1. NEUTROPENIA AND ANEMIA OF CANCER PATIENTS 477 PHCL JAMILAH ALSAIDAN MSC

2. TREATMENT-INDUCED MYELOSUPPRESSION To assist patients in recovering from some of the hematologic toxicities of cancer chemotherapy, several proteins have been developed that stimulate various steps of hematopoiesis; they are designated as growth factors or stimulatory cytokines. These proteins are produced in vivo and bind to specific cell receptors to stimulate stem cell proliferation and differentiation. Hematopoiesis proceeds from a pluripotent stem cell (one that can differentiate in to any of the hematopoietic cell-lines) in an orderly, timed fashion to mature cells

3. HEMATOPOIESIS Image taken from: http://hematologyoutlines.com/atlas

4. TREATMENT INDUCED NEUTROPENIA TREATMENT INDUCED NEUTROPENIA many chemotherapy agents can have toxic effects on the bone marrow. An infection resulting from chemotherapy-induced neutropenia (CIN) is the primary life-threatening event of any chemotherapy course. Patients experience severe CIN when the absolute neutrophil count (ANC) falls below 500 per µL At this time, patients are most vulnerable to bacterial, fungal, and viral infections.

5. TREATMENT INDUCED NEUTROPENIA TREATMENT GOALS: prevent prolonged duration of CIN and its associated infection risk by administering primary and secondary prophylactic myelopoietic cytokines with : standard-dose chemotherapy and high-dose cytotoxic therapy associated with bone marrow transplantation (BMT).

6. TREATMENT INDUCED NEUTROPENIA Introduction Chemotherapy- induced neutropenic infections are the primary life- threatening event of any chemotherapy course. The duration and severity of CIN are the most important predictors of infection risk.

7. TREATMENT INDUCED NEUTROPENIA Introduction Myelopoietic growth factors decrease the following: the time that granulocyte counts remain below 500per µL, the incidence of febrile neutropenia, the number of infectious complications in patients receiving high- dose autologous BMT or allogeneic BMT. Growth Factors are also effective for mobilizing progenitor cells into the peripheral blood so that they can be harvested for autologous or allogeneic transplantation.

8. TREATMENT INDUCED NEUTROPENIA Management WHITE BLOOD CELL GROWTH FACTORS: There are three exogenous growth factor agents commonly used for the management of chemotherapy- induced neutropenia: recombinant human granulocyte–macrophage colony stimulating factor (GM-CSF or Sargramostim), Recombinant human granulocyte colony-stimulating factor (G-CSF or Filgrastim), A covalent conjugate of rhu-G-CSF and mono-methoxypolyethyleneglycol, commonly referred to as pegylated G-CSF or Pegfilgrastim.

9. TREATMENT INDUCED NEUTROPENIA Management Although these agents do not uniformly prevent neutropenia after the administration of myelosuppressive therapy, they have been found to shorten the duration of neutropenia. They are also effective in accelerating neutrophil recovery after BMT and can increase the yield of peripheral blood stem cells collected by leukophoresis for use in peripheral blood stem cell transplantation.

10. TREATMENT INDUCED NEUTROPENIA Management GM-CSF is a127-amino acid glycosylated protein derived from yeast cultures. GM-CSF has multi line age effects on granulopoiesis, stimulating both primitive and terminal differentiation of neutrophils, macrophages, and eosinophils G-CSF is a 175-amino acid non glycosylated protein derived from Escherichia coli cultures. Unlike GM-CSF, the actions of G-CSF are limited to the terminal differentiation of neutrophils.

11. TREATMENT INDUCED NEUTROPENIA Management Pegylated G-CSF is produced by covalently binding a 20-KD monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue of filgrastim. Its action as a colony-stimulating factor is like that of G-CSF, but Pegyla-on results in reduced renal clearance and a prolonged persistence in vivo compared with G-CSF

12. AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) GUIDELINES FOR USE OF HGFs (ASCO) guidelines Primary Prophylactic Secondary Prophylactic

13. PRIMARY PROPHYLACTIC Is actually with the first course of chemotherapy) Use of CSFS if the expected incidence of febrile neutropenia with a chemotherapy regimen is 40% or greater. There are Special circumstances that support CSF use in primary prophylaxis with chemotherapy regimens for which the incidence of febrile CIN is less than 40%

