Clinical Communications Melphalan desensitization following immediate hypersensitivity in a patient undergoing conditioning for autologous hematopoietic cell transplantation Alex Ganetsky, PharmDa, Patricia A. Takach, MDb, Donna-Marie Lynch, NPc, Tracy M. Krause, PharmDa, Jian S. Teh, MDb, Edward A. Stadtmauer, MDd, Mariana Castells, MD, PhDc, and Brendan M. Weiss, MDd
Clinical Implications
This case report describes the first successful rapid desensitization after an immediate hypersensitivity reaction to melphalan during conditioning for autologous hematopoietic cell transplantation. Rapid desensitization for immediate hypersensitivity reactions to chemotherapy has allowed for safe administration of potentially lifesaving therapies.
TO THE EDITOR: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a paraneoplastic disorder associated with an underlying plasma cell neoplasm.1 High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) is considered to confer the highest likelihood for achieving durable responses resulting in long-term survival.2 We describe the case of a 55-year-old man with POEMS syndrome who developed an immediate hypersensitivity reaction to high-dose melphalan during conditioning for autologous HCT and subsequently underwent successful melphalan desensitization. A 55-year-old man was diagnosed with POEMS syndrome after presenting with polyneuropathy, IgA lambda paraproteinemia, elevated vascular endothelial growth factor, organomegaly, and thrombocytosis. While arrangements for autologous HCT were being made, induction therapy with cyclophosphamide and prednisone was started. The patient underwent successful stem cell mobilization with filgrastim and plerixafor and was subsequently admitted to the inpatient HCT Unit. He was prescribed melphalan at a dose of 200 mg/m2 (total dose ¼ 400 mg) administered intravenously over 30 minutes, which was to be followed by reinfusion of autologous stem cells 2 days later. Dexamethasone 20 mg and ondansetron 24 mg were administered orally 30 minutes before melphalan for antiemetic prophylaxis. Three minutes after starting the melphalan infusion, which resulted in approximately 60 mg administered, he developed severe head and chest pressure, mild shortness of breath, cough, and facial flushing. His blood pressure remained stable and heart rate increased from a baseline of 82 to 97 beats per minute. A pulse oximeter measured a SpO2 of 96%, slightly below his baseline of 100%. An electrocardiogram revealed
normal sinus rhythm. A chest X-ray was unremarkable. No fever was noted. The melphalan infusion was stopped and symptoms resolved after a single dose of intravenous diphenhydramine 25 mg. The autologous HCT was aborted. The following day, the Allergy and Immunology team evaluated the patient. A tryptase level obtained approximately 15 hours after the reaction was noted to be within normal limits at 10.8 mg/L. The patient was discharged home 2 days after the event. Notably, this was the patient’s first exposure to melphalan. Prior reports have suggested that melphalan hypersensitivity, an IgE-mediated process with an incidence of approximately 5%, occurs after several courses of intravenous therapy.3 Given the severity of the initial hypersensitivity reaction to melphalan, a 4-bag 16-step desensitization protocol was indicated.4 However, we were unable to use the standard 4-bag 16step approach because of the unique physical and chemical properties of melphalan. Melphalan is stable for only 60 minutes after