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Observation |

Retinal Toxic Reactions Following Photopheresis FREE

Jose Manuel Vagace, MD, PhD; Guillermo Gervasini, PharmD, PhD; Fernando Morais, MD; Julio Benitez, MD, PhD; Nieves Alonso, MD; Diego de Argila, MD; Isabel Arranz, MD; Roberto Bajo, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Hematology (Drs Vagace, Alonso, and Bajo) and Dermatology, (Dr de Argila), University Hospital Infanta Cristina, Badajoz, Spain; Department of Pharmacology, University of Extremadura, Badajoz (Drs Gervasini and Benitez); Department of Ophthalmology, Hospital of Merida, Merida, Spain (Dr Morais); and Department of Biochemistry, Hospital Ramón y Cajal, Madrid, Spain (Dr Arranz).


Arch Dermatol. 2007;143(5):622-625. doi:10.1001/archderm.143.5.622.
Text Size: A A A
Published online

ABSTRACT

Background  Extracorporeal photochemotherapy (ECP), also known as photopheresis, is a generally well-tolerated therapeutic, immunomodulatory approach successfully used in cutaneous T-cell lymphoma and other diseases produced by T-lymphocytes such as graft vs host disease.

Observations  On 2 separate occasions, a 54-year-old white man with Sézary syndrome developed cutaneous phototoxic reactions and chorioretinitis after being treated with ECP. A pharmacokinetic study showed therapeutic blood levels of 8-methoxypsoralen as long as 18 weeks after therapy had been terminated. However, the analysis of mutations in genes involved in the drug's disposition could not explain these abnormal levels.

Conclusions  To our knowledge, there has been no previous description of ECP-related retinal toxic effects. This adverse effect was probably linked to impaired drug elimination. Further studies would be needed to determine the underlying mechanism.

Figures in this Article

Extracorporeal photochemotherapy (ECP) or photopheresis is a therapeutic approach based on the biological effect of 8-methoxypsoralen (8-MOP) plus UV-A light on mononuclear cells collected by apheresis and reinfused into the patient. Photopheresis was first successfully used to treat cutaneous T-cell lymphoma and is now also used to treat T-lymphocyte mediated diseases.1 The treatment is generally well tolerated by the patient, with a low incidence of adverse effects, most of which are mild and transitory.2

One of the reasons for the relative lack of clinical complications is the rapid elimination of the drug. It is known that cytochrome P450 (CYP) is involved because induction of this hepatic enzyme system leads to increased metabolism of the drug.3 Although the specific enzymes involved in 8-MOP metabolism are still unknown, there are indications that polymorphic enzymes such as CYP3A4, CYP3A5, or CYP2A6 could either be involved in the elimination of psoralen-type compounds or be inhibited by them.46 Psoralen has also been suggested to have an interaction with P-glycoprotein,7 a transmembrane protein encoded by the ABCB1 (MDR1) gene, which functions as a drug efflux pump and is involved in resistance to many anticancer therapies. Numerous polymorphisms and haplotypes have been described that can alter the expression and/or function of these genes and could therefore affect 8-MOP metabolism or transport.

We report herein a complication in a patient with Sézary syndrome who was treated with ECP and developed retinal toxic reactions. The case study showed unexplained, extremely durable levels of plasma psoralen.

METHODS

The patient authorized the scientific presentation of the data. The response to treatment was evaluated clinically by the Edelson skin score method,8 which quantifies the severity of the symptoms on a scale of 0 to 400 points. The percentage of lymphocytes with the characteristic pathological (CD3+, CD4+, and CD7) phenotype was determined by quantitative flow cytometry.

