HEMATOPOIETIC AGENTS;GROWTH FACTORS,MINERALS AND VITAMINS Phr.Volkan KAHRAMAN HGF’s

• Hematopoietic growth factors are glycoproteins that stimulate the proliferation and development of clonogenic precursor cell populations.

• Through recombinant technology, hematopoietic growth factors administered at pharmacologic doses can provide significant clinical benefit for the cancer patient undergoing chemotherapy. HGF’s

• Anemia can be reversed with the use of recombinant erythroid stimulating agents (ESAs) reducing transfusions and improving anemia- related symptoms such as fatigue.

• Neutropenia and its complications can be ameliorated by the use of myeloid growth factors (MGFs). HGF’s

• These MGFs have also had a major role in the development of the technology of peripheral blood progenitor cell mobilization, reducing prolonged cytopenias after high-dose chemotherapy.

• Thrombopoietic agents have shown promising activity improving platelet counts in patients with immune thrombocytopenia (ITP), and studies in cancer chemotherapy patients are underway. NEUTROPENIA

• The most common dose-limiting toxicity of conventional cytotoxic chemotherapy is neutropenia and the associated risk of infection.

• Although definitions are variable from institution to institution, neutropenia is defined as an absolute neutrophil count (ANC) of <500/microL or an ANC that is expected to decrease to <500/microL within the next 48 hours. Profound neutropenia is defined as an ANC <100/microL. NEUTROPENIA

• Standard therapy for patients with neutropenia and fever has included hospitalization and intravenous antibiotics; despite these interventions, however, neutropenic fever continues to carry a significant risk of morbidity and mortality. NEUTROPENIA

• In addition to the potential risks of febrile neutropenia (FN) to the cancer patient, neutropenia has limited the intensity of chemotherapy regimens in both standard dose and high-dose chemotherapy settings. CLINICAL USES OF HGF’s

• Transient bone marrow failure following chemotherapy • Hematopoietic stem cell and progenitor cell mobilization • Recovery from hematopoietic cell transplantation • Myelodysplastic syndromes • Aplastic anemia • Human immunodeficiency virus (HIV) infection-associated neutropenia

CLINICAL USES OF HGF’s

• Cytotoxic chemotherapy can cause profound and sometimes prolonged neutropenia, which may result in hospitalization for treatment of fever or cause a potentially fatal infection . • Although profound prolonged neutropenia is most likely in the pre-engraftment phase of hematopoietic cell transplantation (HCT; particularly allogeneic) and in patients undergoing induction therapy for acute leukemia, chemotherapy-related neutropenia can also occur in patients receiving standard-dose chemotherapy for other neoplasms. CLINICAL USES OF HGF’s

• In an attempt to decrease infectious complications, recombinant human granulocyte colony stimulating factor (G-CSF; filgrastim and pegylated filgrastim) and granulocyte-macrophage colony stimulating factor (GM- CSF; sargramostim) have been used to reduce the duration and degree of neutropenia.

• The risk of a clinically important infection rises as the neutrophil count falls below 500/microL.

FEVER

• Fever in a neutropenic patient is usually defined as a single temperature ≥38.3ºC (101ºF) or a temperature ≥38ºC (100.4ºF) sustained over a one-hour period. • However, infection can occur in neutropenic patients and other immunocompromised patients in the absence of fever. • This occurs more often in older adult patients and those receiving corticosteroids. • Presenting signs of infection in such patients may include hypothermia, hypotension, confusion, or clinical deterioration. PRIMARY PROPHYLAXIS

• Primary prophylaxis refers to the initiation of G-CSFs during the first cycle of myelosuppressive chemotherapy, with the goal of preventing neutropenic complications throughout all of the chemotherapy cycles.

• Primary prophylaxis may be used to decrease the incidence of neutropenic fever and the need for hospitalization.

• Primary prophylaxis may also be used to maintain dose- dense or dose-intense chemotherapy strategies. SECONDARY PROPHYLAXIS

• Secondary prophylaxis refers to the administration of a G- CSF in subsequent chemotherapy cycles after neutropenic fever has occurred in a prior cycle.

• A prior episode of fever during neutropenia is a risk factor for developing fever during neutropenia in later cycles, with recurrences noted in 50 to 60 percent of patients.

• Secondary prophylaxis with CSFs reduces this risk by approximately one-half. HGF’s

• Filgrastim • Lenograstim • Sargramostim • Pegfilgrastim • Lipegfilgrastim

G-CSF&GM-CSF

• The commercially available MGFs in the United States include G-CSF (filgrastim and lenograstim), GM-CSF (sargramostim and molgramostim), and pegfilgrastim, a long-acting pegylated version of G-CSF.

• Many placebo-controlled trials have shown that both G-CSF and GM-CSF (sargramostim) are effective at reducing the incidence of neutropenic fever and infectious complications in cancer patients receiving chemotherapy. G-CSF&GM-CSF

• Filgrastim is effective in the treatment of severe neutropenia after autologus hematopoietic stem cell transplantation and high-dose cancer chemotherapy.

• Like GM-CSF,filgrastim shortens the period of severe neutropenia and reduces morbidity secondary to bacterial and fungal infections.

• It promotes the release of CD34+ progenitor cells from the marrow. G-CSF&GM-CSF SIDE EFFECTS

• Transient leukopenia — Following injection, both GM-CSF and G-CSF induce a transient leukopenia in the first 30 minutes after administration.