reconstitution, thus making it logistically infeasible to complete all of the components of each step within an hour time frame, which include preparation of the intravenous admixture, delivery of drug to the floor, and infusion of the dilution. In addition, melphalan is required to be diluted in normal saline to a concentration 0.45 mg/mL, creating a substantial challenge in finding the appropriate volume that would adhere to the infusion and stability properties. To circumvent the logistical issues related to melphalan’s short stability and concentration requirements, we designed a novel 5-bag 17-step melphalan desensitization protocol, as shown in Table I. Melphalan is classified as a strong irritant and may cause skin necrosis and ulceration and is not amenable to skin testing. Four weeks after the initial incident, the patient was admitted directly to the Medical Intensive Care Unit for close observation during the planned desensitization. A tryptase level drawn before the procedure was mildly elevated at 15.3 mg/L, likely attributed in part to a delay in normalization from the intensity of the initial reaction as well as the patient’s mild renal dysfunction. He was premedicated with orally administered cetirizine 10 mg, montelukast 10 mg, and aspirin 325 mg (given history of flushing during reaction) 60 minutes before initiation of desensitization. In addition, he received diphenhydramine 25 mg and famotidine 20 mg intravenously 20 minutes before the start of desensitization. He received dexamethasone 20 mg and ondansetron 24 mg orally 30 minutes before administration of melphalan for antiemetic prophylaxis. An allergic reaction desensitization kit was brought to bedside, which contained epinephrine, diphenhydramine, methylprednisolone, peak flow meter, and blood pressure cuff. Vital signs were taken and recorded every 10 minutes. A nurse observed the patient throughout the entire protocol in a one-to-one fashion. The patient tolerated the desensitization procedure without any reaction. The patient’s required level of care was subsequently downgraded and he was transferred to the inpatient HCT Unit. Two days later he successfully received 4.3 106/kg of CD34þ peripheral blood mononuclear cells. Neutrophil engraftment occurred on day þ13 and platelet engraftment on day þ15. Hypersensitivity reactions to chemotherapy often preclude administration of potentially curative therapy for patients with 1
2
CLINICAL COMMUNICATIONS
TABLE I. Novel 5-bag desensitization protocol
17-step
J ALLERGY CLIN IMMUNOL PRACT MONTH 2016
high-dose
melphalan
Total mL of Melphalan Total mg Amount of bag NS per bag concentration (mg/mL) per bag infused (mL)
Solution Solution Solution Solution Solution
1 2 3 4 5
50 50 50 435 435
Step Solution
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Rate (mL/h)
0.001 0.016 0.160 0.45 0.45
Time (min)
Volume infused per step (mL)
1 20 10 1 40 10 1 80 10 1 160 10 2 20 10 2 40 10 2 80 10 2 160 10 3 20 10 3 40 10 3 80 10 3 160 10 4 80 5 4 160 5 4 320 5 4 999 23.3 5 999 26.1 Total time (min) ¼194.4 min
3.33 6.67 13.33 26.67 3.33 6.67 13.33 26.67 3.33 6.67 13.33 26.67 6.67 13.33 26.67 387.95 434.57 (3.24 h)
0.04 0.8 8.00 195.58 195.58
50.00 50.00 50.00 435.00 435.00
Dose administered with this Cumulative step (mg) dose (mg)
0.003 0.005 0.011 0.021 0.053 0.107 0.213 0.427 0.533 1.067 2.133 4.267 2.997 5.994 11.989 174.424 195.384
0.003 0.008 0.019 0.040 0.093 0.200 0.413 0.840 1.373 2.440 4.573 8.840 11.837 17.829 29.813 204.227 399.630
NS, Normal saline.
