Colony-Stimulating Factors for Febrile Neutropenia during Cancer Therapy N ENGL J MED 2013;368: (Mar 21, 2013) Charles L. Bennett, M.D., Ph.D., Benjamin Djulbegovic, M.D., Ph.D., LeAnn B. Norris, Pharm.D., and James O. Armitage, M.D.. R3 변자민

INDEX I.The Clinical Problem II.Pathophysiology and Effect of Therapy III.Clinical Evidence IV.Clinical Use V.Adverse Effects VI.Areas of Uncertainty / Guidelines VII.Recommendations

CLINICAL PROBLEM F/55, past medical history: none Enlarged left axilary LN → diffuse large-B-cell lymphoma Test results -CBC, LFT, renal function, LDH: WNL -PET–CT: enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum -Bone marrow biopsy: normal 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (CHOP-R) at 21-day intervals planned Is the administration of prophylactic granulocyte colony-stimulating factor (G-CSF) with the first cycle of chemotherapy indicated?

PATHOPHYSIOLOGY & EFFECT OF TX Febrile neutropenia: 1)ANC less than 500/mm 3 2)Body temperature more than 38.5 ℃ Fever Leukopenia inducing endogenous cytokines Infection a)Lack of leukocytes (neutrophils) b)Mucositis (from chemoTx) c)Altered normal flora CSFs Antibiotics

Figure 1. Use of Hematopoietic Growth Factors in the Survival & Differentiation of Hematopoietic Cells

G-CSF … Support the survival and stimulates the proliferation of neutrophil progenitors Promote differentiation into mature cells Cause premature release of neutrophils from the marrow Enhance phagocytic capacity and generation of superoxide anions, and killing of bacteria Synergize with other hematopoietic growth factors

CLINICAL EVIDENCE 4 CSFs –G-CSF: filgrastim, lenograstim –Pegylated G-CSF: pegfilgrastim –GM-CSF: sargramostim Filgrastim (Approved in 1991 by FDA) –Phase 3 trial, 211 small-cell lung cancer patients receiving cyclophosphamide, doxorubicin & etoposide –Febrile neutropenia 40% vs. 76% (P < 0.001) –Median duration of gr4 neutropenia 3d vs. 6 d Pegfilgrastim (Approved in 2002 by FDA) –Phase 3 trial, 928 breast cancer patients receiving doxorubicin and docetaxel –Compatible with filgrastim 50% reduction in febrile neutropenia with primary prophylaxis

CLINICAL USE FilgrastimPegfilgrastim 5 μg/kg daily, s.c. until white cell count recovery 6 mg, s.c. one-time for each cycle 24 to 72 hrs after completion of chemoTx 24 hrs after completion of chemoTx CBC monitoring twice/weekNo monitoring indicated 300mg - $268 / 480mg - $427$ 2,838

Table 1. Risk of Febrile Neutropenia, According to the Type of Cancer & Chemotherapy Regimen – High Risk

Table 1. Risk of Febrile Neutropenia, According to the Type of Cancer & Chemotherapy Regimen – Intermediate Risk Not administered unless 1)More than 65 y.o 2)Major coexisting illness 3)Preexisting condition 4)Compromised marrow reserve from previous chemoTx or RTx

Curative intent, or chemoTx more efficacious at full dose → indicated! Palliative care → dose reduction preferred! Mobilization of peripheral blood progenitor cells → indicated! After chemoTx in acute leukemia → indicated! After autologous transplantation → indicated! After allogenic stem-cell transplantation → dose not indicated !

ADVERSE EFFECTS Injection site discomfort Constitutional symptoms (fever, malaise) Bone pain Rarely, spleen rupture AML or MDS? -Meta-analysis of 25 phase 3 trials: 22 vs. 43 patients developing AML or MDS (RR, 1.92; AR, 0.41 % points, P < 0.05) -US Research, German National Registry, European Group: no increased risk of AML among peripheral blood donors

AREAS OF UNCERTAINTY / GUIDELINES ASCONCCNEORTC CSFs be administered prophylactically if 1)The risk of febrile neutropenia is greater than 20% 2)Equally effective treatments that do not require CSF support are not available For intermediate group, consider: patient’s age, co-existing illness, etc Do NOT administer if 1)Patient is receiving concomitant RTx with chemotherapy 2)Patient had documented periods of afebrile neutropenia G-CSF, pegylated G-CSF, GM-CSFG-CSF, pegylated G- CSF

RECOMMENDATIONS F/55, past medical history: none Enlarged left axilary LN → diffuse large-B-cell lymphoma Test results -CBC, LFT, renal function, LDH: WNL -PET–CT: enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum -Bone marrow biopsy: normal 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (CHOP-R) at 21-day intervals planned Administration of G-CSF or pegylated G-CSF is not recommended with the first treatment cycle F/55, past medical history: none Enlarged left axilary LN → diffuse large-B-cell lymphoma Test results -CBC, LFT, renal function, LDH: WNL -PET–CT: enlarged lymph nodes with abnormal uptake in the left axilla, mediastinum, and retroperitoneum -Bone marrow biopsy: normal 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone with rituximab (CHOP-R) at 21-day intervals planned