{"id":545,"date":"2020-02-16T21:52:29","date_gmt":"2020-02-16T16:22:29","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=545"},"modified":"2020-02-16T21:52:29","modified_gmt":"2020-02-16T16:22:29","slug":"drugs-acting-on-hematopoietic-growth-factors","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/drugs-acting-on-hematopoietic-growth-factors\/","title":{"rendered":"Drugs Acting on Hematopoietic Growth Factors"},"content":{"rendered":"\n<p><strong>Hematopoietic Growth Factors<\/strong><\/p>\n\n\n\n<p>Multipotent stem cells in bone marrow divide to produce specific stem cells , that differentiate into myeloid and lymphatic stem cells\u2026giving rise to respective lineage of erythrocyte, thrombocyte and WBCs.<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"569\" height=\"407\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-158.png?w=569\" alt=\"\" class=\"wp-image-546\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-158.png 569w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-158-300x215.png 300w\" sizes=\"(max-width: 569px) 100vw, 569px\" \/><\/figure>\n\n\n\n<p>Hematopoietic growth factors (HGFs) \u00e0 cytokines that govern haematopoiesis by regulating<\/p>\n\n\n\n<ul><li>&nbsp;proliferation,<ul><li>differentiation,<\/li><\/ul><ul><li>maturation,<\/li><\/ul><ul><li>function, and<\/li><\/ul><ul><li>viability of the cellular components of blood and their progenitor cells.<\/li><\/ul><\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"285\" height=\"270\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-159.png?w=285\" alt=\"\" class=\"wp-image-547\" \/><\/figure>\n\n\n\n<p><img loading=\"lazy\" decoding=\"async\" width=\"285\" height=\"271\" src=\"\">&nbsp;\u2022 production of HGFs is primarily by the cells of the bone marrow except erythropoietin.<\/p>\n\n\n\n<ul><li>Haematological toxicity is the most common side effect of chemotherapy.<\/li><li>Several hematopoietic growth factors are currently available for clinical use<ul><li>And synthesized mainly by DNA recombinant technology.<\/li><\/ul><\/li><li>four major HGFs currently used clinically:<ul><li>Erythropoietin (EPO)<\/li><\/ul><ul><li>Granulocyte colony-stimulating factor (G-CSF or CSF3)<\/li><\/ul><ul><li>Granulocyte-macrophage colony-stimulating factor (GM-CSF)<\/li><\/ul><ul><li>Interleukin-11 (IL-11).<\/li><\/ul><\/li><\/ul>\n\n\n\n<ul><li>Thrombopoietin is also included, although the currently available clinical agents are thrombopoietin mimetics due to antigenicity of the native cytokine.<\/li><li>ERYTHROPOIETIN GROWTH FACTORS<\/li><li><strong>Erythropoietin<\/strong><ul><li>primary regulator of red blood cell production, \u2022 primarily produced in the kidney (interstitial fibroblasts and proximal tubular cells)<\/li><\/ul><ul><li>\u2022 Endogenous EPO levels are depressed in cancer patients \u2013 chronic anaemia<\/li><\/ul><ul><li>1977 &#8211; purification and cloning -Recombinant human erythropoietin &#8211; <strong>Epoetin alfa.<\/strong><\/li><\/ul><ul><li>initially approved \u2013 <strong>anaemia in chronic renal failure patients on dialysis<\/strong><strong><\/strong><\/li><\/ul><ul><li>later &#8211; <strong>HIV-related anaemia<\/strong><\/li><\/ul><ul><li>the indication was expanded to include <strong>chemotherapy-related anaemia.<\/strong><\/li><\/ul><\/li><li>The approval was based on a randomized placebo-controlled trial,<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"308\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-160.png?w=480\" alt=\"\" class=\"wp-image-548\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-160.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-160-300x193.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<p>To explore further the impact of anemia and its management on the patient undergoing cancer chemotherapy<\/p>\n\n\n\n<ul><li>three large open label community-based clinical trials<ul><li>anaemia in the setting of chemotherapy<\/li><\/ul><ul><li>&gt;7,000 enrolled in the three trials<\/li><\/ul><ul><li><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"265\" src=\"\">provided a very robust database<\/li><\/ul><\/li><\/ul>\n\n\n\n<p>The weekly administration strategy appeared to be as effective as three times a week and has become the clinical standard for administration.