Is your patient at risk for chemotherapy-induced neutropenia? A look at formalizing risk assessment

Transcription

1 Amgen sponsored symposium at the 2014 CAGPO Annual Meeting Is your patient at risk for chemotherapy-induced neutropenia? A look at formalizing risk assessment

2 Welcome Krista Noonan MD, FRCPC

3 Housekeeping Please complete the sign-in sheet that can be found in the centre of your table Before you leave, please complete the symposium evaluation form Touch pads will be used for the interactive workshop portion of the symposium If you have questions, please save these for the designated Question & Answer session. You can ask your question live using a microphone OR you can submit your written question using the Question Cards located in the centre of your table

4 Symposium Objectives Understand the clinical impact of chemotherapy-induced neutropenia and its complications Discuss the efficacy and safety of Granulocyte colony-stimulating factors (G-CSFs) in CIN Recognize patient-, disease-, and treatment-related risk factors for febrile neutropenia, and the need to formally assess patient risk

5 Agenda 12:45 12:50 PM Welcome 12:50 1:10 PM 1:10 1:30 PM Presentation Management of Neutropenia in Patients with Cancer Interactive Workshop Assessing Neutropenia Risk 1:30 1:40 PM Question & Answer Period 1:40 1:45 PM Closing Comments

6 Please use your touchpad Touchpad Question I currently manage patients with: a) Breast cancer b) Non-Hodgkin s lymphoma c) Both d) Neither 50.0% % 0.0% 0.0% A B C D Total: 2

7 Neutropenia Management Krista Noonan MD, FRCPC Medical Oncologist, H. Bliss Murphy Cancer Center Assistant Professor of Oncology, Memorial University

8 Program Objectives Understand the clinical impact of chemotherapy-induced neutropenia (CIN) and its complications Review the clinical practice guidelines for CIN management Discuss the efficacy and safety of G-CSFs in CIN

9 NCI CTCAE Grading System for Febrile Neutropenia Grade ANC (x 10 9 /L) 3 Grade 1 - Mild -- Grade 2 - Moderate -- Grade 3 - Severe ANC <1.0 x 10 9 /L with a single temperature of >38.3 C (101 F) or sustained temperature of 38 C (100.4 F) for >1 hour Grade 4 - Life-threatening, disabling Life-threatening consequences; urgent intervention indicated NCI = National Cancer Institute; CTCAE = common terminology criteria for adverse events Adapted from NCI CTCAE v

10 Impact of Chemotherapy-Induced Neutropenia Clinical Outcomes Quality of Life Economic Dose reductions 1 Risk of delay in chemotherapy cycle 1 Reduced relative dose intensity (RDI) 1 Infection 2 Treatment-related death 3 Hospitalization 2 Social isolation 1 Interference with life activities 1 Work, family Psychological distress 1 Hospitalization costs 2 Costs of additional care 2 Out-of pocket expenses 4 1. Lyman. Clin Cornerstone 2006;8:S Crawford et al. Cancer 2004;100: Kuderer et al. Cancer 2006;106: Fortner et al. BMC Cancer 2004;4:22.

11 Impact of Neutropenia on Dose Intensity Dose delay and reduction in early-stage breast cancer (n=436) 1 Reason for dose delays Reason for dose reductions Neutropenia Other causes 42% 58% 47% 53% Reductions in chemotherapy dose intensity may be associated with lower survival rates 2,3 1. Link et al. Cancer 2001;92: ; 2. Crawford et al. Cancer 2004;100: Chirivella et al. Breast Cancer Res Treat 2009;114:

12 Cumulative proportion surviving Cumulative proportion surviving Dose Intensity Should be Maintained to Achieve Maximal Benefit (Breast Cancer) Retrospective analysis of effect of RDI <85%* in breast cancer (n=793) Disease-free survival (n=790) Overall survival (n=791) 1,0 RDI <85% RDI 85% 1,0 RDI <85% RDI 85% 0,8 0,8 0,6 Adjusted HR = 1.57 (95%CI 1.06, 2.31) p= ,4 0, Years Years RDI = relative dose intensity *Adjuvant anthracycline-based non-taxane chemotherapy in early breast cancer patients HR adjusted for affected lymph nodes, stage and progesterone receptors Adapted from Chirivella et al. Breast Cancer Res Treat 2009;114: ,6 Adjusted HR = 1.45 (95%CI 0.90, 2.32) p=0.0055

