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(OPP)
[1–4] [INVALID Stage]
Journal of
Oncology Pharmacy Practice
Case Report
Delayed hypersensitivity reaction related to the use of pegfilgrastim
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214542493 opp.sagepub.com
Aliakbar Dadla1, Susan Tannenbaum2, Breton Yates3 and Lisa Holle4
Abstract Filgrastim and pegfilgrastim are granulocyte colony-stimulating factor products, which have been part of the supportive treatment of cancer patients for years to increase the white blood cell count and absolute neutrophil count with the objective of preventing neutropenic fever in patients at risk because of chemotherapy. Pegfilgrastim is a glycosylated form of filgrastim with a prolonged duration of effect, a reduced renal clearance, and relatively fewer side effects. We present a patient with early breast cancer who developed a rash more than a week after the use of pegfilgrastim. Clinicians must be aware of the possibility of a delayed hypersensitivity reaction as the application of this drug is increasing and an adverse event can result in delay of chemotherapy treatment.
Keywords Allergic, pegfilgrastim, neulasta, reaction, rash
Introduction Pegylated granulocyte colony-stimulating factor (G-CSF) (pegfilgrastim (NeulastaÕ , Amgen)) is a covalent conjugate of recombinant human G-CSF and monomethoxypolyethyene glycol. While regular G-CSF (filgrastim) has a half-life of 3–41 h, pegfilgrastim with its reduced renal clearance and consequent prolonged persistence in vivo has a half-life of 15–80 h.2 This allows it to be administered as a single subcutaneous injection once per cycle of chemotherapy. It is being used increasingly in oncology as a simple and cost-effective means of maintaining adequate neutrophil levels during intensive combination chemotherapy. There have been few case reports describing dermatological reactions to filgrastim3–5 and even fewer case reports to pegfilgrastim.6–9 On review of the literature, we found three case reports describing an immediate type hypersensitivity reaction occurring within a day of receiving pegfilgrastim.6–8 Another reports biopsyproven Sweet syndrome (also known as acute febrile neutrophilic dermatosis—a rare skin condition marked by fever and painful skin lesions) within 3 days of administration. Lastly, there is also a case report with biopsy-proven pyoderma gangrenosum within 3 days of administration.9
To our knowledge this is the first biopsy-proven case report with a delayed type IV dermatological reaction after the administration of pegfilgrastim.
Case Informed consent was obtained from the patient to report this case and present accompanying photographs. We present the case of a 52-year-old Caucasian woman with a T1bN0 infiltrating ductal carcinoma of the right breast, which was estrogen receptor- and progesterone receptor-positive, HER2 (Human epidermal growth factor receptor 2)/neu negative with a high-intermediate 1
Dept. of Internal Medicine, University of Connecticut Health Center, Hartford, USA 2 Dept. of Hematology Oncology, University of Connecticut Health Center, Farmington, USA 3 Dept. of Dermatology, University of Connecticut Health Center, Farmington, USA 4 Dept. of Pharmacy, University of Connecticut Health Center, Farmington, USA Corresponding author: Aliakbar Dadla, Dept. of Internal Medicine, University of Connecticut Health Center, 24 Park Place, Apt 18 D, Hartford, CT 06106, USA. Email: [email protected]
Downloaded from opp.sagepub.com at Australian National University on November 7, 2015
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(OPP)
[1–4] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
Figure 1. Rash on forehead.
Oncotype DxÕ (Genomic Health) score of 27. She received her first cycle of chemotherapy with docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 (TC) followed by day 2 pegfilgrastim 6 mg subcutaneously, and did well. The patient was scheduled to receive this regimen once every 3 weeks. Concurrent medications were valacyclovir, multivitamin, vitamin C, vitamin D, probiotic, senokot, and lorazepam (as needed). Eight days after her 2nd cycle of chemotherapy (TC (same doses day 1) + day 2 pegfilgrastim), the patient developed minimal rash on her arms and abdomen as well as a sore throat, which was self-limiting. The same occurred again 8 days after the 3rd cycle of chemotherapy (TC (same doses day 1) + day 2 pegfilgrastim) when the patient developed a sore throat. On day 9 after the 3rd cycle, the patient developed a rash on her face, scalp, back of her neck, lower abdomen, and hands (Figures 1 to 3). She presented to the emergency department and was sent home on oral corticosteroids and diphenhydramine but came back the next day with lip swelling and a more severe rash. The rash was pruritic, not painful, and described as diffuse, erythematous, maculopapular, and raised. Other than the lip swelling she denied any shortness of breath, wheeze, cough, phlegm, fever, or chills. She was admitted for further work up and a punch biopsy of one of her abdominal lesions was obtained. The skin biopsy (Figure 4) showed perivascular and interstitial inflammatory cell infiltrate of lymphocytes, histiocytes, and eosinophils in the dermis with PAS (Periodic acid-Schiff) stain negative for fungal elements consistent with an allergic reaction, such as to a drug. On treatment with intravenous corticosteroids and diphenhydramine her rash improved significantly. She was discharged the same day with oral corticosteroid taper. Despite her corticosteroid taper, her rash waxed and waned until day 18 at which time it resolved completely. The patient made an informed decision to proceed with her fourth and final cycle of chemotherapy
Figure 2. Rash on posterior aspect of the scalp and neck.