<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"458\" height=\"264\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-161.png?w=458\" alt=\"\" class=\"wp-image-549\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-161.png 458w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-161-300x173.png 300w\" sizes=\"(max-width: 458px) 100vw, 458px\" \/><\/figure>\n\n\n\n<p><strong>DARBEPOETIN ALFA<\/strong><\/p>\n\n\n\n<ul><li>165 amino acid protein that stimulates erythropoiesis<\/li><li>differs from erythropoietin and contains <strong>5-N-linked oligosaccharide chains<\/strong><\/li><li><strong>increase<\/strong> the <strong>molecular weight<\/strong> of darbepoetin alfa to 37,100 Da<\/li><li><strong>3 times longer half-life<\/strong> and increased biologic activity.<\/li><li>2001- anaemia associated with chronic renal failure<\/li><li>2006 &#8211; anaemia due to the effects of concomitant myelosuppressive chemotherapy.<\/li><\/ul>\n\n\n\n<p><strong>Continuous Erythropoietin Receptor Activator (CERA)<\/strong><\/p>\n\n\n\n<ul><li>&nbsp;Epoetin beta, <strong>third-generation<\/strong> molecule,<\/li><li>incorporating a large polymer chain<\/li><li>similar to the previous synthetic EPO drugs, except that it is <strong>connected to polyethylene glycol&nbsp;(PEG)<\/strong>, which makes it <strong>last longer <\/strong>in the body.&nbsp;<\/li><li>up to <strong>6 times <\/strong>longer than darbepoetin alfa and up to <strong>20 times <\/strong>longer than epoetin.<\/li><li>2008- approved for the treatment of&nbsp;<a href=\"https:\/\/en.wikipedia.org\/wiki\/Anemia\">aneamia<\/a>&nbsp;in patients with&nbsp;<a href=\"https:\/\/en.wikipedia.org\/wiki\/Chronic_kidney_disease\">chronic kidney disease<\/a>.&nbsp;<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"519\" height=\"389\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-162.png?w=519\" alt=\"\" class=\"wp-image-550\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-162.png 519w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-162-300x225.png 300w\" sizes=\"(max-width: 519px) 100vw, 519px\" \/><\/figure>\n\n\n\n<p>ASCO\/ASH guidelines recommendations<\/p>\n\n\n\n<ul><li>Hb level at initiation- &lt;10g\/dl<\/li><\/ul>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; In patients with Hb 10-12g\/dl, ESAs are to be used according to circumstances and clinical judgement<\/p>\n\n\n\n<p>For <strong>symptomatic patients with AOC without a reversible cause, transfusion is recommended<\/strong> rather than ESAs<\/p>\n\n\n\n<p><strong>A<\/strong><strong>dverse effects<\/strong><\/p>\n\n\n\n<ul><li>Increases the risk of death,<\/li><li>Myocardial infarction,<\/li><li>Stroke<\/li><li>venous thromboembolism and<\/li><li>tumour progression or recurrence.<\/li><li>can also lead to an increase in adverse cardiovascular events, hypertension, seizures.<\/li><\/ul>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"165\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-163.png?w=480\" alt=\"\" class=\"wp-image-551\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-163.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-163-300x103.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"480\" height=\"279\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-164.png?w=480\" alt=\"\" class=\"wp-image-552\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-164.png 480w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-164-300x174.png 300w\" sizes=\"(max-width: 480px) 100vw, 480px\" \/><\/figure>\n\n\n\n<ul><li>FDA announced on&nbsp;<strong>April 13, 2017 <\/strong>the <strong>elimination of the risk evaluation and mitigation strategy (REMS)<\/strong> for ESAs.<\/li><\/ul>\n\n\n\n<p>By eliminating the REMS:<\/p>\n\n\n\n<ul><li>Hospitals that dispense ESAs to patients with cancer will no longer be required to enrol and become certified to dispense ESAs.