• Systemic reactions — GM-CSF can induce flu-like symptoms, including fever, flushing, malaise, myalgia, arthralgia, anorexia, and headache, and mild elevations of serum aminotransferases and rash are also reported. These effects are usually mild, are alleviated by antipyretics, and disappear with continued administration. G-CSF&GM-CSF SIDE EFFECTS

• Bone pain — GM-CSF and G-CSF both have been commonly associated with mild to moderate bone pain, coincident with or shortly after administration. • Gastrointestinal: Nausea and vomiting • Splenomegaly - reported in chronic use • Splenic rupture in persons receiving recombinant CSF3 for peripheral blood stem cell mobilization (including healthy donors), • Transient dyspnea and pulmonary infiltrates on chest radiography.

DOSE AND TIMING

• When used for primary and secondary prophylaxis, the recommended dose of G-CSF (filgrastim), is 5 mcg/kg per day and for GM-CSF (sargramostim), 250 mcg/m2 per day.

• To reduce cost, the dose is usually rounded off to the nearest vial size.

• Therapy is usually begun 24 to 72 hours after cessation of chemotherapy. Pegfilgrastim and other long-acting agents • Pegfilgrastim, a pegylated formulation of G-CSF, has a prolonged half-life, permitting the administration of a single dose rather than daily administration.

• The recommended dose (6 mg in adults, 100 mcg/kg [maximum 6 mg] in children) is given 24 hours after chemotherapy, with at least 14 days elapsing until the next planned chemotherapy dose. Pegfilgrastim and other long-acting agents • Pegfilgrastim is at least as effective as and more convenient to administer than G-CSF for primary prophylaxis. • Many trials in fact suggest better efficacy for pegfilgrastim over G-CSF. NEUPOGEN NEUPOGEN

• The recommended starting dosage of NEUPOGEN is 5 mcg/kg/day‚ administered as a single daily injection by subcutaneous injection‚ by short intravenous infusion (15 to 30 minutes)‚ or by continuous intravenous infusion.

• Administer the first dose of NEUPOGEN at least 24 hours after cytotoxic chemotherapy and at least 24 hours after bone marrow infusion. NEUPOGEN

• Prior to use‚ remove the vial or prefilled syringe from the refrigerator and allow NEUPOGEN to reach room temperature for a minimum of 30 minutes and a maximum of 24 hours.

• Discard any vial or prefilled syringe left at room temperature for greater than 24 hours.

• Do not administer NEUPOGEN if particulates or discoloration are observed. NEUPOGEN

• Subcutaneous Injection Inject NEUPOGEN subcutaneously in the outer area of upper arms, abdomen, thighs, or upper outer areas of the buttock.

If required for intravenous administration‚ NEUPOGEN (vial only) may be diluted in 5% Dextrose. NEUPOGEN is compatible with glass bottles‚ polyvinyl chloride (PVC) and polyolefin intravenous bags‚ and polypropylene syringes. Do not dilute with saline at any time because the product may precipitate. PLERIXAFOR

• Mozobil, a hematopoietic stem cell mobilizer, is indicated in combination with granulocyte-colony stimulating factor (G- CSF) to mobilize hematopoietic stem cells (HSCs) to the peripheral blood for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. • The recommended dose of Mozobil by subcutaneous injection is based on body weight:  20 mg fixed dose or 0.24 mg/kg of body weight for patients weighing ≤83 kg.  0.24 mg/kg of body weight for patients weighing >83 kg

PLERIXAFOR PLERIXAFOR PLERIXAFOR SIDE EFFECTS

• Anaphylactic shock and hypersensitivity reactions • Potential for tumor cell mobilization in leukemia patients • Increased circulating leukocytes and decreased platelet counts • Potential for tumor cell mobilization • Potential for splenic enlargement PLERIXAFOR

Each single-use vial is filled to deliver 1.2 mL of 20 mg/mL solution containing 24 mg of plerixafor. VITAMIN B12 AND FOLIC ACID

• Vitamin B12 and folic acid are dietary essentials. • A deficiency of either vitamin impairs DNA synthesis in any cell in which chromosomal replication and division are taking place. • The hematopoietic system is especially sensitive to deficiencies of these vitamins. • An early sign of deficiency is magaloblastic anemia. • Abnormal macrocytic red blood cells are produced,and the patient becomes severely anemic.

VITAMIN B12 AND FOLIC ACID

• Abnormal hematopoiesis,termed pernicious anemia, spurred investigations that ultimately led to the discovery of vitamin B12 and folic acid. • Pernicious anemia (PA) is typically treated with parenteral (ie, intramuscular or deep subcutaneous) vitamin B12, in a dose of 1000 mcg (1 mg) every day for one week, followed by 1 mg every week for four weeks and then, if the underlying disorder persists, 1 mg every month for the remainder of the patient's life. • The mechanisms responsible for the neurological lesions of vitamin B12 deficiency are less well understood. VITAMIN B12 AND FOLIC ACID

• Vitamin B12 deficiency is recognized clinically by its impact on the hematopoietic and nervous system. • The diagnosis of a vitamin B12 deficiency usually can be made using measurements of the serum vitamin B12. • Vitamin B12 deficiency can irreversibly damage the nervous system. • Neurologic signs;paresthesias of the hands and feet, decreased deep tendon reflexes,and in the later stages, confusion,moodiness,loss of memory,and even a loss of central vision. VITAMIN B12 AND FOLIC ACID

• Humans depend on exogenous sources of vitamin B12. • In nature the primary sources are certain microorganisms that grow in soil,sewage,water or the intestinal lumen of animals that synthesize the vitamin. • The daily nutritional requirement of 3-5µg must be obtained from animal by-products in the diet. • Many food sources are rich in folates,especially fresh green vegatables,liver,yeast,and some fruits.However,lengthy cooking can destroy up to 90% of the folate content of such food.