Figure 3. Rash on outer aspect of thigh.
(TC (same doses day 1)) without pegfilgrastim. At the time of the last treatment (9 weeks from the start of chemotherapy), the total white blood cell count was 10,600 K/ml (neutrophils 76%) and declined to 3000 K/ml (neutrophils 38.8%) 2 weeks posttreatment; the rash did not reoccur.
Discussion Adjuvant chemotherapy with TC for early breast cancer has improved survival.10–12 According to one trial with 506 patients receiving TC, rates for febrile
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[1–4] [INVALID Stage]
Dadla et al.
3
neutropenia (FN) were 8% for older patients (age >65 years) and 4% for younger patients.11 In a recent metaanalysis evaluating 902 patients treated with TC, the FN rate was 29% without primary prophylaxis, and therefore it is a standard part of treatment with TC.13 Filgrastim and pegfilgrastim have been part of the supportive treatment of cancer patients for years. Their main use is to increase the absolute neutrophil count with the primary objective of preventing the appearance of FN in patients at risk. Risk is dictated by the chemotherapeutic regimen itself and due to patient
Figure 4. Skin biopsy perivascular and interstitial inflammatory cell infiltrate in the dermis.
factors, including comorbidities such as age of the patient and diabetes.14 There have been case reports of immediate hypersensitivity reactions to both docetaxel as well as cyclophosphamide, with most cases occurring with docetaxel. Typically these occur with or soon after drug administration.15–18 The time course of the reaction in our patient and the fact that the rash did not return when it was withheld from the last cycle points to this rash being due to the pegfilgrastim. The Naranjo Probability Scale and The World Health Organization Collaborating Centre for International Drug Monitoring and Uppsala Monitoring Centre Scale are generally the most accepted and widely used methods for causality assessment in clinical practice.19,20 We chose the Naranjo Scale for its objectivity and simplicity. The Naranjo criteria classify the probability that an adverse event is related to drug therapy based on a list of weighted questions, which examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose–response relationships and previous patient experience with the medication. The adverse drug reaction then is assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable for a score of 5–8, possible for 1–4, and doubtful if the score is 0. The Naranjo criteria do not take into account drug–drug interactions. Drugs are evaluated individually for causality, and points
Table 1. Naranjo adverse drug reaction scale for this reaction. Question
Answer
Score
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event occur after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was re-administered? 5. Are there alternative causes (other than the drug) that could have on their own caused the reaction? On literature review most cases describe allergic reactions to docetaxel and cyclophosphamide as Type I hypersensitivity reaction occurring within a day of administration.13–16 Additionally these drugs were continued without reaction for cycle 4; no other drugs were withheld other than pegfilgrastim. 6. Did the reaction reappear when a placebo was given? 7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?