<\/li><li>While the REMS is no longer necessary to ensure the benefits outweigh the risks, the serious risks of shortened overall survival and\/or increased risk of tumour progression or recurrence associated with these drugs remain.<\/li><\/ul>\n\n\n\n<ul><li>Health care providers are encouraged to discuss the risks and benefits of using ESAs with each patient before initiating use.<\/li><\/ul>\n\n\n\n<p><strong>Head-to-Head Study of<\/strong><\/p>\n\n\n\n<p><strong>Darbepoetin alfa versus Epoetin Alfa&nbsp; <\/strong><strong>\u00e0<\/strong><strong> <\/strong>Similar clinical efficacy in<\/p>\n\n\n\n<ul><li>boosting haemoglobin levels<ul><li>reducing the need for red blood cell transfusions and mortality<\/li><\/ul><\/li><\/ul>\n\n\n\n<p>No differences were observed between the two groups for \u00e0health-related quality of life assessment<\/p>\n\n\n\n<p><strong>Epoetin alfa is the better pharmacoeconomic value <\/strong>of the two currently available Erythropoietic agents.<\/p>\n\n\n\n<p><strong>Misuse of ESAs<\/strong><\/p>\n\n\n\n<ul><li>Erythropoiesis-stimulating agents have a history of misuse by athletes<\/li><li>The primary reason athletes use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity.<\/li><\/ul>\n\n\n\n<p>ESAs increase haematocrit and total red cell mass in the body, providing a good advantage in sports where such practice is banned<\/p>\n\n\n\n<p><strong>Myeloid Growth Factors<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"445\" height=\"348\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-165.png?w=445\" alt=\"\" class=\"wp-image-553\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-165.png 445w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-165-300x235.png 300w\" sizes=\"(max-width: 445px) 100vw, 445px\" \/><\/figure>\n\n\n\n<ul><li>conventional cytotoxic <strong>chemotherapy<\/strong>&#8211; most common <strong>dose-limiting toxicity- neutropenia<\/strong> and the associated risk of infection.<\/li><\/ul>\n\n\n\n<p>The likelihood of developing fever in this setting of neutropenia (defined as an absolute neutrophil count [ANC] &lt;500 cells per ml) is approximately 10% per day<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"494\" height=\"268\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-166.png?w=494\" alt=\"\" class=\"wp-image-554\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-166.png 494w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-166-300x163.png 300w\" sizes=\"(max-width: 494px) 100vw, 494px\" \/><\/figure>\n\n\n\n<p><strong>G-CSF<\/strong><\/p>\n\n\n\n<p><strong>Filgrastim<\/strong><\/p>\n\n\n\n<p>\u2013 produced in Escherichia coli<\/p>\n\n\n\n<p>\u2013 has an amino acid sequence identical to endogenous CSF3, with the exception of the addition of an N-terminal methionine and absence of glycosylation.<\/p>\n\n\n\n<p>\u2013 The half-life ~ 3.5 hours&nbsp;<\/p>\n\n\n\n<p><strong>Pegfilgrastim<\/strong><\/p>\n\n\n\n<p>\u2013 polyethylene glycol-conjugated version of filgrastim<\/p>\n\n\n\n<p>\u2013 The half-life ~ 33 hours<\/p>\n\n\n\n<p><strong>Lenograstim<\/strong><\/p>\n\n\n\n<p>\u2013 a glycosylated recombinant CSF3 derived from a mammalian cell system (Chinese hamster ovaries)<\/p>\n\n\n\n<p><strong>G<\/strong><strong>M-CSF<\/strong><\/p>\n\n\n\n<p><strong>Sargramostim<\/strong><\/p>\n\n\n\n<ul><li>recombinant human granulocyte-macrophage colony stimulating factor (rhu GM-CSF)<\/li><li>produced in a yeast (S. cerevisiae) expression system.<\/li><li>The amino acid sequence of Sargramostim differs from the natural human GM-CSF by a substitution of leucine at position 23<\/li><li>T1\/2 is 60 mins<\/li><\/ul>\n\n\n\n<p><strong>Molgramostim<\/strong><\/p>\n\n\n\n<ul><li>an immunostimulant<\/li><li>prescribed for<ul><li>treatment of Ganciclovir-induced neutropenia<\/li><\/ul><ul><li>chemotherapy-associated neutropenia<\/li><\/ul><ul><li>bone marrow transplantation associated complications.