14. Special circumstances that support CSF use in primary prophylaxis with chemotherapy regimens for which the incidence of febrile CIN is less than 40% are: patients receiving dose-intensive chemotherapy, poor performance status(eastern cooperative oncology group score ≥2), age more than 65years, advanced cancer (metastatic disease, having received multiple chemotherapy regimens), pre existing neutropenia secondary to disease, extensive prior chemotherapy, previous radiation to the pelvis (as this area contains a large amount of bone marrow), open wounds and active tissue infections, decreased immune function (human immuno deficiency virus infection, acquired immunodeficiency syndrome, cytopenias, diabetes mellitus),

15. Special circumstances that support CSF use in primary prophylaxis with chemotherapy regimens for which the incidence of febrile CIN is less than 40% are: history of recurrent febrile neutropenia with previous chemotherapy of similar or lesser myelosuppressive potential, or serum albumin level of 3.5g per dl or less in patients with non-Hodgkin’s lymphoma or multiple myeloma

16. SECONDARYPROPHYLAXIS Secondary prophylaxis with CSF is defined as use: after a previous febrile CIN episode or previous CIN when dose reduction or delay is not appropriate [e.g., Incurable tumors such as germ cell (testicular) cancers, intermediate / high-grade non-hodgkin’s lymphoma, and hodgkin’s lymphoma] and for patients being treated in the adjuvant or neoadjuvant setting.

17. The use of CSFs for the treatment of febrile neutropenia is recommended only if serious prognostic comorbidities are present. Studies have not yet supported a decrease in the number of neutropenic days or duration of hospitalization beyond antibiotics and/or antifungal therapy alone. Serious concomitant illnesses include pneumonia, hypotension, and multi-organ dysfunction.

18. There is a mathematical model developed by Silber et al The object is to correlate first cycle Absolute Neutrophil Count ANC with a predicted need for CSF in subsequent chemotherapy dose and maintenance Their mathematical model is complex, but soon guidelines using first-cycle nadir counts can be used to select patients who should receive CSF with subsequent cycles for chemotherapy dose maintenance.

19. Reference IntervalUnitsFlagResultTest CBC WITH DIFFERENTIAL 4.8-10.810 3 µLL2.0White Blood Count 130-40010 3 µL278Platelets 43.0-65.0%L14.8Polys 2.2-4.810 3 µLL0.3Polys (absolute) 10 3 µL0.1Bands (absolute)

20. TO CALCULATE THE ANC 1. FIND THE WBC, THE POLYS AND BANDS ON THE CBC. WBC 2.0 POLYS 14.8% BANDS 5% 2. ADD THE POLYS AND BANDS. (14.8 + 5 = 19.8) 3. MULTIPLY THE SUM OF THE POLYS AND BANDS BY THE WBC. 19.8 X 2.0 = 39.6 4. MULTIPLY THE PRODUCT BY 10. 39.6 X 10 = 396 THIS PERSON HAS AN ANC OF 396

21. TO CALCULATE THE ANC TO CALCULATE THE ANC FROM ABSOLUTE NUMBERS THE FORMULA IS: ABSOLUTE POLYS + ABSOLUTE BANDS MULTIPLIED BY 1000 = ANC (0.3 + 0.1) X 1000 = 400

22. Pharmacokinetics. Dosing frequencyserum half-life IVserum half- life SC volume of distribution absorption and distribution dailyis approx. 3.5 hours 150 ml/kgfollow first- order pharmacokineti cs ( LINEAR) G-CSF 60minutes162 minutes ( approx. 3 hours) follow first- order pharmacokineti cs ( LINEAR) GM-CSF Once per chemotherapy treatment cycle 15-80 hoursfollow first- order pharmacokineti cs ( LINEAR) Pegfilgastrim

23. DOSING. After G-CSF use is discontinued the ANC falls rapidly for 1 to 3 days before a new, lower baseline level is maintained. The time to reach a desired ANC with GM-CSF may be 1 day longer, but the ANC levels are more sustained, with little or no decrease after discontinuation.