PHOTOPHERESIS

We used a previously described ECP technique9 with minor modifications. Briefly, we used a Fresenius blood cell separator (AS.TEC-204, program PBSC-Ly; Fresenius AG, Bad Homburg, Germany) to collect 100 to 150 mL of mononuclear cell concentrate. The mononuclear cell concentrate buffy coat was adjusted to a constant volume of 300 mL by addition of isotonic sodium chloride solution and 3 mL of 8-MOP aqueous solution (Gerot Pharmazeutika, Vienna, Austria) to give a final drug concentration of 200 ng/mL. The buffy coat was transferred to a UV-A permeable bag (MacoPharma, Tourcoing, France) and irradiated with UV-A under continuous shaking at 2 J/cm2 for 15 minutes using a UV-A irradiator (UVAFEC) previously developed by our group.10 Finally, the resulting 8-MOP–photoactivated mononuclear cell concentrate was reinfused into the patient within 30 minutes. The effectiveness of the irradiation was evaluated by the response of the irradiated cells to phytohemagglutinin and by the flow-cytometric determination of cell viability (BrdU Flow Kits; Becton Dickinson & Co, Franklin Lakes, NJ).

This protocol was applied in biweekly cycles, each consisting of 2 procedures given on 2 consecutive days.

PHARMACOKINETICS

With the last ECP cycle administered, we monitored the psoralen plasma levels by high-performance liquid chromatography using the method described by Gómez et al.11 Ten samples from different patients receiving the same ECP protocol were used for comparison purposes.

GENOTYPING

In an attempt to determine the existence of gene polymorphisms that could affect psoralen disposition and hence at least in part explain the extreme durability of therapeutic blood levels of the drug observed in our patient, we tested for the presence of the commonest polymorphisms that affect the CYP3A4 and CYP3A5 genes in whites, namely CYP3A4*1B12 and CYP3A5*3, and for the existence of CYP2A6 functional variant alleles (CYP2A6*2,14CYP2A6*4,15CYP2A6*5,16 and CYP2A6*917) using previously described techniques. Finally, the presence of the ABCB1C1236T, G2677T, and C3435T allelic variants was determined by direct sequencing using a method developed in our laboratory.

REPORT OF A CASE

A 54-year-old man diagnosed with Sézary syndrome was admitted to our hospital for ECP treatment. Physical examination showed generalized pruriginous erythrodermia and axillary and inguinal lymph node enlargement. The laboratory evaluation showed leukocytosis (16.9 × 109/L with 69% of Sézary cells in the blood smear), and normal hemoglobin level (16.6 g/dL) and platelet count (278 × 103/μL). A characteristic T-lymphoma immunophenotype (CD3+, CD4+, and CD7) was observed in 88% of lymphocytes and 42% of leukocytes. Skin and lymph node biopsies confirmed the diagnosis of cutaneous T-cell lymphoma, and rearrangements of the T-cell receptor γ chain gene were demonstrated in both biopsy specimens and in peripheral blood. The hepatic and renal biochemistry measurements and findings from the cardiovascular and ocular examinations were normal.

The patient underwent intensive treatment with photopheresis cycles initially accompanied by corticosteroid therapy. After the fourth cycle, the patient developed cutaneous phototoxic reactions following overexposure to sunlight. He had taken no other drugs or natural products that could explain this adverse reaction. One week after the fifth cycle, he presented abrupt bilateral loss of visual acuity (2/20 in both eyes). Ophthalmic exploration showed chorioretinitis, and findings from subsequent studies ruled out underlying pathologic conditions associated with uveitis. He was treated with methylprednisolone (250 mg intravenously every 6 hours for 5 days), which resulted in complete retinal healing and total recovery of visual acuity.

Given the good response of the lymphoma to the therapy, we decided to apply a further ECP cycle with absolute protection from UV-A radiation and observation of the psoralen levels. The monitoring revealed unexpected detectable concentrations of the drug long after its administration (Table). Four weeks after this treatment, the patient presented a new chorioretinitis, which again responded to high doses of corticosteroids. No further photopheresis was performed.

Table Graphic Jump LocationTable. Psoralen Plasma Levels Shown by the Patient After Receiving the Sixth Cycle of Extracorporeal Photochemotherapy (ECP)

The Figure shows the aforementioned clinical complications and the patient's response to therapy. The patient is presently receiving treatment with oral retinoids, the lymphoma is in remission, and the visual acuity is 16/20 OU.