13 Chemo Induced Neutropenia: Management Guidelines

14 Primary Prophylaxis with G-CSF: Summary of International Guidelines Primary prophylaxis with G-CSF 1 Neutropenic event risk ASCO EORTC NCCN Moderate to high Use G-CSF (~20%) Use G-CSF ( 20%) Use G-CSF (>20%) Intermediate Recommend G-CSF (<20%) Consider G-CSF (10-20%) Consider G-CSF (10-20%) Low Not specified G-CSF not recommended (<10%) G-CSF not recommended for most patients (<10%) Risk factor assessment Kouroukis et al. Curr Oncol 2008;15:9-23; 2. Smith et al. J Clin Oncol 2006;24:1-19; 3. Aapro et al. Eur J Cancer 2011;47:8-32; 4. Crawford et al. V

15 Combined Recommendations of 2006 ASCO & 2010 EORTC Guidelines: FN Risk Assessment STEP 1: Assess FN risk for the planned chemotherapy regimen The patient s FN risk should be routinely assessed prior to each chemotherapy cycle Dose-dense chemotherapy regimens should always be considered high risk for FN (FN risk 20%) Patients with NHL > 65 years old receiving curative chemotherapy should be considered at high risk of FN FN risk 20% FN risk 10 20% FN risk < 10% PROPHYLACTIC G-CSF RECOMMENDED High Risk Age 65 years (high risk) Increased Risk Advanced disease Previous episode of FN No antibiotic prophylaxis No G-CSF use STEP 2: Assess factors that may increase FN risk Other factors: Open wounds or active infections Poor performance and/or nutritional status Hemoglobin < 120 g/l Combined chemo-radiotherapy Cytopenias due to tumour bone marrow involvement Serious comorbidities Female gender Reassess at each cycle G-CSF USE NOT RECOMMENDED STEP 3: Define the patient's overall FN risk for planned chemotherapy regimen Overall FN risk 20% Overall FN risk < 20% This algorithm illustrates the combined recommendations of the 2006 ASCO and 2010 EORTC guidelines on the prophylactic use of G-CSFs. Adapted from 1. Kouroukis et al. Curr Oncol. 2008;15:9-23 and 2. Aapro et al. Eur J Cancer 2011;47:8-32

16 Commercial G-CSF Formulations G-CSFs are indicated to reduce the incidence of FN in patients receiving myelosuppressive anti-cancer drugs Pegylated G-CSF 1 G-CSF 2 Generic/brand Pegfilgrastim/Neulasta Filgrastim/NEUPOGEN Dosing 6 mg 5 µg/kg per day Administration Single injection 24 hrs after administration of chemotherapy Should not be administered <14 days before administration of chemotherapy Should be administered once per chemotherapy cycle Adverse events Medullary bone pain with pegfilgrastim (26%) similar to that seen with filgrastim, and greater than seen with placebo (23% vs. 16%) In clinical trials, most adverse events were attributed to the malignancy or its treatment Monitoring CBC and platelet count prior to chemotherapy; regular monitoring of hematocrit, WBC, and platelet count as clinically indicated 1. Neulasta Product Monograph, Amgen Canada Inc NEUPOGEN Product Monograph, Amgen Canada Inc Daily injections 24 hrs after chemotherapy for up to 14 days, until ANC 10 x 10 9 /L after nadir Should not be administered <24 h before administration of chemotherapy Medullary bone pain only AE consistently shown to be related to filgrastim (24%) In clinical trials, most adverse events were sequelae of malignancy or its treatment CBC and platelet count prior to chemotherapy and twice per week during filgrastim therapy

17 Meta-analysis of G-CSF Prophylaxis Relative risk (RR) of febrile neutropenia with primary G-CSF prophylaxis vs. no prophylaxis in patients with solid tumours or lymphoma (25 studies, n=5316) Treatment 1 Treatment 2 No. studies No. patients RR of FN (95% CI) P-value Pegfilgrastim No PP G-CSF ( ) Filgrastim No PP G-CSF ( ) < Pegfilgrastim Filgrastim PP G-CSF = primary prophylaxis with G-CSF ( ) 0.04 Adapted from Cooper et al. BMC Cancer 2011;11:404.