24. DOSING AND ADMINISTRATION Filgrastim and sargramostim dosing should begin 24 to 72 hours after chemotherapy and continue daily past the ANC nadir. Pegfilgrastim, in contrast, is administered once per cycle (24 hours after chemotherapy is given in the cycle) and SHOULD NOT be administered in the period between 14days before and 24 hours after cytotoxic chemotherapy is administered. Administration with in this time period may have the undesired effect of increasing the sensitivity of rapidly dividing myeloid cells to chemotherapy

25. DOSING AND ADMINISTRATION Route and FrequencyDoseDRUG SC or IV daily250 µg/m 2 / day rounded to nearest 50 µg GM- CSF ( sargramostim) SC or IV daily5 µg/kg/ day rounded to the nearest vial size ( 300 µg or 480µg) ≤70kg = 300µg vial G-CSF ( Filgastrim) SC once per chemotherapy cycle6mg fixed dosePegylated G-CSF Pegfilgastrim

26. DOSING AND ADMINISTRATION The original recommendations for Filgrastim and sargramostim use were to treat until an ANC of10,000 per µl was reached, but most clinicians now treat until the ANC is greater than1,500 to 2,500 per µl for 2 consecutive days or for a maximum of 14days. Filgrastim and sargramostim should be discontinued at least 24hours before the next chemotherapy course. Discontinuation of the agents 48hours before the next cycle of chemotherapy has also been shown to decrease the chance of worsening CIN with subsequent cycles.

27. SIDE EFFECTS Body temperature elevation local injection site reactions bone pain or arthralgias. Capillary leak syndrome More common Rare

28. SIDE EFFECTS. Particular side effects of the CSFS that should be managed appropriately include temperature elevation, local injection site reactions, and bone pain or arthralgias. Body temperature elevation can occur 30 minutes to 4 hours after injection and usually peaks at 38 ˚C or less. Patients can be given acetaminophen or ibuprofen before injection to prevent this reaction. If temperature rises above 38.2 ˚C or does not respond to antipyretics, an underlying infection must be considered. Site reactions are typically localized and caused by the injection technique.

29. SIDE EFFECTS. The injection sites should be rotated, and the CSF should be injected at room temperature. It is often helpful to cool the skin with ice for a few minutes before injection. Medullary bone pain and arthralgias are common reactions and can be treated with analgesics. The pain can be severe but usually resolves 1 to 3 days after CSF use is discontinued. Capillary leak syndrome is rarely associatedwiththeyeast-derived gm-csf(sargramostim) product that is currently available.

30. PRECAUTIONS Administration with combined chemotherapy and radiotherapy has not been studied, and the use of CSF with daily radiation therapy may worsen neutropenia or damage the bone marrow Interaction with lithium!!!!!

31. PRECAUTIONS Lithium results in rapid release of neutrophils as they develop; thus, close monitoring is warranted in patients receiving concomitant lithium and CSF therapy. Lower CSF doses and/or a shorter duration of therapy may be required Sargramostim is contraindicated in patients sensitive to yeast-derived products, Filgrastim is contraindicated in patients sensitive to E.Coli- derived products.

32. ANEMIA INDUCED BY ONCOLOGICAL DISEASE TREATMENT

33. CAUSES. ANEMIA IN PATIENTS WITH CANCER MAY HAVE SEVERAL POTENTIAL CAUSES. The causes must be differentiated to make sure that all treatable causes are identified.

34. CAUSES. Cancer may cause anemia directly by : Acute or chronic blood loss Intratumor bleeding Erythrophagocytosis Splenomegaly Bone marrow replacement Cancer may cause anemia by physiologic effects of the cancer: Production of cytokines Abnormalities of iron utilization Blunted erythropoietic response by inhibitory cytokines

35. CAUSES. Most common etiology is chemotherapy or radiotherapy Patients at highest risk for therapy induced anemia are those that: Were anemic before therapy Undergo treatment with combined modalities (chemotherapy or radiotherapy)

36. MUST RULE OUT Immune hemolytic anemias Microangiopathic hemolysis Nutritional deficiences

37. TREATMENT GOALS Maintain hemoglobin (HGB) At a target range of 11to13g per dL During chemotherapy and/or radiation therapy. Decrease the sequelae of anemia such as fatigue, shortness of breath, and requirements for blood transfusions. Improve the patient’s quality of life.

