White blood cell growth factors (G/GM-CSF) A practice guidelines Prof. Dr. Khaled Abouelkhair, PhD Medical Oncology SCE, Royal College, UK Ass. Professor of Clinical Oncology Mansoura University, Egypt

Review Questions In Haemolysis what do you expect levels of Haptoglobin, Reticulocytes and LDH to be? In Haemolysis what do you expect levels of Haptoglobin, Reticulocytes and LDH to be? Which test is used to differentiate between Immune mediated and non immune mediated haemolysis? Which test is used to differentiate between Immune mediated and non immune mediated haemolysis? What are common causes of Macrocytic Anaemia? What are common causes of Macrocytic Anaemia? What are the causes of Microcytic Hypochromic ? What are the causes of Microcytic Hypochromic ?

Precautions of CSF Adult respiratory distress syndrome, specifically in neutropenic patients with sepsis Allergic-type reactions Avoid the simultaneous use of chemotherapy and radiation therapy with filgrastim; DO NOT administer within 24 hours before or after cytotoxic chemotherapy Possible growth stimulation of tumors!!! Leukocytosis (monitoring twice weekly recommended) in therapeutic use. Bleomycin containing regimens!!!!

Precautions of CSF Myelodysplastic syndrome or acute myeloid leukemia development when used in patients with congenital neutropenia PBPC mobilization (data inconclusive) Risk of development of myelodysplastic syndrome or acute myeloid leukemia when used in patients with congenital neutropenia Sickle cell disease, severe sickle cell crisis (some resulting in death) Splenic rupture, some fatal

How to Practice?

Goal of G-CSF Overall survival Response rate Treatment related mortality Antibiotics course and hospital days WBC count Placebo for the patient, family, and doctors

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

Primary prophylaxis Primary prophylaxis is 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.

In 2012 guidelines, CSF is recommended in FN risk > 20% as primary prophylaxis. Adjust the risk to >20% …… CSF reduced incidence of FN (1% vs 17%) and hospitalization for FN(1%vs 14%) for breast cancer patient receiving Docetaxel 100mg/m 2 q3wk Meta-analysis in lymphoma showed CSF significantly reduced the relative risk of severe neutropenia (RR 0.67), febrile neutropenia (RR 0.74), and infection (RR 0.74). No benefit on the patients requiring intravenous antibiotics, infection-related mortality, complete tumor response, freedom from treatment failure, or overall survival

CSF reduce the incidence of FN when the rate is approximately 20%. When available, alternative regimens offering equivalent efficacy, but not requiring CSF support, should be utilized. Adjustment according to patient’s co- morbidity and general conditions, which make the patient unlikely to be enrolled in clinical trials.

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. In breast cancer adjuvant therapy, G-CSF recipients experienced fewer episodes of hospitalization for FN and greater dose-intensity compared to historical controls.

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-intense) regimens 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. NHL CHOP-14 better than CHOP-21 CHOEP-14 better than CHOEP-21? R-CHOP -21 vs CHOP-14?

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 cells In allogeneic transplantation, CSF may increase the incidence of severe GVHD and reduce survival. AML Use of CSFs for priming effects is not recommended. CSF use following initial induction therapy is reasonable, but no impact on remission rate, remission duration, or survival CSF use is recommended after completion of consolidation

Type of CSF, dosage, duration CSF should be given hrs after myelotoxic chemotherapy. G-CSF, Filgrastim, (NEUPOGEN) : 5μg/kg/day GM-CSF, Sargramostim, (LEUKINE): 250μg/m 2 /day Pegylated G-CSF, Long acting G-CSF, Pegfilgrastim (NEUOLASTA): 6mg once G-CSF vs GM-CSF in equivalency: no comment Pegylated G-CSF shouldn’t be use for stem cell mobilization.

Bone pain The commonest side effect The commonest side effect NSAIDS NSAIDS Antihistamines Antihistamines Reduce total days Reduce total days

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. Using Steroids is not advised as falsely increase granulocytes, Lymphopenia and suppress immunity.

A patient with lymphoma excretes 1.5g urinary protein but has a negative dipstick test. The reason for this seeming inconsistency is: A. The molecular weight of the excreted protein is too low to be detected by dipsticks B. Tamm-Horsfall proteins block the reaction of the secreted protein and the dipstick C. Dipsticks preferentially detect albumin rather than immunoglobulin because albumin is negatively charged D. Dipsticks only recognize heavy chain sequences. E. The urine is not sufficiently concentrated