cancer.3 In the current case, the patient developed a moderate hypersensitivity with immediate systemic reactions to high-dose melphalan during conditioning for autologous HCT. Given the favorable long-term outcomes associated with this treatment for POEMS syndrome, a decision was made to proceed with melphalan desensitization. We devised a novel 5-bag 17-step rapid desensitization protocol that the patient successfully completed and received the full therapeutic dose of drug. To the best of our knowledge, this is the first reported case of successful implementation of a rapid melphalan desensitization protocol. Immediate hypersensitivity reactions to chemotherapy occur because of IgE or non-IgE-mediated activation of tissue mast cells and peripheral blood basophils and may include a myriad of symptoms.5 Given the respiratory and cardiovascular manifestations our patient experienced during the hypersensitivity
reaction, the patient required a longer desensitization procedure ranging from a 16- to 20-step process.4,6 Rapid drug desensitization induces a temporary state of immune tolerance by incrementally introducing the agent responsible for the hypersensitivity, permitting delivery of the full therapeutic dose. The mechanisms by which rapid desensitization provides temporary tolerance include allowing for binding of antigenic determinants to IgE but without cross-linking, inhibition of antigen/IgE-bound FcεR1 receptor complex internalization, and downregulation of tyrosine kinases Syk and Lyn.7-9 Desensitization induces a temporary state of tolerance and requires continuous administration of the medication. If new courses of the medication are required, desensitization must be repeated.6 a
Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, Pa b Section of Allergy and Immunology, Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa c Division of Rheumatology and Immunology, Brigham and Women’s Hospital, Boston, Mass d Division of Hematology and Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts. Received for publication September 22, 2015; revised January 6, 2016; accepted for publication January 13, 2016. Available online - Corresponding author: Alex Ganetsky, PharmD, Department of Pharmacy, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: [email protected]. 2213-2198 Ó 2016 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2016.01.005 REFERENCES 1. Li J, Zhou DB. New advances in the diagnosis and treatment of POEMS syndrome. Br J Haematol 2013;161:303-15. 2. Dispenzieri A. How I treat POEMS syndrome. Blood 2012;119:5650-8. 3. Kingsley CD. Hypersensitivity reactions. In: Perry MC, editor. Perry’s The Chemotherapy Source Book. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 160-87. 4. Castells MC. Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century. J Investig Allergol Clin Immunol 2014;24:72-9. 5. Blatman KSH, Castells MC. Desensitization for chemotherapy and monoclonal antibodies: indications and outcomes. Curr Allergy Asthma Rep 2014;14:453-60. 6. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-6. 7. Castells M, Sancho-Serra Mdel C, Simarro M. Hypersensitivity to antineoplastic agents: mechanisms and treatment with rapid desensitization. Cancer Immunol Immunother 2012;61:1575-84. 8. Sancho-Serra Mdel DC, Simarro M, Castells M. Rapid IgE desensitization is antigen specific and impairs early and late mast cell responses targeting FcεR1 internalization. Eur J Immunol 2011;41:1004-13. 9. Macglashan D, Miura K. Loss of syk kinase during IgE-mediated stimulation of human basophils. J Allergy Clin Immunol 2004;114:1317-24.
Clinical Implications
This case report describes the first successful rapid desensitization after an immediate hypersensitivity reaction to melphalan during conditioning for autologous hematopoietic cell transplantation. Rapid desensitization for immediate hypersensitivity reactions to chemotherapy has allowed for safe administration of potentially lifesaving therapies.
TO THE EDITOR: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a paraneoplastic disorder associated with an underlying plasma cell neoplasm.1 High-dose melphalan followed by autologous hematopoietic cell transplantation (HCT) is considered to confer the highest likelihood for achieving durable responses resulting in long-term survival.2 We describe the case of a 55-year-old man with POEMS syndrome who developed an immediate hypersensitivity reaction to high-dose melphalan during conditioning for autologous HCT and subsequently underwent successful melphalan desensitization. A 55-year-old man was diagnosed with POEMS syndrome after presenting with polyneuropathy, IgA lambda paraproteinemia, elevated vascular endothelial growth factor, organomegaly, and thrombocytosis. While arrangements for autologous HCT were being made, induction therapy with cyclophosphamide and prednisone was started. The patient underwent successful stem cell mobilization with filgrastim and plerixafor and was subsequently admitted to the inpatient HCT Unit. He was prescribed melphalan at a dose of 200 mg/m2 (total dose ¼ 400 mg) administered intravenously over 30 minutes, which was to be followed by reinfusion of autologous stem cells 2 days later. Dexamethasone 20 mg and ondansetron 24 mg were administered orally 30 minutes before melphalan for antiemetic prophylaxis. Three minutes after starting the melphalan infusion, which resulted in approximately 60 mg administered, he developed severe head and chest pressure, mild shortness of breath, cough, and facial flushing. His blood pressure remained stable and heart rate increased from a baseline of 82 to 97 beats per minute. A pulse oximeter measured a SpO2 of 96%, slightly below his baseline of 100%. An electrocardiogram revealed
