Although a survival advantage was found with 14-day cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP-14) compared with 21-day cycles in older patients with aggressive NHL, no such benefit was demonstrated in a trial enrolling a lower-risk group of younger patients with aggressive NHL.
isolation and characterization of thrombopoietin in 1994 eventually led to the development
Haematopoitic growth factors dr. varun
HAEMATOPOEITIC GROWTH FACTORS DR. VARUN GOEL MEDICAL ONCOLOGIST RAJIV GANDHI CANCER INSTITUTE, DELHI
some of the important cytokines that determine which type of blood cell will be created.
INTRODUCTIONhematopoietic 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.
• 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.
• 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.
• 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
• 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.
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
• 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.
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
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
DOSESEpoetin 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
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.
• 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.
• 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
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.
• 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.
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.
• 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
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
• 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.
• 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.
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.
• 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.
• 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.
Goal of G-CSF• Overall survival• Response rate• Treatment related mortality• Antibiotics course and hospital days
Clinical Situations• Primary prophylaxis• Secondary prophylaxis• Therapy of patient with neutropenia• CSF to increase chemotherapy dose density and intensity• In older patients• Other situations
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
• 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
• When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized.
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.
• 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.
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.
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.
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.
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
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
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.
• 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
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
• 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.
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
• 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
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/mcLSerious allergic-type reactions splenic rupture in persons receiving recombinant CSF3 for peripheral blood stem cell mobilization (including healthy donors), adult respiratory distress syndrome
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.
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.
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)
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
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.
• Thrombocytopenia- important clinical problem in hematology/oncolgy• Platelet transfusion - remains the primary therapeutic modality
Thrombopoietin Agents• Recombinant human thrombopoietin (rhTPO) • glycosylated protein • i/v• pegylated human recombinant megakaryocyte growth and development factor (PEG-rHuMGDF) • nonglycosylated protein • s/c
• 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.
• 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.
Second-generation thrombopoietin mimetics1) 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
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
• 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.