Pettengell, R

Schwenkglenks, M

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LETTER TO THE EDITORIncidence of neutropenia, chemotherapy delivery, and use ofcolony-stimulating factor in patients with non-Hodgkin lymphomaof different age groupsRUTH PETTENGELL1* & MATTHIAS SCHWENKGLENKS2*1Cellular and Molecular Medicine, St. George’s University of London, London, UK and 2Institute of Pharmaceutical Medicine,University of Basel, Basel, Switzerland(Received 1 July 2010; revised 10 January 2011; accepted 11 January 2011)Chemotherapy regimens used to treat non-Hodgkinlymphoma (NHL), such as cyclophosphamide, dox-orubicin, vincristine, and prednisone (CHOP), withor without rituximab, are associated with a high(20%) risk of febrile neutropenia (FN) [1]. Olderage is an additional risk factor for FN [1,2], andexisting comorbidities increase FN-associated mor-tality [3].Neutropenic complications are potentially life-threatening [4] and represent the most frequentdose-limiting toxicity of myelosuppressive che-motherapy [1,5], often resulting in treatment delaysand dose reductions [6]. For low relative doseintensity (RDI), which is especially common amongolder patients with NHL [7], an association withpoorer outcomes has been reported [8], emphasizingthat when a curative regimen has been selected andplanned, there should be as little deviation from theplanned dose intensity as possible. Colony-stimulat-ing factors (CSFs) have been shown to reduce theincidence and severity of neutropenic events across abroad range of malignancies and regimens, support-ing the delivery of full chemotherapy dose intensity[1,5,9].The Impact of Neutropenia in Chemotherapy –European Study Group (INC-EU) prospective,observational study previously reported the incidenceand risk of chemotherapy-induced neutropenia(CIN), FN, and dose modifications in patients withbreast cancer and lymphoma [10]. In comparison topatients with breast cancer, those with lymphomaexperienced higher incidences of FN and grade IVneutropenia. Here we present results from a sub-analysis of patients with NHL, assessing the impactof age on the frequency of neutropenic events,chemotherapy delivery, and CSF use.The INC-EU prospective, observational studyenrolled 749 patients with breast cancer or lympho-ma initiating a new course of chemotherapy during2004–2005, recruited from 66 clinical centers inBelgium, France, Germany, Spain, and the UK [10].Inclusion and exclusion criteria for this study havebeen previously reported in detail [10]. For thissubgroup analysis, patients with NHL (n¼ 240) weredivided into three age groups: 60 years (n¼ 84),61–70 years (n¼ 77), and 470 years (n¼ 79). Theprimary outcome measure was incidence of CIN;secondary outcome measures were incidence of FN,patterns of chemotherapy delivery (dose delays/reductions, RDI, and non-completion), and use ofCSFs and risk of death (in the presence and absenceof FN). Grade IV neutropenia was defined as anabsolute neutrophil count (ANC) 50.56 109/L andFN as grade IV neutropenia and temperature 388C.CSF use was defined as primary prophylaxis (CSFuse in the first cycle before a documented gradeIII–IV CIN occurred or denoted as primary prophy-laxis by study site) or reactive use (secondary CSFprophylaxis in cycles other than the first, or CSFused as treatment). Baseline, treatment, and out-come parameters were summarized by age group andcompared. The temporal relationship of dose delaysCorrespondence: Ruth Pettengell, St. George’s University of London, Cellular and Molecular Medicine, Cranmer Terrace, London SW17 0RE, UK.Tel: þ44(20)8725-5454. Fax: þ44(20)8725-0158. E-mail: rpetteng@sgul.ac.uk*On behalf of the Impact of Neutropenia in Chemotherapy – European Study Group (INC-EU).There is an accompanying commentary that discusses this paper. Please refer to the issue Table of Contents.Leukemia & Lymphoma, June 2011; 52(6): 1133–1136ISSN 