<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>INDICATIONS AND USAGE<\/strong><\/p>\n\n\n\n<ul><li>Cancer Patients Receiving Myelosuppressive Chemotherapy<\/li><li>Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy<\/li><li>Cancer Patients Receiving Bone Marrow Transplant<\/li><li>Patients Undergoing Peripheral Blood Progenitor Cell Collection and Therapy<\/li><li>Patients With Severe Chronic Neutropenia<\/li><\/ul>\n\n\n\n<p><strong>SCHEDULE AND DOSE<\/strong><\/p>\n\n\n\n<ul><li>subcutaneous doses of&nbsp;&nbsp; G-CSF- <strong>5 mcg\/kg\/day<\/strong><\/li><li>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;GM-CSF- <strong>250 mcg\/m2\/day<\/strong>,<\/li><li><strong>beginning 24 hours after chemotherapy <\/strong>and continuing until the post-nadir ANC recovery is complete.(10)<\/li><li>Initial recommendations were to continue the treatment until an ANC of &gt;10,000 cells per ml was achieved, but ASCO guidelines recommend that consideration be given to stopping CSF at ANC levels of &lt;10,000 based on clinical experience and cost considerations.<\/li><li>The availability of a <strong>long-acting formulation of G-CSF <\/strong>has simplified scheduling to a <strong>single subcutaneous injection of 6 mg of Pegfilgrastim <\/strong>24 hours after chemotherapy.<\/li><li>After administration of these agents \u00e0 there is a transient decrease in the peripheral WBC count, likely as a result of increased neutrophil adherence to endothelial cells.<\/li><li>It is estimated that in the presence of G-CSF, this process occurs within 1 day rather than the normal 5-day process in unstimulated bone marrow.<\/li><li>With the use of GM-CSF, kinetic studies have shown a less dramatic enhancement of proliferation of leukocytes but a prolongation of circulating neutrophil half-life resulting in a sustained leukocytosis.<\/li><li>In addition to effects on proliferation and maturation of neutrophils, both CSFs enhance<ul><li>&nbsp;activities of neutrophils,<\/li><\/ul><ul><li>including the respiratory burst,<\/li><\/ul><ul><li>adherence,<\/li><\/ul><ul><li>superoxide release,<\/li><\/ul><ul><li>bacterial killing.<\/li><\/ul><\/li><li><strong>Adverse effect of CSF<\/strong><\/li><\/ul>\n\n\n\n<p>&nbsp;<strong>Common<\/strong><\/p>\n\n\n\n<ul><li>Gastrointestinal: Nausea and vomiting<ul><li>mild-to-moderate bone pain.<\/li><\/ul><ul><li>&nbsp;Splenomegaly &#8211; reported in chronic use<\/li><\/ul><ul><li>transient dyspnoea and pulmonary infiltrates on chest radiography.<\/li><\/ul><ul><li>&nbsp;leucocytosis<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Serious<\/strong><\/p>\n\n\n\n<ul><li>allergic-type reactions<ul><li><strong>splenic rupture <\/strong>in persons receiving recombinant CSF3 for peripheral blood stem cell mobilization.<\/li><\/ul><ul><li>adult respiratory distress syndrome<\/li><\/ul><\/li><li><strong>Side effects of G-CSF<\/strong><\/li><li>\u2022 Better tolerated than GM-CSF<\/li><li>\u2022 Rarely cause <strong>Sweet syndrome<\/strong><ul><li><strong>Acute febrile neutrophilic dermatosis<\/strong><\/li><\/ul><ul><li>sudden onset of fever,<\/li><\/ul><ul><li>an elevated WBC count, and<\/li><\/ul><ul><li>tender, red, well-demarcated papules<\/li><\/ul><\/li><\/ul>\n\n\n\n<p><strong>Side effects of GM-CSF<\/strong><\/p>\n\n\n\n<p>\u2022 Flu like symptoms<\/p>\n\n\n\n<p>\u2022 In vitro evidence that it may stimulate HIV replication but clinical studies not corroborating<\/p>\n\n\n\n<p><strong>GUIDELINE RECOMMENDATIONS<\/strong><\/p>\n\n\n\n<ul><li>Primary prophylaxis with a CSF starting with the first cycle and continuing through subsequent cycles of chemotherapy is recommended in patients who have an <strong>approximately 20% or higher risk <\/strong>for febrile neutropenia based on patient disease and treatment-related factors.<\/li><li>Secondary prophylaxis with a CSF is recommended for patients who experienced a neutropenic complication from a prior cycle of chemotherapy (for which primary prophylaxis was not received),<\/li><li>CSFs should <strong>not be routinely used <\/strong>for patients with <strong>neutropenia who are afebrile.