No Yes Yes
0 +2 +1
Yes No
+2 +2
Not done Not done
0 0
Not done
0
Yes
+1
Yes (biopsy) Total
+1 9
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(OPP)
[1–4] [INVALID Stage]
4
Journal of Oncology Pharmacy Practice 0(0)
deducted if another factor may have resulted in the adverse event, thereby weakening the causal association. Utilizing the Naranjo adverse drug reaction scale (Table 1), pegfilgrastim in this case gets a score of 9 (Definite).19 In the case of pegfilgrastim, a 20-kDa polyethylene glycol molecule is covalently conjugated to the N-terminal methionine residue of filgrastim. This results in a long-acting drug with a half-life of 15– 80 h.2 The polyethylene glycol moiety renders pegfilgrastim too large for renal clearance, thus leaving neutrophil receptor-mediated clearance as the primary mechanism of removal.9 One paper postulates that since pegfilgrastim requires receptor-mediated clearance, it may trigger an abnormally high neutrophil proliferation beyond its intended action. Some of these neutrophils then deposit in the skin causing dermatological reactions.9 Another paper with a case of advanced pancreatic cancer postulates that the tumor itself may produce its own G-CSF, which leads to production of antibodies that cross react with exogenous G-CSF,6 though that patient only received pegfilgrastim and filgrastim was not administered. At this point we cannot be sure if our case involved the above mechanisms or rather was an idiosyncratic reaction as seen with other commonly used medications. We alert clinicians to the possibility of delayed hypersensitivity reactions to pegfilgrastim due to its purposefully slow clearance as a result of its drug design. The use of this drug is critical to the timely and safe delivery of chemotherapy and awareness of this potential toxicity is important. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Amgen, Inc. Neupogen (package insert). Thousand Oaks: Amgen, Inc, 2013. 2. Amgen, Inc. Neulasta (package insert). Thousand Oaks: Amgen, Inc, 2013. 3. Alvarez-Ruiz S, Pen˜as PF, Ferna´ndez-Herrera J, et al. Maculopapular eruption with enlarged macrophages in eight patients receiving G-CSF or GM-CSF. J Eur Acad Dermatol Venereol 2004; 18: 310–313. 4. Brumit MC, Shea TC and Brecher ME. Transfusion medicine illustrated. G-CSF-associated rash in an allogeneic PBPC donor. Transfusion 2003; 43: 1343.
5. Ferran M, Gallardo F, Salar A, et al. Granulomatous dermatitis with enlarged histiocytes: A characteristic pattern of granulocyte colony-stimulating factor. Report of two cases and review of the literature. Dermatol 2006; 212: 188–193. 6. Bustillo I, Kaley K and Saif MW. Rash associated with the use of pegylated filgrastim in a patient with advanced pancreatic cancer. Cutan Ocul Toxicol 2009; 28: 181–184. 7. Scott WR, Silberstein L, Flatley R, et al. Cutaneous reaction to pegfilgrastim presenting as severe generalized skin eruption. Br J Dermatol 2009; 161: 717–719. 8. Hanna GG, Edgar D and Clarke JE. A case of prolonged type 1 hypersensitivity reaction to pegfilgrastim. Clin Oncol (R Coll Radiol) 2008; 20: 315–316. 9. Draper BK, Robbins JB and Stricklin GP. Bullous Sweet’s syndrome in congenital neutropenia: Association with pegfilgrastim. J Am Acad Dermatol 2005; 52: 901–905. 10. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Clarke M and Coates AS. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 2008; 371: 29–40. 11. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005; 293: 1073–1081. 12. Jones S, Homes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US oncology research trial 9735. J Clin Oncol 2009; 27: 1177–1183. 13. Younis T, Rayson D and Thompson K. Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: A systematic review and meta-analysis. Support Care Cancer 2012; 20: 2523–2530. 14. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. 15. Kaya AO, Buyukberber S, Coskun U, et al. Acute erythema and edematous skin reaction and ectropion following docetaxel in a patient with non-small cell lung cancer. Cutan Ocol Toxicol 2008; 27: 327–331. 16. Chew L and Chuen VS. Cutaneous reaction associated with weekly docetaxel administration. J Oncol Pharm Pract 2009; 15: 29–34. 17. Lakin JD and Cahill RA. Generalized urticaria to cyclophosphamide Type I hypersensitivity to an immunosuppressive agent. J Allergy Clin Immunol 1976; 58: 160–171. 18. Popescu NA, Sheehan MG, Kouides PA, et al. Allergic reactions to cyclophosphamide: Delayed clinical expression with positive immediate skin tests to drug metabolites in 5 patients. J Allergy Clin Immunol 1996; 97: 26–33. 19. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–245. 20. The Uppsala Monitoring Centre. The use of WHO-UMC system for standarised causality assessment, http://whoumc.org/Graphics/24734.pdf (accessed 5 June 2014).