38. CLINICAL PRESENTATION CLINICAL PRESENTATION AND DIAGNOSIS PATIENTS WITH CHEMOTHERAPY-INDUCED ANEMIA MAY DIFFER IN CLINICAL PRESENTATION SevereModerateMild* <8 g/dLHgB 8 to 10g/dLHgB>10g/dL Weakness, vertigo, concentration impairment, dyspnea, headaches, irritability May have fatigue or be asymptomatic National Cancer Institute definition

39. SYMPTOMS THAT WARRANT TREATMENT Patients that have had blood transfusion in the past six months Past radiation therapy to greater than 20% of the skeleton Advanced age Cardiac disease Pulmonary disease Use of highly myelosuppressive therapy

40. TREATMENT Immediate correction with blood transfusion Elderly, pt with severe symptoms Mildly symptomatic initiate (rhu EPO)

41. TREATMENT rhuEPO mimics the actions of endogenous erythropoiten It is a glycoprotein produced and secreted by the kidney in response to low oxygen tension On release into the blood-stream erythropoietin migrates to its site of action with in the bone marrow, where it is responsible for the amplification and terminal differentiation of erythroid progenitors and precursors for the formation of new red blood cells

42. TREATMENT Two available commercially EPOETIN ALFA AND DARBEPOETIN ALFA Differ in half life therefore dosing schedules differ

43. TREATMENT Obtain baseline values for! Vit B 12 Folate Adequate stores Iron Hgb Reticulocytes Transferrin ferritin

44. TREATMENT Upward Dose adjustmentsInitial Dose and ScheduleAgent After 6 weeks, if < 1 g/dL increase in Hgb, increase dose: If was 2.25 µg / kg week 4.5µg / kg /wk If was 200 µg / wk 300 µg / wk 2.25 µg / kg SC weekly OR 200µg SC every other week Darbepoetin alfa After 4 week; if < 1 g/dL increase in Hgb, increase dose: If was 40000 units SC wk 60000 If was 150 units/kg SC three times a week 300 units /kg three times per week 150 units/kg SC three times a week OR 40000 units SC weekly Epoetin Alfa If after an additional 4-6 weeks of therapy the patient fails to respond, discontinue therapy unless there is clear evidence that the patient is benefitting from therapy

45. TREATMENT Downward dose adjustmentsInitial Dose and ScheduleAgent If transfusion independent Hgb increases by >1g/ dL in any two week period or if Hgb is greater than 12g/dL, decrease the erythropoietin by 25% If hgb is > than 13g/dL, hold dose until Hgb falls below 12; then reinitiate with 25% reduction 2.25 µg / kg SC weekly OR 200µg SC every other week Darbepoetin alfa 150 units/kg SC three times a week OR 40000 units SC weekly Epoetin Alfa Source: National Oncology Alliance treatment Guidelines for Anemia; 2005

46. TREATMENT FAILURES NO FACTORS PREDICTIVE OF RESPONSIVENESS/UNRESPONSIVENESS ONE IS ENDOGENOUS ERYTHROPOIETIN LEVELS IF IT IS 1000 UNITS PER LITER OR GREATER SOME CLINICIANS WONT USE RHU EPO OTHERS USE 500 UNITS PER LITER AS THE CUT OFF POINT

47. MONITORING PARAMETERS Vit B 12 Folate Iron Hgb Reticulocytes Transferrin ferritin Monitored every four weeks once pt is begun on therapy

48. MONITORING PARAMETERS If Hgb rises too quickly; approx. 1g/dL during two weeks or exceeds 13g/dL; a dose reduction is warranted During clinical studies patient that had increases in Hgb of 1g/dL during two weeks were associated with an increased risk of neurologic events as seizures, cardiac events as cardiac arrest,, CHF, HTN, vascular thrombosis/ischemia/infarction/AMI, fluid overload, edema If Hgb fails to increase after 4-6 weeks of therapy, a dose increase is warranted

49. THE ADMINISTRATION OF IRON TO IMPROVE RESPONSE IV ADMINISTRATION OF IRON CAN BE ATTEMPTED IF THE TRANSFERRIN SATURATION IS 15% OR LESS, OR FERRITIN IS 100NG/ML OR LESS

50. SIDE EFFECTS SIDE EFFECTS ARE MINIMAL MEDULLARY BONE PAIN IS REPORTED MOST COMMONLY HYPERTENSION THAT DEVELOPS IN RENAL FAILURE PATIENTS BECAUSE OF THE INCREASED RED BLOOD CELLS DOES NOT OCCUR USUALLY IN CANCER PATIENTS