1042-8194 print/ISSN 1029-2403 online  2011 Informa UK, Ltd.DOI: 10.3109/10428194.2011.555023with episodes of grade IV CIN and FN was assessed.Causes of death and treatment discontinuation in thehighest age group were evaluated on a patient-by-patient basis.Baseline characteristics were comparable betweengroups, except for parameters known to vary with age(Table I). The incidence of cardiovascular andcardiac comorbidities, lactate dehydrogenase 4500IU/L, and glucose 4160 mg/dL (8.8 mmol/L)increased with age, and the glomerular filtrationrate decreased with age. In addition, the proportionof female patients increased with age.The majority of patients received CHOP, eitheron a 3-weekly (74%) or 2-weekly (17%) schedule.The proportion of patients with 2-weekly CHOPincreased with age (8%, 17%, and 27% of patientsaged 60, 61–70, and 470 years, respectively). Formost patients, six cycles of chemotherapy wereplanned across all age groups. In the 60, 61–70,and 470 year-old groups, 83%, 83%, and 79% ofpatients, respectively, received rituximab.Grade IV CIN and FN occurred frequently in allage groups. Overall, 54% of patients experiencedgrade IV CIN; there was a trend toward an increasedincidence with age [Figure 1(A)]. Twenty-twopercent of patients developed FN in any cycle; theincidence did not increase with age [Figure 1(B)].The relative risk (RR) of death for patients whoexperienced FN in any cycle, versus those without FN,was 1.7 for the younger age groups combined (95%confidence interval [CI] 0.2–18.6; p¼ 0.535). Forpatients 470 years, the RR was 10.9 (95% CI 2.4–49.4; p¼ 0.001), suggesting that although the inci-dence of FN did not increase with age, patients in thisage group were at increased risk of death from FN.Overall, 28% of patients received primary CSFprophylaxis and 29% of patients required other CSFuse. Use of daily CSF (filgrastim) was highest inpatients aged 61–70 years; pegfilgrastim was usedmost frequently in patients 470 years. The propor-tion of patients receiving primary CSF prophylaxiswas comparable across all age groups (24%, 29%,and 30% of patients aged 60, 61–70, and 470years, respectively). Reactive CSF use was seenfrequently and to a similar extent in each age group(32%, 25%, and 29% of patients aged 60, 61–70,and 470 years, respectively).Patients in the oldest age group were less likely tocomplete their planned treatment: 27% of patients470 years did not complete their planned che-motherapy, as compared to 19% and 14% of patientsaged 60 and 61–70 years, respectively. Of the non-completers 470 years, 48% discontinued due toadverse events, 38% died, and 14% withdrewconsent or were discontinued due to non-compli-ance. In this age group, 90% of adverse eventsleading to discontinuation and 88% of deathsinvolved CIN, FN, or infection.The occurrence of dose delays, dose reductions,and RDI 85% is shown in Figure 1(C). Theproportion of patients with dose delays 4 daysincreased with age. Figure 1(D) shows the propor-tion of dose delays that occurred in the absence ofneutropenic events, after grade IV CIN, or after FN.With increasing age, a greater proportion of patientsexperienced dose delays in the absence of neutrope-nia, and in the presence of grade IV CIN withoutFN. The proportion of patients with dose reductions10% was comparable across age groups. RDI85% occurred in 30% of patients overall, and wasmost frequent in patients 470 years (almost 40% ofthis group) [Figure 1(C)].The high incidence of RDI 85% in patients 470years appears to have been driven by an increasednumber of dose delays in these patients, which mayhave protected against FN, possibly explaining whyFN rates in this group were not higher than theoverall average. This potential protective effect ofdose delays was not attributable to pre-planneddecreases in RDI, which would have been recordedseparately, as per study protocol.Although rates of FN