Downloaded from opp.sagepub.com at Australian National University on November 7, 2015
(OPP)
[1–4] [INVALID Stage]
Journal of
Oncology Pharmacy Practice
Case Report
Delayed hypersensitivity reaction related to the use of pegfilgrastim
J Oncol Pharm Practice 0(0) 1–4 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1078155214542493 opp.sagepub.com
Aliakbar Dadla1, Susan Tannenbaum2, Breton Yates3 and Lisa Holle4
Abstract Filgrastim and pegfilgrastim are granulocyte colony-stimulating factor products, which have been part of the supportive treatment of cancer patients for years to increase the white blood cell count and absolute neutrophil count with the objective of preventing neutropenic fever in patients at risk because of chemotherapy. Pegfilgrastim is a glycosylated form of filgrastim with a prolonged duration of effect, a reduced renal clearance, and relatively fewer side effects. We present a patient with early breast cancer who developed a rash more than a week after the use of pegfilgrastim. Clinicians must be aware of the possibility of a delayed hypersensitivity reaction as the application of this drug is increasing and an adverse event can result in delay of chemotherapy treatment.
Keywords Allergic, pegfilgrastim, neulasta, reaction, rash
Introduction Pegylated granulocyte colony-stimulating factor (G-CSF) (pegfilgrastim (NeulastaÕ , Amgen)) is a covalent conjugate of recombinant human G-CSF and monomethoxypolyethyene glycol. While regular G-CSF (filgrastim) has a half-life of 3–41 h, pegfilgrastim with its reduced renal clearance and consequent prolonged persistence in vivo has a half-life of 15–80 h.2 This allows it to be administered as a single subcutaneous injection once per cycle of chemotherapy. It is being used increasingly in oncology as a simple and cost-effective means of maintaining adequate neutrophil levels during intensive combination chemotherapy. There have been few case reports describing dermatological reactions to filgrastim3–5 and even fewer case reports to pegfilgrastim.6–9 On review of the literature, we found three case reports describing an immediate type hypersensitivity reaction occurring within a day of receiving pegfilgrastim.6–8 Another reports biopsyproven Sweet syndrome (also known as acute febrile neutrophilic dermatosis—a rare skin condition marked by fever and painful skin lesions) within 3 days of administration. Lastly, there is also a case report with biopsy-proven pyoderma gangrenosum within 3 days of administration.9
To our knowledge this is the first biopsy-proven case report with a delayed type IV dermatological reaction after the administration of pegfilgrastim.
Case Informed consent was obtained from the patient to report this case and present accompanying photographs. We present the case of a 52-year-old Caucasian woman with a T1bN0 infiltrating ductal carcinoma of the right breast, which was estrogen receptor- and progesterone receptor-positive, HER2 (Human epidermal growth factor receptor 2)/neu negative with a high-intermediate 1
Dept. of Internal Medicine, University of Connecticut Health Center, Hartford, USA 2 Dept. of Hematology Oncology, University of Connecticut Health Center, Farmington, USA 3 Dept. of Dermatology, University of Connecticut Health Center, Farmington, USA 4 Dept. of Pharmacy, University of Connecticut Health Center, Farmington, USA Corresponding author: Aliakbar Dadla, Dept. of Internal Medicine, University of Connecticut Health Center, 24 Park Place, Apt 18 D, Hartford, CT 06106, USA. Email: [email protected]
Downloaded from opp.sagepub.com at Australian National University on November 7, 2015
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(OPP)
[1–4] [INVALID Stage]
2
Journal of Oncology Pharmacy Practice 0(0)
Figure 1. Rash on forehead.
Oncotype DxÕ (Genomic Health) score of 27. She received her first cycle of chemotherapy with docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 intravenously on day 1 (TC) followed by day 2 pegfilgrastim 6 mg subcutaneously, and did well. The patient was scheduled to receive this regimen once every 3 weeks. Concurrent medications were valacyclovir, multivitamin, vitamin C, vitamin D, probiotic, senokot, and lorazepam (as needed). Eight days after her 2nd cycle of chemotherapy (TC (same doses day 1) + day 2 pegfilgrastim), the patient developed minimal rash on her arms and abdomen as well as a sore throat, which was self-limiting. The same occurred again 8 days after the 3rd cycle of chemotherapy (TC (same doses day 1) + day 2 pegfilgrastim) when the patient developed a sore throat. On day 9 after the 3rd cycle, the patient developed a rash on her face, scalp, back of her neck, lower abdomen, and hands (Figures 1 to 3). She presented to the emergency department and was sent home on oral corticosteroids and diphenhydramine but came back the next day with lip swelling and a more severe rash. The rash was pruritic, not painful, and described as diffuse, erythematous, maculopapular, and raised. Other than the lip swelling she denied any shortness of breath, wheeze, cough, phlegm, fever, or chills. She was admitted for further work up and a punch biopsy of one of her abdominal lesions was obtained. The skin biopsy (Figure 4) showed perivascular and interstitial inflammatory cell infiltrate of lymphocytes, histiocytes, and eosinophils in the dermis with PAS (Periodic acid-Schiff) stain negative for fungal elements consistent with an allergic reaction, such as to a drug. On treatment with intravenous corticosteroids and diphenhydramine her rash improved significantly. She was discharged the same day with oral corticosteroid taper. Despite her corticosteroid taper, her rash waxed and waned until day 18 at which time it resolved completely. The patient made an informed decision to proceed with her fourth and final cycle of chemotherapy
Figure 2. Rash on posterior aspect of the scalp and neck.