18 Patients (%) G-CSF Shown to Be Superior to Antibiotic Prophylaxis Alone in Preventing Neutropenia GEPARTRIO RCT in 1,256 patients with breast cancer receiving TAC Neutropenia grade 4 Febrile neutropenia CIP x days 5-14 (n=253) G-CSF x days 5-10 (n=374) PEG on day 2 (n=303) PEG+CIP (n=314) Pegfilgrastim +/- ciprofloxacin was significantly more effective than daily G-CSF or ciprofloxacin alone in preventing FN, grade 4 neutropenia, leukopenia & hospitalization for neutropenia CIP = ciprofloxacin; G-CSF = granulocyte-colony stimulating factor; PEG = pegfilgrastim *p<0.001 vs. CIP; p<0.01; p<0.001 vs. daily G-CSF Adapted form von Minckwitz et al. Ann Oncol 2008;19:292-8.

19 Patients (%) Summary of Reduction in Risk of FN with G-CSF in Real-World Settings Incidence of FN in real-world studies in women with breast cancer in Canada with and without G-CSF No G-CSF prophylaxis G-CSF prophylaxis p<0.001 p=not reported p=not reported p= ,4% 36,8% 36,5% 31% ,4% FEC-D (n=671) 1 FEC-D (n=127) 2 9,5% 1. Madarnas et al. Curr Oncol 2011;18:119-25; 2. Assi et al. J Clin Oncol 2011;29:E11520; 3. Rayson et al. Curr Oncol 2012;19:e216-8; 4. Altwairgi et al. Curr Oncol 2013;20:e Combined (FEC-D, FEC100, or TC) (n=79) 3 AC-T = doxorubicin, cyclophosphamide, paclitaxel; FN = febrile neutropenia; FEC-D = 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel; FEC100 = 5-fluorouracil, epirubicin, cyclophosphamide; TC = docetaxel, cyclophosphamide; TCH = docetaxel-platinum and trastuzumab 0% 14% Combined (FEC-D, AC-T, TC, or TCH) (n=239) 4

20 Patients (%) Summary of Reduction in Risk of FN with G- CSF in Real-World Settings Incidence of FN in real-world studies in women with breast cancer in Canada with and without G-CSF No G-CSF prophylaxis G-CSF prophylaxis p< p=not reported p< ,8% 38% 32% ,4% TC (n=89) 1 TC (n=134) 2 4,2% TC (n=340) 3 1% FN = febrile neutropenia; TC = docetaxel, cyclophosphamide 1. Myers et al. 32nd SABCS, San Antonio, TX, 2009; 2. Younus et al. Curr Oncol 2012;19:332-4; 3. Yu et al. CAMO 2013

21 Prophylactic CSF Use Reduced Febrile Neutropenia Rate, Hospitalization Risk, and Antibiotic Use Cochrane analysis of 8 RCTs comparing CSFs with placebo or no treatment in patients with breast cancer (n=2156) Benefits Pooled risk ratio (95% CI) NNT FN rate 0.27 (95% CI )* 12 Early mortality (attributed to progression) 0.32 (95% CI )* 79 Hospitalization risk 0.14 (95% CI )* 13 Intravenous antibiotic use 0.35 (95% CI )* 18 Infection-related mortality 0.14 (95% CI ) - Risks Pooled risk ratio (95% CI) NNH Bone pain 5.88 (95% CI ) 3 Injection-site reactions 3.59 (95% CI ) 3 CSF = colony stimulating factor; FN = febrile neutropenia; NNT = number needed to treat; NNH = number needed to harm; RR = risk ratio; *Statistically significant reduction; Finding based on 23 fatal events in 2143 patients; wherein 19 of these 23 events occurred in one study and 17 events attributed to progression of disease by study authors Renner et al. Cochrane Database Syst Rev 2012;10:CD

22 Safety Issues: Toxicities Associated with G-CSFs Acute toxicity 1 Bone pain (25-30%) Headache Fatigue Nausea Myalgia Insomnia Fever Anorexia Cutaneous toxicity 1 Injection site reactions Generalized de novo toxicities (rare) Exacerbation of pre-existing cutaneous inflammatory disorders (rare) Pulmonary toxicity 1 Insufficient evidence of correlation to CSFs Leukemogenicity 1 Data from dose-dense trials and hematology reports not conclusive Higher rates have been related to higher doses of genotoxic drugs Splenic rupture 2,3 Patients with left upper abdominal and/or shoulder tip pain should be evaluated for an enlarged spleen or splenic rupture Allergic reactions 2,3 Allergic-type reactions, including anaphylaxis, skin rash, urticaria and erythema/flushing with initial or subsequent treatment have been reported 1. Kouroukis et al. Curr Oncol 2008;15:9-23; 2. Neulasta Product Monograph, Amgen Canada Inc. 2012; 3. NEUPOGEN Product Monograph, Amgen Canada Inc. 2013