Place holder to copy figure label and caption
Figure.

A, Clinical complications of extracorporeal photochemotherapy (ECP): images of solar erythema and the first chorioretinitis episode; B, cycles of ECP and corticosteroid treatment; and C, clinical evolution of lymphoma evaluated by skin score and percentage of pathological phenotype lymphocytes. PK indicates pharmacokinetics.

Graphic Jump Location

COMMENT

Data from over 160 centers in Europe and the United States have shown ECP to have a very low adverse effect profile, and, to our knowledge, no cases of retinal toxic effects have previously been reported. However, our patient developed cutaneous phototoxic reactions and chorioretinitis after the fifth cycle of ECP. Chorioretinitis reappeared 4 weeks after a further ECP cycle, coinciding with unexpected measurable plasma levels of 8-MOP.

Psoralen may produce various eye injuries including corneal and lens opacities, conjunctival hyperemia, lessened tear production, and increased retinal photosensitivity.1820 Chorioretinitis, however, has not been described. In general, avoiding exposure to sunlight is recommended for just 48 hours after each ECP cycle. In our patient, with such persistent drug levels, subsequent exposure to intense sunlight could have photoactivated the 8-MOP because the UV-A radiation is not completely filtered by the lens. Nonetheless, other mechanisms such as immune processes cannot be ruled out. Our ECP procedure is performed by adding 8-MOP directly to the mononuclear cell concentrate instead of oral administration. The amount of psoralen administered to a patient in this way is negligible, which explains why psoralen was not detected in the blood at any time in any of the 10 comparison ECP patients. The half-life of 8-MOP in blood following oral administration is approximately 1 hour. However, for our patient, the pharmacokinetic study carried out after administration of the last ECP cycle showed that he had measurable drug levels even 18 weeks later (Table). A psoralen blood concentration of at least 50 ng/mL and simultaneous exposure to UV-A radiation are needed for phototoxic effects to take place in tissue.21 With the dose used in every procedure of ECP (0.06 mg) and assuming total impairment of drug elimination, at least 5 procedures would be necessary to reach levels of 50 ng/mL in a patient weighing approximately 70 kg. Our patient manifested the first ocular toxic effect after the 10th procedure.

The detectable drug level at time zero following the final ECP cycle (40 ng/mL; Table) demonstrated the existence of drug accumulation during the former ECP procedures, which made us suspect the existence of an alteration in a metabolic route involved in the drug's elimination. We tried to confirm this hypothesis by determining the presence of polymorphisms in drug metabolizing enzymes and transporters possibly involved in psoralen disposition. Of the CYP genes analyzed, the patient only carried the CYP3A5*3 allelic variant, which is present in more than 90% of the white population.22 He was also found to be heterozygous for 3 polymorphisms found in the P-glycoprotein–encoding gene ABCB1, namely C1236T, G2677T, and C3435T. While these mutations have been related to decreased P-glycoprotein functionality and subsequent drug accumulation and toxic effects,23 in our opinion it is unlikely that a heterozygous haplotype relatively common in the white population24 would lead to such an accumulation of 8-MOP as observed in the present case. Additional polymorphism, haplotype, and even phenotype analyses are needed to explain the extremely persistent drug levels in this patient.

In summary, to our knowledge, this is the first report of retinal toxic reactions resulting from ECP therapy. The mechanism of this adverse effect probably involves a genetic defect that seriously affects genes involved in 8-MOP metabolism or transport. Further studies should be undertaken to try to identify this defect and to determine whether it might be useful to explore this possibility before the implementation of photopheresis therapies to prevent similar problems in other patients.

ARTICLE INFORMATION

Correspondence: Jose Manuel Vagace, MD, PhD, Department of Hematology, Infanta Cristina University Hospital, Avda Elvas s/n, E-06080 Badajoz, Spain (jvagacev@aehh.org).