Figure 3. Rash on outer aspect of thigh.
(TC (same doses day 1)) without pegfilgrastim. At the time of the last treatment (9 weeks from the start of chemotherapy), the total white blood cell count was 10,600 K/ml (neutrophils 76%) and declined to 3000 K/ml (neutrophils 38.8%) 2 weeks posttreatment; the rash did not reoccur.
Discussion Adjuvant chemotherapy with TC for early breast cancer has improved survival.10–12 According to one trial with 506 patients receiving TC, rates for febrile
Downloaded from opp.sagepub.com at Australian National University on November 7, 2015
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[1–4] [INVALID Stage]
Dadla et al.
3
neutropenia (FN) were 8% for older patients (age >65 years) and 4% for younger patients.11 In a recent metaanalysis evaluating 902 patients treated with TC, the FN rate was 29% without primary prophylaxis, and therefore it is a standard part of treatment with TC.13 Filgrastim and pegfilgrastim have been part of the supportive treatment of cancer patients for years. Their main use is to increase the absolute neutrophil count with the primary objective of preventing the appearance of FN in patients at risk. Risk is dictated by the chemotherapeutic regimen itself and due to patient
Figure 4. Skin biopsy perivascular and interstitial inflammatory cell infiltrate in the dermis.
factors, including comorbidities such as age of the patient and diabetes.14 There have been case reports of immediate hypersensitivity reactions to both docetaxel as well as cyclophosphamide, with most cases occurring with docetaxel. Typically these occur with or soon after drug administration.15–18 The time course of the reaction in our patient and the fact that the rash did not return when it was withheld from the last cycle points to this rash being due to the pegfilgrastim. The Naranjo Probability Scale and The World Health Organization Collaborating Centre for International Drug Monitoring and Uppsala Monitoring Centre Scale are generally the most accepted and widely used methods for causality assessment in clinical practice.19,20 We chose the Naranjo Scale for its objectivity and simplicity. The Naranjo criteria classify the probability that an adverse event is related to drug therapy based on a list of weighted questions, which examine factors such as the temporal association of drug administration and event occurrence, alternative causes for the event, drug levels, dose–response relationships and previous patient experience with the medication. The adverse drug reaction then is assigned to a probability category from the total score as follows: definite if the overall score is 9 or greater, probable for a score of 5–8, possible for 1–4, and doubtful if the score is 0. The Naranjo criteria do not take into account drug–drug interactions. Drugs are evaluated individually for causality, and points
Table 1. Naranjo adverse drug reaction scale for this reaction. Question
Answer
Score
1. Are there previous conclusive reports on this reaction? 2. Did the adverse event occur after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reaction reappear when the drug was re-administered? 5. Are there alternative causes (other than the drug) that could have on their own caused the reaction? On literature review most cases describe allergic reactions to docetaxel and cyclophosphamide as Type I hypersensitivity reaction occurring within a day of administration.13–16 Additionally these drugs were continued without reaction for cycle 4; no other drugs were withheld other than pegfilgrastim. 6. Did the reaction reappear when a placebo was given? 7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?