were similar across agegroups, myelosuppression impacted most strongly onTable I. Patient and disease characteristics.Characteristic60 years(n¼ 84)61–70 years(n¼ 77)470 years(n¼ 79)Age in years:mean+SD49.0+ 9.5 65.9+ 3.1 75.9+ 4.4Female gender: pts (%) 28 (33.3) 33 (42.9) 44 (55.7)Body surface area*:mean+SD1.89+ 0.19 1.84+ 0.16 1.78+ 0.18IPI index: pts{ (%)Low (0–1) 42 (51.2) 16 (20.8) 17 (21.8)Intermediate (2–3) 35 (42.7) 49 (63.6) 48 (61.5)High (4) 5 (6.1) 12 (15.6) 13 (16.7)Glomerular filtrationrate in mL/min{:mean+SD105+ 31 79+ 25 63+ 18ANC 51.56 109/L:pts{ (%)4 (4.9) 4 (5.4) 2 (2.6)Cardiovascularcomorbidity: pts (%)14 (16.7) 18 (23.4) 33 (41.8)Cardiac comorbidity:pts (%)7 (8.3) 10 (13.0) 15 (19.0)Liver comorbidity:pts (%)1 (1.2) 2 (2.6) 2 (2.5)Renal comorbidity:pts (%)3 (3.6) 7 (9.1) 6 (7.6)*Calculated using the Mosteller formula.{n5 expected due to missing values.{Estimated using the Cockroft–Gault formula.SD, standard deviation; pts, patients; ANC, absolute neutrophilcount.1134 Letter to the Editoroutcomes in patients 470 years, who were at higherrisk of FN-related mortality and more likely todiscontinue treatment due to CIN, FN, and infec-tious complications. Although most elderly patientswith cancer can tolerate standard chemotherapyregimens [5], our data suggest that patients 470years are at higher risk of a worse outcome followinga neutropenic event. Appropriate supportive care andclose clinical monitoring are therefore of particularimportance for this population. Results of a recentintegrated analysis suggested that elderly patientswith breast cancer (65 years) benefited fromprimary prophylaxis with pegfilgrastim: the incidenceof FN, dose reductions, and FN-related hospitaliza-tions was reduced in these patients, in comparisonto those receiving current practice neutropeniamanagement [11].Despite the fact that the European Organisationfor Research and Treatment of Cancer (EORTC)guidelines for the elderly recommend that prophy-lactic CSF is given to all patients465 years receivingmyelotoxic chemotherapy [12], there was no in-creased use of CSF in patients 470 years ascompared to younger patients, either as primaryprophylaxis or reactive use. A considerable propor-tion of patients required CSF as secondary prophy-laxis or treatment. This, together with the overallhigh FN rate and low RDI, may suggest a falseeconomy: where primary CSF prophylaxis is notgiven, a substantial proportion of patients requirereactive initiation of CSF during their treatmentcourse.In summary, CIN and FN were considerable inpatients with NHL across all age groups. AlthoughFN rates were similar across all age groups,myelosuppression had the greatest impact on patients470 years, suggesting that CSF prophylaxis may beparticularly relevant for this population.Potential conflict of interest: Disclosure formsprovided by the authors are available with the full textof this article at www.informahealthcare.com/lal.Medcept ltd, Switzerland, provided medical writingsupport on behalf of Amgen (Europe) GmbH.Figure 1. Incidence of CIN and dose modifications with age. Incidence of (A) grade IV CIN (ANC5 500/mm3 or, if ANC unavailable,white blood cell count51000/mm3) and (B) FN (grade IV CIN plus fever [388C]) in cycle 1 and in any cycle. Error bars represent 95%CIs. (C) Proportion of patients experiencing dose delays4 days, dose reductions10%, and RDI 85%. Non-administered cycles weretaken into account to calculate dose reductions and RDI, except in the case of patient death. Error bars represent 95% CIs. (D) Proportion ofpatients experiencing dose delays4 days after FN, after grade IV CIN but in the absence of FN, and in the absence of a neutropenic event.CIN, chemotherapy-induced neutropenia; ANC, absolute neutrophil count; FN, febrile neutropenia; CI, confidence interval; RDI, relativedose intensity.Letter to the Editor 1135References1. Aapro MS, Cameron DA, Pettengell R, et al. EORTCguidelines for the use of granulocyte-colony stimulating factorto reduce the incidence of chemotherapy-induced febrileneutropenia in adult patients with lymphomas and solidtumours. Eur J Cancer 2006;42:2433–2453.2. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Updateof recommendations for the use of white blood cell growthfactors: an evidence-based clinical practice guideline. J ClinOncol 2006;24:3187–3205.3. Kuderer NM, Dale DC, Crawford J, Cosler LE, Lyman GH.Mortality, morbidity, and cost associated with febrile neu-tropenia in adult cancer patients. Cancer 2006;106:2258–2266.4. Crawford J, Dale JC, Lyman GH. Chemotherapy-inducedneutropenia: risks, consequences, and new directions for itsmanagement. Cancer 2004;100:228–237.5. Lyman GH. Impact of chemotherapy dose intensity oncancer patient outcomes. J Natl Compr Canc Netw 2009;7:99–108.6. Picozzi VJ, Pohlman BL, Morrison VA, et al. Patterns ofchemotherapy administration in patients with intermediate-grade non-Hodgkin’s lymphoma. Oncology 2001;15:1296–1306.7. Lyman GH, Dale JC, Friedberg J, Crawford J, Fisher RI.Incidence and predictors of low chemotherapy dose-intensityin aggressive non-Hodgkin’s lymphoma: a nationwide study.J Clin Oncol 2004;22:4302–4311.8. Bosly A, Bron D, van Hoof A, et al. Achievement of optimalaverage relative dose intensity and correlation with survival indiffuse large B-cell lymphoma patients treated with CHOP.Ann Haematol 2008;87:277–283.9. Kuderer NM, Dale JC, Crawford J, Lyman GH. Impact ofprimary prophylaxis with granulocyte colony-stimulatingfactor on febrile neutropenia and mortality in adult cancerpatients receiving chemotherapy: a systematic review. J ClinOncol 2007;25:3158–3167.10. Pettengell R, Schwenkglenks M, Leonard R, et al. Neutropeniaoccurrence and predictors of reduced chemotherapy delivery:results from the INC-EU prospective observational Europeanneutropenia study. Support Care Cancer 2008;16: 1299–1309.11. Aapro M, Schwenkglenks M, Lyman GH, et al. Pegfilgrastimprimary prophylaxis vs. current practice neutropenia manage-ment in elderly breast cancer patients receiving chemotherapy.Crit Rev Oncol Hematol 2010;74:203–210.12. Repetto L, Biganzoli L, Koehne CH, et al. EORTC Cancer inthe Elderly Task Force guidelines for the use of colony-stimulating factors in elderly patients with cancer. Eur JCancer 2003;39:2264–2272.1136 Letter to the Editor

Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP. Ann Haematol

Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management.

EORTC Cancer in the Elderly Task Force guidelines for the use of colonystimulating factors in elderly patients with cancer.

Impact of chemotherapy dose intensity on cancer patient outcomes.

Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review.

Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: a nationwide study.

morbidity, and cost associated with febrile neutropenia in adult cancer patients.

Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study.

Patterns of chemotherapy administration in patients with intermediategrade non-Hodgkin’s lymphoma.

Pegfilgrastim primary prophylaxis vs. current practice neutropenia management in elderly breast cancer patients receiving chemotherapy. Crit Rev Oncol Hematol 2010;74:203–210.

Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline.

Incidence of neutropenia, chemotherapy delivery, and use of colony-stimulating factor in patients with non-Hodgkin lymphoma of different age groups

Ruth Pettengell

Matthias Schwenkglenks

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Pettengell, Ruth

Schwenkglenks, Matthias

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Incidence of neutropenia, chemotherapy delivery, and use of colony-stimulating factor in patients with non-Hodgkin lymphoma of different age groups

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