23 Bone Pain Associated with G-CSFs Incidence of bone pain analysis of G-CSF studies 1 Any bone pain Grade 3/4 PEG vs. FIL (7 trials, n=731) PEG vs. no G-CSF (5 trials, n=2223) FIL = filgrastim; PEG = pegfilgrastim 62.3% (95% CI 57.2, 67.2) 66.1% (95% CI 60.9, 71.0) 32.7% (95% CI 30.0, 35.6) 23.0% (95% CI 20.6, 25.7) 6.6% (95% CI 4.3, 9.6) 7.9% (95% CI 5.3, 11.2) 3.4% (95% CI 2.4, 4.6) 2.0% (95% CI 1.3, 3.0) Generally mild-to-moderate in severity 2,3 Controlled in most patients with non-narcotic analgesics 3 <6% required narcotic analgesics 2 1. Gregory et al. Commun Oncol 2010;7: Neulasta Product Monograph, Amgen Canada Inc NEUPOGEN Product Monograph, Amgen Canada Inc

24 Economic Analysis of Prophylactic Pegfilgrastim in Breast Cancer Objective Compare cost-effectiveness of pegfilgrastim single-dose with filgrastim 6 and 11 days per cycle as primary prophylaxis against FN in Stage-II breast cancer patients from a Canadian health service payer perspective Study population Women 50 years of age (range 30-80) with breast cancer receiving 4-8 cycles of chemotherapy with approximately 20% risk for FN Study perspective Payer in Canada (insurance company, public payer) Model time horizon Life time (from time of starting chemotherapy to death) Analysis type Cost-utility (cost per quality-adjusted life-year (QALY) saved) De Angelis et al. IXth World Conf Clin Pharmacol Ther, Quebec, 2008.

25 Pegfilgrastim is a Cost-Effective Option in Breast Cancer Pegfilgrastim more effective and less expensive vs. 11-day filgrastim Lowered costs by $1,725 Prophylaxis strategy Cost (CAN$) Pegfilgrastim primary prophylaxis $10,229 Filgrastim primary prophylaxis (11-day) $11,954 Difference -$1,725 QALY = quality-adjusted life-year Incremental cost-effectiveness ratio (cost/qaly): pegfilgrastim dominant strategy (i.e., less costly and more effective) Adapted from De Angelis et al. IXth World Conf Clin Pharmacol Ther, Quebec, 2008.

26 Pegfilgrastim is a Cost-Effective Option in Breast Cancer Pegfilgrastim more effective but more expensive vs. 6-day filgrastim Costs $2,953 more, but remains cost effective Prophylaxis strategy Cost (CAN$) Pegfilgrastim primary prophylaxis $10,229 Filgrastim primary prophylaxis (6-day) $7,276 Difference $2,953 QALY = quality-adjusted life-year Incremental cost-effectiveness ratio (cost/qaly): pegfilgrastim $31,415/QALY Adapted from De Angelis et al. IXth World Conf Clin Pharmacol Ther, Quebec, 2008.

27 Monitoring and Reporting A Collaborative Approach Teach daily monitoring practices, for example: Examine mucous membranes Look for other subtle signs of infection Educate patient and family about signs and symptoms Teach patients about the importance of prompt reporting of suspicious symptoms: Temperature >38.0ºC Shaking chills Dysuria Dyspnea Respiratory congestion Pain Eggenberger et al. Clin J Oncol Nurs 2004.