No Yes Yes
0 +2 +1
Yes No
+2 +2
Not done Not done
0 0
Not done
0
Yes
+1
Yes (biopsy) Total
+1 9
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XML Template (2014) [26.6.2014–5:08pm] //blrnas3/cenpro/ApplicationFiles/Journals/SAGE/3B2/OPPJ/Vol00000/140059/APPFile/SG-OPPJ140059.3d
(OPP)
[1–4] [INVALID Stage]
4
Journal of Oncology Pharmacy Practice 0(0)
deducted if another factor may have resulted in the adverse event, thereby weakening the causal association. Utilizing the Naranjo adverse drug reaction scale (Table 1), pegfilgrastim in this case gets a score of 9 (Definite).19 In the case of pegfilgrastim, a 20-kDa polyethylene glycol molecule is covalently conjugated to the N-terminal methionine residue of filgrastim. This results in a long-acting drug with a half-life of 15– 80 h.2 The polyethylene glycol moiety renders pegfilgrastim too large for renal clearance, thus leaving neutrophil receptor-mediated clearance as the primary mechanism of removal.9 One paper postulates that since pegfilgrastim requires receptor-mediated clearance, it may trigger an abnormally high neutrophil proliferation beyond its intended action. Some of these neutrophils then deposit in the skin causing dermatological reactions.9 Another paper with a case of advanced pancreatic cancer postulates that the tumor itself may produce its own G-CSF, which leads to production of antibodies that cross react with exogenous G-CSF,6 though that patient only received pegfilgrastim and filgrastim was not administered. At this point we cannot be sure if our case involved the above mechanisms or rather was an idiosyncratic reaction as seen with other commonly used medications. We alert clinicians to the possibility of delayed hypersensitivity reactions to pegfilgrastim due to its purposefully slow clearance as a result of its drug design. The use of this drug is critical to the timely and safe delivery of chemotherapy and awareness of this potential toxicity is important. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest None declared.
References 1. Amgen, Inc. Neupogen (package insert). Thousand Oaks: Amgen, Inc, 2013. 2. Amgen, Inc. Neulasta (package insert). Thousand Oaks: Amgen, Inc, 2013. 3. Alvarez-Ruiz S, Pen˜as PF, Ferna´ndez-Herrera J, et al. Maculopapular eruption with enlarged macrophages in eight patients receiving G-CSF or GM-CSF. J Eur Acad Dermatol Venereol 2004; 18: 310–313. 4. Brumit MC, Shea TC and Brecher ME. Transfusion medicine illustrated. G-CSF-associated rash in an allogeneic PBPC donor. Transfusion 2003; 43: 1343.
5. Ferran M, Gallardo F, Salar A, et al. Granulomatous dermatitis with enlarged histiocytes: A characteristic pattern of granulocyte colony-stimulating factor. Report of two cases and review of the literature. Dermatol 2006; 212: 188–193. 6. Bustillo I, Kaley K and Saif MW. Rash associated with the use of pegylated filgrastim in a patient with advanced pancreatic cancer. Cutan Ocul Toxicol 2009; 28: 181–184. 7. Scott WR, Silberstein L, Flatley R, et al. Cutaneous reaction to pegfilgrastim presenting as severe generalized skin eruption. Br J Dermatol 2009; 161: 717–719. 8. Hanna GG, Edgar D and Clarke JE. A case of prolonged type 1 hypersensitivity reaction to pegfilgrastim. Clin Oncol (R Coll Radiol) 2008; 20: 315–316. 9. Draper BK, Robbins JB and Stricklin GP. Bullous Sweet’s syndrome in congenital neutropenia: Association with pegfilgrastim. J Am Acad Dermatol 2005; 52: 901–905. 10. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Clarke M and Coates AS. Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: patient-level meta-analysis of randomised trials. Lancet 2008; 371: 29–40. 11. Muss HB, Woolf S, Berry D, et al. Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 2005; 293: 1073–1081. 12. Jones S, Homes FA, O’Shaughnessy J, et al. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US oncology research trial 9735. J Clin Oncol 2009; 27: 1177–1183. 13. Younis T, Rayson D and Thompson K. Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: A systematic review and meta-analysis. Support Care Cancer 2012; 20: 2523–2530. 14. Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 update of recommendations for the use of white blood cell growth factors: An evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. 15. Kaya AO, Buyukberber S, Coskun U, et al. Acute erythema and edematous skin reaction and ectropion following docetaxel in a patient with non-small cell lung cancer. Cutan Ocol Toxicol 2008; 27: 327–331. 16. Chew L and Chuen VS. Cutaneous reaction associated with weekly docetaxel administration. J Oncol Pharm Pract 2009; 15: 29–34. 17. Lakin JD and Cahill RA. Generalized urticaria to cyclophosphamide Type I hypersensitivity to an immunosuppressive agent. J Allergy Clin Immunol 1976; 58: 160–171. 18. Popescu NA, Sheehan MG, Kouides PA, et al. Allergic reactions to cyclophosphamide: Delayed clinical expression with positive immediate skin tests to drug metabolites in 5 patients. J Allergy Clin Immunol 1996; 97: 26–33. 19. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–245. 20. The Uppsala Monitoring Centre. The use of WHO-UMC system for standarised causality assessment, http://whoumc.org/Graphics/24734.pdf (accessed 5 June 2014).
Downloaded from opp.sagepub.com at Australian National University on November 7, 2015