<\/strong><\/li><li>CSFs <strong>should not be routinely used <\/strong>as <strong>adjunctive <\/strong>treatment with <strong>antibiotic therapy <\/strong>for patients with fever and neutropenia.<\/li><\/ul>\n\n\n\n<p><strong>Precautions of CSF<\/strong><\/p>\n\n\n\n<ul><li>\u2022 Avoid the simultaneous use of chemotherapy and radiation therapy with G-CSF and GM-CSF;<\/li><li>DO NOT administer within 24 hours before or after cytotoxic chemotherapy<\/li><li>\u2013 Potential sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy.<\/li><li>\u2022 Possible growth stimulation of tumors<\/li><\/ul>\n\n\n\n<p><strong>H<\/strong><strong>EAD TO HEAD TRIAL<\/strong><\/p>\n\n\n\n<p>&nbsp;<strong>Filgrastim(G-CSF) vs. Sargramostim(GM-CSF)<\/strong><\/p>\n\n\n\n<p>\u2022 <strong>no firm evidence <\/strong>indicating the superiority of one over another<\/p>\n\n\n\n<ul><li>patients who received <strong>G\u2010CSF <\/strong>had <strong>faster recovery of ANC<\/strong><ul><li>fewer patients:<\/li><\/ul><\/li><li>requiring red blood cell transfusions, with fever<\/li><li>hospital admissions<\/li><li>less intravenous antibiotic therapy<\/li><li>There were no significant differences in outcomes between G\u2010CSF alone and the sequential regimen GM-CSF followed by G-CSF<\/li><\/ul>\n\n\n\n<p><strong>G\u2010CSF alone is superior to GM\u2010 CSF alone<\/strong> for the mobilization of CD34+ cells and reduction of toxicities following myelosuppressive chemotherapy.<\/p>\n\n\n\n<p><strong>Comparative Effectiveness of Filgrastim, Pegfilgrastim, and Sargramostim<\/strong><\/p>\n\n\n\n<ul><li><strong>Pegfilgrastim reduces FN <\/strong>incidence to a significantly greater extent than Filgrastim<\/li><li><strong>Risk of hospitalization <\/strong>for neutropenic complications during cancer chemotherapy is <strong>lower with Pegfilgrastim <\/strong>prophylaxis than with Filgrastim or Sargramostim prophylaxis.<\/li><li>Of the three types of G-CSFs evaluated, <strong>Pegfilgrastim<\/strong> seemed to be <strong>more cost effective <\/strong>than Filgrastim and Lenograstim.<\/li><\/ul>\n\n\n\n<p><strong>PLATELETS GROWTH FACTORS<\/strong><\/p>\n\n\n\n<p><strong>INTERLEUKIN-11<\/strong><\/p>\n\n\n\n<ul><li>IL-11 is a bone marrow stroma-derived growth factor<\/li><li><strong>stimulates haematopoiesis<\/strong>.<\/li><li>&nbsp;In combination with IL-3, IL-11 <strong>promotes megakaryocytopoiesis <\/strong>by stimulating the formation of colony-forming units megakaryocyte and burst-forming units megakaryocyte.<\/li><li>In addition, IL-11 promotes thrombopoiesis by <strong>increasing the size and ploidy of megakaryocytes.<\/strong><\/li><\/ul>\n\n\n\n<p><strong>Endogenous IL-11 \u2013 Oprelvekin<\/strong><\/p>\n\n\n\n<p>\u2022 &nbsp;&nbsp;&nbsp; Oprelvekin &#8211; a rHu IL-11, produced in E. Coli<\/p>\n\n\n\n<ul><li>half-life was 6.9 \u00b1 1.7 hrs<\/li><\/ul>\n\n\n\n<p>\u2022 &nbsp;&nbsp;&nbsp; Platelet counts begin to rise 5 to 9 days after the initial dose<\/p>\n\n\n\n<ul><li>Indication-<strong>prevention of severe thrombocytopenia<\/strong> and the <strong>reduction of the need for platelet transfusions <\/strong>following myelosuppressive chemotherapy in adult patients with <strong>nonmyeloid malignancies <\/strong>who are at high risk of severe thrombocytopenia<\/li><li><strong>not indicated following myeloablative chemotherapy<\/strong><\/li><\/ul>\n\n\n\n<ul><li>0ther ILs that were demonstrated in model systems to accelerate platelets are <strong>IL-3 and IL-6<\/strong>.<\/li><li>However, early clinical trials of <strong>both these molecules <\/strong>were met with <strong>significant toxicities<\/strong>.<\/li><li>&nbsp;<strong>IL-11 &#8211; <\/strong>more tolerable<\/li><li><strong>30% reduction was seen in the need for platelet transfusions <\/strong>among the patients who required platelet support during the previous cycles of chemotherapy when compared with the control group<\/li><li>the <strong>current clinical approval <\/strong>is limited to the <strong>secondary prophylaxis <\/strong>setting.