and induces
megakaryocyte maturation, leading to
increased platelet production
• Oprelvekin - a rHu IL-11
• produced in E. Coli
• Platelet counts begin to rise 5 to 9 days after
the initial dose

63. • Side effects –
– allergic reactions and anaphylaxis – may be
serious.
– Edema in 2/3 patients,
– Dyspnea in 50% patients
• At present, platelet transfusion remains the
primary therapeutic modality for treatment
of thrombocytopenia in the oncology setting.

64. Thank u….