28 Summary Guidelines recommend G-CSFs in patients at risk Recommended when FN risk is 20% Consider if FN risk <20% if additional risk factors G-CSF use has demonstrated efficacy and safety in patients with cancer undergoing chemotherapy incidence of febrile neutropenia rate of dose delays/reductions hospitalization for FN use of IV antibiotics Short-term side effects are generally mild to moderate Most common adverse event is bone pain

29 Interactive Workshop Assessing Neutropenia Risk

30 Febrile Neutropenia Risk Assessment Guide Web-based platform accessible via computer or tablet Assists healthcare practitioners in assessing the risk of FN Integrates multiple guidelines and data sources Developed for two disease types: breast cancer & non-hodgkin s lymphoma Two modes of functionality: User & Editor Today we will focus on the User mode

31 Development Faculty Breast Cancer Dr. Susan Dent Dr. Jean Dufresne Dr. Christine Simmons Non-Hodgkin s Lymphoma Dr. John Kuruvilla Dr. David MacDonald Dr. Laurie Sehn

32 Neutropenia Case Study 1 Breast Cancer (Node +ve) Treated with AC-T (weekly)

33 Breast Cancer Case: Presentation Patient profile R.H. 48 year old Asian female; primary school teacher; married with 2 grown children Menarche: 14 y, 1st pregnancy: 23 y Peri-menopausal Presentation Palpable lump Clinical exam: 2.0 cm mass in right breast; 1 palpable LN in axilla LN = lymph node

34 Breast Cancer Case: Workup Surgery Lumpectomy Axillary lymph node dissection Pathology 2.7 cm, infiltrating ductal carcinoma, grade 3, clear margins 2/12 nodes involved ER+/PR-/HER 2 negative Staging Bone scan, chest x-ray, ultrasound abdomen: no evidence of metastasis ER/PR = estrogen receptor/progesterone receptor Diagnosis: breast cancer, stage IIB T2N1M0

35 Case: Discussion 4 The patient begins treatment with AC-T (weekly) AC q3wk x 4, then T q1wk x 12 Please use your touchpad Q. Do you think the chemotherapy regimen puts this patient at high risk (>20%) for FN? A. Yes B. No Yes 0.0% (0) No 100.0% (2) AC-T = doxorubicin, cyclophosphamide, paclitaxel Total: 2

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39 Risk of FN with AC-T Regimens in Prospective Trials EORTC guidelines categorize dose-dense AC-T as high risk (>20%) 1 AC-T regimen Dose dense AC q2wk x 4, then T q2wk x 4 Weekly AC q3wk x 4, then T q1wk x 12 q3wk AC q3wk x 4, then T q3wk x 4 Febrile neutropenia (or infection) % *Some patients may have received PP G-CSF AC-T = doxorubicin, cyclophosphamide, paclitaxel; FN = febrile neutropenia Reference 2% with G-CSF support Citron % with G-CSF support Burstein % Sparano (11%)* Henderson % Citron % Mamounas <1% Sparano Aapro et al. Eur J Cancer 2011;47:8 32; 2. Citron et al. J Clin Oncol 2003;21:1431-9; 3. Burstein et al. J Clin Oncol 2005;23:8340-7; 4. Sparano et al. NEJM 2008;358: ; 5. Henderson et al. J Clin Oncol 2003;21:976-83; 6. Mamounas et al. J Clin Oncol 2005;23:

40 Breast Cancer Case: Additional Patient Information Patient profile Height: 1.6 M, weight: 50 kg, BMI: 19.5 Medical history Used birth control pill until age 42 y Family history of breast cancer (maternal aunt) Comorbid COPD, managed with ICS BMI = body mass index; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroid

41 Case: Discussion Risk factors present Female Comorbid COPD Chemotherapy cycle (1 st cycle) Poor nutrition

42 Case: Discussion 8 Q. Considering both the chemotherapy regimen and additional patient factors, do you think this patient is at high risk (>20%) for FN? Please use your touchpad A. Yes B. No 100.0% 0.0% Yes 2 Total: 2 No 0

43 Odds ratio Increasing Number of Comorbidities Associated with Increasing FN Risk Multivariate analysis of the impact of comorbidities on the risk of FN in patients with various cancer types (n=63,033)* (95% CI ; p=0.02) 1.13x greater risk (95% CI ; p<0.001) No. of comorbidities at diagnosis *Final sample included patients with breast, lung, prostate, or colorectal cancer FN = febrile neutropenia 1.39x greater risk (95% CI ; p<0.001) 1.81x greater risk Hosmer et al. Support Care Cancer 2011;19:333-41

44 Patients with FN (%) FN Risk Varies According to Age and Comorbidities Incidence of FN according to age and comorbidities among women with early-stage breast cancer receiving TC at London RCP in Ontario (n=134) Overall 20% of patients developed FN (n=27/134) Primary G-CSF prophylaxis: 4.2% (n=3/71) NO G-CSF: 38% (n=24/63) 60 FN rate in all patients % 15% 23% 29% 0 (n=41) (n=40) (n=22) (n=31) <65 y, no comorbidity <65 y + comorbidity 65 y, no comorbidity 65 y + comorbidity *Only 3/71 patients given primary prophylaxis with G-CSF developed FN FN = febrile neutropenia; TC = docetaxel 75 mg/m 2 + cyclophosphamide 600 mg/m 2 every 3 weeks for 4 cycles Younus et al. Curr Oncol 2012;19:332-4.