normal sinus rhythm. A chest X-ray was unremarkable. No fever was noted. The melphalan infusion was stopped and symptoms resolved after a single dose of intravenous diphenhydramine 25 mg. The autologous HCT was aborted. The following day, the Allergy and Immunology team evaluated the patient. A tryptase level obtained approximately 15 hours after the reaction was noted to be within normal limits at 10.8 mg/L. The patient was discharged home 2 days after the event. Notably, this was the patient’s first exposure to melphalan. Prior reports have suggested that melphalan hypersensitivity, an IgE-mediated process with an incidence of approximately 5%, occurs after several courses of intravenous therapy.3 Given the severity of the initial hypersensitivity reaction to melphalan, a 4-bag 16-step desensitization protocol was indicated.4 However, we were unable to use the standard 4-bag 16step approach because of the unique physical and chemical properties of melphalan. Melphalan is stable for only 60 minutes after reconstitution, thus making it logistically infeasible to complete all of the components of each step within an hour time frame, which include preparation of the intravenous admixture, delivery of drug to the floor, and infusion of the dilution. In addition, melphalan is required to be diluted in normal saline to a concentration 0.45 mg/mL, creating a substantial challenge in finding the appropriate volume that would adhere to the infusion and stability properties. To circumvent the logistical issues related to melphalan’s short stability and concentration requirements, we designed a novel 5-bag 17-step melphalan desensitization protocol, as shown in Table I. Melphalan is classified as a strong irritant and may cause skin necrosis and ulceration and is not amenable to skin testing. Four weeks after the initial incident, the patient was admitted directly to the Medical Intensive Care Unit for close observation during the planned desensitization. A tryptase level drawn before the procedure was mildly elevated at 15.3 mg/L, likely attributed in part to a delay in normalization from the intensity of the initial reaction as well as the patient’s mild renal dysfunction. He was premedicated with orally administered cetirizine 10 mg, montelukast 10 mg, and aspirin 325 mg (given history of flushing during reaction) 60 minutes before initiation of desensitization. In addition, he received diphenhydramine 25 mg and famotidine 20 mg intravenously 20 minutes before the start of desensitization. He received dexamethasone 20 mg and ondansetron 24 mg orally 30 minutes before administration of melphalan for antiemetic prophylaxis. An allergic reaction desensitization kit was brought to bedside, which contained epinephrine, diphenhydramine, methylprednisolone, peak flow meter, and blood pressure cuff. Vital signs were taken and recorded every 10 minutes. A nurse observed the patient throughout the entire protocol in a one-to-one fashion. The patient tolerated the desensitization procedure without any reaction. The patient’s required level of care was subsequently downgraded and he was transferred to the inpatient HCT Unit. Two days later he successfully received 4.3 106/kg of CD34þ peripheral blood mononuclear cells. Neutrophil engraftment occurred on day þ13 and platelet engraftment on day þ15. Hypersensitivity reactions to chemotherapy often preclude administration of potentially curative therapy for patients with 1
2
CLINICAL COMMUNICATIONS
TABLE I. Novel 5-bag desensitization protocol
17-step
J ALLERGY CLIN IMMUNOL PRACT MONTH 2016
high-dose
melphalan
Total mL of Melphalan Total mg Amount of bag NS per bag concentration (mg/mL) per bag infused (mL)
Solution Solution Solution Solution Solution
1 2 3 4 5
50 50 50 435 435
Step Solution
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Rate (mL/h)
0.001 0.016 0.160 0.45 0.45
Time (min)
Volume infused per step (mL)
1 20 10 1 40 10 1 80 10 1 160 10 2 20 10 2 40 10 2 80 10 2 160 10 3 20 10 3 40 10 3 80 10 3 160 10 4 80 5 4 160 5 4 320 5 4 999 23.3 5 999 26.1 Total time (min) ¼194.4 min
3.33 6.67 13.33 26.67 3.33 6.67 13.33 26.67 3.33 6.67 13.33 26.67 6.67 13.33 26.67 387.95 434.57 (3.24 h)
0.04 0.8 8.00 195.58 195.58
50.00 50.00 50.00 435.00 435.00
Dose administered with this Cumulative step (mg) dose (mg)
0.003 0.005 0.011 0.021 0.053 0.107 0.213 0.427 0.533 1.067 2.133 4.267 2.997 5.994 11.989 174.424 195.384
0.003 0.008 0.019 0.040 0.093 0.200 0.413 0.840 1.373 2.440 4.573 8.840 11.837 17.829 29.813 204.227 399.630
NS, Normal saline.