<\/li><li>In clinical practice, <strong>IL-11 has been limited in use by side effects<\/strong> that are typical of other ILs with fever, and malaise, as well as other side effects.<\/li><\/ul>\n\n\n\n<p><strong>THROMBOPOIETIN (TPO)<\/strong><\/p>\n\n\n\n<ul><li>humoral regulator of platelet production.<\/li><li><strong>polyethylene glycol<\/strong>\u2013conjugated truncated form of TPO known as <strong><em>megakaryocyte growth and development factor (PEG-MGDF)<\/em><\/strong>,<\/li><li>Stimulates- platelet release.<\/li><li>In <strong>early clinical trials <\/strong>PEG-MGDF and <strong>recombinant TPO <\/strong>were <strong>successful in shortening the duration of thrombocytopenia<\/strong>, elevating the platelet nadir and <strong>reducing the need for transfusion <\/strong>by approximately 30% to 50%.<\/li><li>Unfortunately, the <strong>development of PEG-MGDF <\/strong>was <strong>halted <\/strong>after a normal volunteer study revealed the <strong>development of cross-reacting antibodies<\/strong>, to native TPO, resulting in prolonged thrombocytopenia.<\/li><\/ul>\n\n\n\n<p><strong>THROMBOPOIETIN-RECEPTOR AGONISTS<\/strong><\/p>\n\n\n\n<ul><li>To avoid the development of auto-antibodies, drug development switched to small molecules in the form of TPO -receptor agonists.<\/li><li>&nbsp;Romiplostim and Eltrombopag -mimics endogenous TPO<\/li><li>by binding to and activating the platelet TPO receptor (TPO\/R, Mpl, or CD110 antigen).<\/li><li>Activation of TPO\/R stimulates platelet production by proliferation and differentiation of megakaryocytes.<\/li><\/ul>\n\n\n\n<p><strong>Thrombopoietin Mimetics<\/strong><\/p>\n\n\n\n<ol type=\"1\"><li><strong>Romiplostim<\/strong><\/li><\/ol>\n\n\n\n<p>subcutaneous<\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 human TPO receptor-binding peptide joined by disulphide &nbsp;&nbsp;&nbsp; bonds to an immunoglobulin Fc fragment<\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 no homology to endogenous thrombopoietin<\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 No cross-reactivity (16)<\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 FDA approved for patients with ITP.<\/p>\n\n\n\n<p>2)<strong> Eltrombopag<\/strong><\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 oral TPO agonist<\/p>\n\n\n\n<p>&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; \u2022 FDA approved for patients with ITP.<\/p>\n\n\n\n<p>\u2022 Both are currently being studied in patients with chemotherapy-induced thrombocytopenia<\/p>\n\n\n\n<p><strong>Side effects <\/strong>\u2013<\/p>\n\n\n\n<p>\u2013 allergic reactions and anaphylaxis<\/p>\n\n\n\n<p>\u2013 Oedema in 2\/3 patients,<\/p>\n\n\n\n<p>\u2013 Dyspnoea in 50% patients<\/p>\n\n\n\n<p>\u2022 <strong>At present, platelet transfusion remains the primary therapeutic modality for treatment of thrombocytopenia in the oncology setting.<\/strong><\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td><\/td><td><strong>Eltrombopag trial data<\/strong><\/td><td><strong>Romiplostim trial data<\/strong><\/td><\/tr><tr><td>Overall response<\/td><td>67%<\/td><td>83%<\/td><\/tr><tr><td>Durable response<\/td><td>47%<\/td><td>49%<\/td><\/tr><\/tbody><\/table><\/figure>\n","protected":false},"excerpt":{"rendered":"<p>Hematopoietic Growth Factors Multipotent stem cells in bone marrow divide to produce specific stem cells , that differentiate into myeloid and lymphatic stem cells\u2026giving rise to respective lineage of erythrocyte, thrombocyte and WBCs. Hematopoietic growth factors (HGFs) \u00e0 cytokines that govern haematopoiesis by regulating &nbsp;proliferation, differentiation, maturation, function, and viability of the cellular components of[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/545"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=545"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/545\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=545"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=545"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=545"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}