45 Odds ratio Comorbidities Associated with Increased Risk of Grade 4 Neutropenia Impact of comorbidities on incidence of grade 4 neutropenia in patients with breast cancer (n=444) 8 Categorically defined as the presence vs. the absence of the comorbid condition Liver impairment* 4.38x greater risk 2.29x (95% CI ; p=0.021) (95% CI ; p=0.007) Vascular comorbidity greater risk *As defined by baseline bilirubin >17.1 μmol/l Schwenkglenks et al. Support Care Cancer 2011;19:483-90

46 Odds ratio Comorbidities Associated with Poorer Outcomes of FN Univariate analysis of the impact of comorbidities on risk of complications* in patients with FN (n=746) 8 6 Categorically defined as the presence vs. the absence of the comorbid condition (95% CI ; p<0.001) Klastersky et al. J Clin Oncol 2000;18: x greater risk (95% CI ; p=0.003) 4.10x greater risk (95% CI ; p=0.01) Diabetes COPD Cardiac disease *Complications: death or a serious medical complication (e.g., hypotension, respiratory failure, intensive care unit admission, disseminated intravascular coagulation, altered mental state, congestive cardiac failure, bleeding requiring transfusion, arrhythmia, renal failure requiring investigation or treatment, but not viral or fungal infection) Active chronic bronchitis, emphysema, decrease in forced expiratory volumes, and need for oxygen therapy, corticosteroids, and/or bronchodilators; Ischemic heart disease or congestive heart failure; COPD = chronic obstructive pulmonary disease; FN = febrile neutropenia 2.62x greater risk

47 Case: Discussion Q. Do you think this patient is a candidate for G-CSF primary prophylaxis? A. Yes B. No 50.0% % Please use your touchpad Yes 1 Total: 2 No 1

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51 What If? Q. What if her chemotherapy regimen was FEC-D? Do you think this would impact her risk for FN? A. Yes, patient would likely be at high risk B. No, risk level would not change % Please use your touchpad 0.0% Yes FEC = 5-fluorouracil + epirubicin + cyclophosphamide + docetaxel 0 Total: 2 No 2

52 Patients with FN (%) 1. Aapro et al. Eur J Cancer 2011;47:8 32; 2. Roche et al. J Clin Oncol 2006;24: ; 3. Martin et al. J Natl Cancer Inst 2008;100:805-14; 4. Levine et al. J Clin Oncol 1998;16: Risk of FN with FEC or FEC-D in Randomized Clinical Trials EORTC guidelines categorize FEC-D and FEC as intermediate risk (10-20%) No PP G-CSF use 10 11,2% 8,4% 9.5% 8,5% 0 FEC-D (n=1003) Roche FEC (n=996) Roche FEC (n=632) Martin FEC (n=351) Levine FEC = fluorouracil, epirubicin, cyclophosphamide; FEC-D = 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel; FN = febrile neutropenia

53 Patients with FN (%) 1. Aapro et al. Eur J Cancer 2011;47:8 32; 2. Madarnas et al. Curr Oncol 2011;18:119-25; 3. Assi et al. J Clin Oncol 2011;29:E11520; 4. Rayson et al. Curr Oncol 2012;19:e216-8; 5. Raza et al. Curr Oncol 2009;16:8-12; 6. Altwairgi et al. Curr Oncol 2013;20:e171-9 Risk of FN with FEC-D in Real-World Clinical Practice EORTC guidelines categorize FEC-D as intermediate risk (10-20%) 1 80 No G-CSF prophylaxis G-CSF prophylaxis 60 p<0.001 p=not reported p=not reported p=not reported p= ,4% ,4% 6,4% Ontario Madarnas 2011 (n=671) 2 36,8% 9,5% New Brunswick Assi 2011 (n=127) 3 0% Nova Scotia Rayson 2012 (n=37) 4 23,4% *G-CSF use limited to patients with documented FN and none of the patients were treated with G-CSF primary prophylaxis; 88% received FEC-D; FEC-D = 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel; FN = febrile neutropenia N/A* Ontario Raza 2009 (n=98) 5 27% 12% Ontario Altwairgi 2013 (n=239) 6