cancer.3 In the current case, the patient developed a moderate hypersensitivity with immediate systemic reactions to high-dose melphalan during conditioning for autologous HCT. Given the favorable long-term outcomes associated with this treatment for POEMS syndrome, a decision was made to proceed with melphalan desensitization. We devised a novel 5-bag 17-step rapid desensitization protocol that the patient successfully completed and received the full therapeutic dose of drug. To the best of our knowledge, this is the first reported case of successful implementation of a rapid melphalan desensitization protocol. Immediate hypersensitivity reactions to chemotherapy occur because of IgE or non-IgE-mediated activation of tissue mast cells and peripheral blood basophils and may include a myriad of symptoms.5 Given the respiratory and cardiovascular manifestations our patient experienced during the hypersensitivity
reaction, the patient required a longer desensitization procedure ranging from a 16- to 20-step process.4,6 Rapid drug desensitization induces a temporary state of immune tolerance by incrementally introducing the agent responsible for the hypersensitivity, permitting delivery of the full therapeutic dose. The mechanisms by which rapid desensitization provides temporary tolerance include allowing for binding of antigenic determinants to IgE but without cross-linking, inhibition of antigen/IgE-bound FcεR1 receptor complex internalization, and downregulation of tyrosine kinases Syk and Lyn.7-9 Desensitization induces a temporary state of tolerance and requires continuous administration of the medication. If new courses of the medication are required, desensitization must be repeated.6 a
Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, Pa b Section of Allergy and Immunology, Division of Pulmonary, Allergy and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa c Division of Rheumatology and Immunology, Brigham and Women’s Hospital, Boston, Mass d Division of Hematology and Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa No funding was received for this work. Conflicts of interest: The authors declare that they have no relevant conflicts. Received for publication September 22, 2015; revised January 6, 2016; accepted for publication January 13, 2016. Available online - Corresponding author: Alex Ganetsky, PharmD, Department of Pharmacy, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104. E-mail: [email protected]. 2213-2198 Ó 2016 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaip.2016.01.005 REFERENCES 1. Li J, Zhou DB. New advances in the diagnosis and treatment of POEMS syndrome. Br J Haematol 2013;161:303-15. 2. Dispenzieri A. How I treat POEMS syndrome. Blood 2012;119:5650-8. 3. Kingsley CD. Hypersensitivity reactions. In: Perry MC, editor. Perry’s The Chemotherapy Source Book. Philadelphia: Lippincott Williams & Wilkins; 2012. p. 160-87. 4. Castells MC. Rapid drug desensitization for hypersensitivity reactions to chemotherapy and monoclonal antibodies in the 21st century. J Investig Allergol Clin Immunol 2014;24:72-9. 5. Blatman KSH, Castells MC. Desensitization for chemotherapy and monoclonal antibodies: indications and outcomes. Curr Allergy Asthma Rep 2014;14:453-60. 6. Brown SG. Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 2004;114:371-6. 7. Castells M, Sancho-Serra Mdel C, Simarro M. Hypersensitivity to antineoplastic agents: mechanisms and treatment with rapid desensitization. Cancer Immunol Immunother 2012;61:1575-84. 8. Sancho-Serra Mdel DC, Simarro M, Castells M. Rapid IgE desensitization is antigen specific and impairs early and late mast cell responses targeting FcεR1 internalization. Eur J Immunol 2011;41:1004-13. 9. Macglashan D, Miura K. Loss of syk kinase during IgE-mediated stimulation of human basophils. J Allergy Clin Immunol 2004;114:1317-24.