54 Patients with FN (%) Risk of FN with FEC-D in Real World Clinical Practice EORTC guidelines categorize FEC-D as intermediate risk (10-20%) 1 Incidence of any-cycle* FN in meta-analysis of 9 real-world studies (n=1342) ,6% 20 63% reduction (RRR=0.37, 95% CI , p<0.0001) 9,1% 0 No G-CSF prophylaxis G-CSF prophylaxis *Majority of FN events occurred during the first docetaxel-based cycle; FEC-D = 5-fluorouracil, epirubicin, cyclophosphamide, docetaxel; FN = febrile neutropenia; RRR = relative risk reduction 1. Aapro et al. Eur J Cancer 2011;47:8 32; 2. Younis et al. Support Care Cancer 2012;20:

55 Case: Discussion Q. Do you think this patient is a candidate for G-CSF primary prophylaxis? 50.0% 50.0% A. Yes B. No 10 Please use your touchpad Yes 1 Total: 2 No 1

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59 Neutropenia Case Study 2 NHL Diffuse Large B-Cell Treated with R-CHOP

60 NHL Case: Presentation Patient profile P.F. 61 year old male, retired golf pro, gives lessons 4-6 hrs/wk Married with 3 grown children Non-smoker, non-drinker Treatment regimen Beginning 1 st cycle of R-CHOP-21 Diagnosis: diffuse large B-cell lymphoma, stage IVB R-CHOP = cyclophosphamide + doxorubicin + vincristine + prednisone + rituximab

61 Case: Discussion Q. Do you think the chemotherapy regimen (R-CHOP-21) puts this patient at high risk (>20%) for FN? A. Yes B. No 50.0% % Please use your touchpad Yes 1 Total: 2 No 1

62 1. Aapro et al. Eur J Cancer 2011;47:8-32; 2. Coiffier et al. N Engl J Med 2002;346:235-42; 3. Rituxan Product Monograph, 2013; 4. Watanabe et al. J Clin Oncol 2011;29:3990-8; 5. Blayney et al. J Clin Oncol 2003;21:2466-7; 6. Pfreundschuh et al. Lancet Oncol 2008;9: Risk of FN with CHOP/R-CHOP in Clinical Trials EORTC guidelines categorize CHOP-21 as high risk (>20%) and R-CHOP-21 as intermediate risk (10-20%) 1 Regimen CHOP-21/R-CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab) CHOP-14/R-CHOP-14 (cyclophosphamide, doxorubicin, vincristine, prednisone ± rituximab) R-CHOP CHOP Grade 3/4 neutropenia 97% 88% FN (grade 3-5 infection) Reference 22.8% (12%) 24% (20%) Coiffier 2,3 R-CHOP 97% 15%* Watanabe 4 R-CHOP 68% with G-CSF 7% with G-CSF Watanabe 4 CHOP 90% with G-CSF (19%) with G-CSF Blayney 5 R-CHOP 52% with G-CSF (28%) with G-CSF CHOP 48% with G-CSF (29%) with G-CSF Pfreundschuh 6 *40% of patients received G-CSF in accordance with guidelines; Grade 4 leucocytopenia FN = febrile neutropenia

63 Patients with FN (%) 1. Aapro et al. Eur J Cancer 2011;47:8-32; 2. Gerlier et al. BMC Cancer 2010;10:642; 3. Pettengell R, et al. Support Care Cancer 2008;16: ; 4. Pettengell et al. Support Care Cancer 2012;20: Risk of FN with R-CHOP Regimens in Real-World Studies EORTC guidelines categorize R-CHOP-21 as intermediate risk (10-20%) % No PP G-CSF Some PP G-CSF use PP G-CSF % 22% 17% 19% 20% PP G-CSF use 0% 100% 22% 31% 36% 84% 0 NHL Regimens Gerlier (n=39) 2* 33% R-CHOP R-CHOP-21 R-CHOP-14 Pettengel 2008 (n=178 & 41) 3 INC-EU R-CHOP-21 R-CHOP-14 Pettengel 2012 (n=702 & 409) 4 IMPACT-NHL *Mainly R-CHOP-21 (33%), R-ACVBP-14 (15%), CHOP-21 (8%) FN = febrile neutropenia; PP = primary prophylaxis; R-CHOP = rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone

64 NHL Case: Presentation Medical history CAD triple CABG 3 years ago Hypertension controlled with ACE inhibitor Type 2 diabetes mellitus controlled with glyburide Physical examination Performance status: ECOG 1 BP: 120/85 mm Hg Hepatosplenomegaly, paracervical, submandibular, axillary, and inguinal lymphadenopathy BP = blood pressure; CAD = coronary artery disease; CABG = coronary artery bypass graft; ECOG = Eastern Cooperative Oncology Group

65 NHL Case: Workup Clinical and laboratory assessments Lab tests Hb WBC ANC ALP AST Creatinine PLT LDH Result (normal values) 110 ( g/l) 7.0 (4-10 x 10 9 /L) 2.4 ( x 10 9 /L) 74 ( U/L) 60 (<50 U/L) 108 (45-90 μmol/l) 98 ( x 10 9 /L) 384 ( U/L) ALP = alkaline phosphatase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; Hb = hemoglobin; LDH = lactate dehydrogenase; PLT = platelet; WBC = white blood cell

66 Case: Discussion Risk factors present Comorbid cardiovascular disease Comorbid diabetes Baseline cytopenias Chemotherapy cycle (1 st cycle)

67 Case: Discussion Q. Considering both the chemotherapy regimen and patient factors, do you think this patient is at high risk (>20%) for FN? A. Yes B. No 50.0% % Please use your touchpad Yes 1 Total: 2 No 1

68 Case: Discussion Q. Do you think this patient is a candidate for G-CSF primary prophylaxis? A. Yes B. No 100.0% 15 Please use your touchpad 0.0% Yes 2 Total: 2 No 0

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74 What If? Q. What if the patient was 65 years old? Do you think this would impact his risk for FN? A. Yes, patient would likely be at high risk B. No, risk level would not change 15 Please use your touchpad 0.0% 0.0% Yes 0 Total: 0 No 0

75 Patients with FNH (%) Age 65 y Associated with Increased FN Risk Hospitalized FN rates according to age in a retrospective analysis of 1355 patients with NHL 40 p< % 1.79x greater risk* 13.3% 0 65 y (n=619) <65 y (n=736) *Hazard ratio of 1.79 determined with fixed multivariate model of 1186 patients (95% CI ; p<0.001); FNH = febrile neutropenia (hospitalized); NHL = non-hodgkin s lymphoma Lyman, Delgado. Cancer 2003;98:2402-9

76 Cumulative probability of FNH Age 65 y Associated with Increased FN Risk Cumulative probability of hospitalized FN according to age in retrospective survey of 1355 patients with NHL 0,40 0,35 0,30 0,25 0,20 0,15 0,10 0,05 0,00 <65 65 Lyman, Delgado. Cancer 2003;98: Time (days) *Hazard ratio of 1.79 determined with fixed multivariate model of 1186 patients (95% CI ; p<0.001); FNH = febrile neutropenia (hospitalized); NHL = non-hodgkin s lymphoma 1.79x greater risk* 65 y vs. <65 y

77 Estimated risk of FN (%) Older Age Associated with Increased FN Risk Estimated risk of FN following R-CHOP in an 80 kg patient with NHL based on risk model % Any cycle Cycle 1 5% 8% 14% 1% 1% *Multivariate analysis based on data from 240 patients with NHL FN = febrile neutropenia; NHL = non-hodgkin s lymphoma Pettengell et al. Br J Haematol 2009;144: Age (years) 22% 3% 34% 6% 2.20x greater risk per additional 10 y for cycle 1*

78 Case: Discussion Risk factors present Comorbid cardiovascular disease Comorbid diabetes Baseline cytopenias Chemotherapy cycle (1 st cycle) Age 65 years

79 Case: Discussion Q. Do you think this patient is a candidate for G-CSF primary prophylaxis? 100.0% A. Yes B. No 15 Please use your touchpad 0.0% Yes 2 Total: 2 No 0

80 Febrile Neutropenia Risk Assessment Guide

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83 Questions from the Audience

84 Housekeeping Please complete the symposium evaluation form and sign-in sheet before you leave If you would like access to the FN Risk Assessment Guide, please be sure to provide your address on the evaluation form Please remember to leave your touchpads on the table

85 THANK YOU