Financial Disclosure: None reported.

Accepted for Publication: November 7, 2006.

Author Contributions: Dr Vagace had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Vagace, Gervasini, Benitez, and Bajo. Acquisition of data: Vagace, Gervasini, Morais, Alonso, de Argila, and Arranz. Analysis and interpretation of data: Vagace, Gervasini, Morais, Benitez, Alonso, de Argila, Arranz, and Bajo. Drafting of the manuscript: Gervasini and Morais. Critical revision of the manuscript for important intellectual content: Vagace, Gervasini, Morais, Benitez, Alonso, de Argila, and Arranz. Administrative, technical, and material support: Gervasini, Morais, and Arranz. Study supervision: Vagace, Gervasini, Benitez, de Argila, Arranz, and Bajo.

Funding/Support: This study was supported in part by grants PI 020406 and 03/1432 from Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain, and Fondo Social Europeo; and grants SCSS0502 from Junta de Extremadura, Consejeria de Sanidad y Consumo, Merida, Spain, and 2PRO4A052 from Junta de Extremadura, Consejería de Educación Ciencia y Tecnología, Merida.

REFERENCES

Vagace Valero  JMAlonso Escobar  NDe Argila Fernandez-Duran  D  et al.  Fotoféresis: nueva terapia inmunomoduladora para enfermedades mediadas por linfocitos T. An Med Interna 2003;20421- 426
PubMed
Salvaneschi  LPerotti  CTorretta  L Adverse effects associated with extracorporeal photochemotherapy [letter]. Transfusion 2000;40121
PubMed Link to Article
Staberg  BHueg  B Interaction between 8-methoxypsoralen and phenytoin: consequence for PUVA therapy. Acta Derm Venereol 1985;65553- 555
PubMed
Edwards  DJBellevue  FH  IIIWoster  PM Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996;241287- 1290
PubMed
Mäenpää  JSigusch  HRaunio  H  et al.  Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes. Biochem Pharmacol 1993;451035- 1042
PubMed Link to Article
Koenigs  LLPeter  RMThompson  SJRettie  AETrager  WF Mechanism-based inactivation of human liver cytochrome P450 2A6 by 8-methoxypsoralen. Drug Metab Dispos 1997;251407- 1415
PubMed
Barthomeuf  CGrassi  JDemeule  MFournier  CBoivin  DBeliveau  R Inhibition of P-glycoprotein transport function and reversion of MDR1 multidrug resistance by cnidiadin. Cancer Chemother Pharmacol 2005;56173- 181
PubMed Link to Article
Edelson  RBerger  CGasparro  F  et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 1987;316297- 303
PubMed Link to Article
Perotti  CTorretta  LViarengo  G  et al.  Feasibility and safety of a new technique of extracorporeal photochemotherapy: experience of 240 procedures. Haematologica 1999;84237- 241
PubMed
Vagace  JMVargas  MLMelero  J  et al.  Un Nuevo Sistema de Irradiación Ultravioleta (UVAFEC) para Fotoféresis.  Valencia, Spain Congreso Sociedad Española de Transfusión Sanguínea2004;
Gómez  MIAzana  JMArranz  IHarto  ALedo  A Plasma levels of 8-methoxypsoralen after bath-PUVA for psoriasis: relationship to disease severity. Br J Dermatol 1995;13337- 40
PubMed Link to Article
Cavalli  SAHirata  MHHirata  RD Detection of MboII polymorphism at the 5′ promoter region of CYP3A4. Clin Chem 2001;47348- 351
PubMed
van Schaik  RHvan der Heiden  IPvan den Anker  JNLindemans  J CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 2002;481668- 1671
PubMed
Oscarson  MGullsten  HRautio  A  et al.  Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett 1998;438201- 205
PubMed Link to Article
Oscarson  MMcLellan  RAGullsten  H  et al.  Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett 1999;448105- 110
PubMed Link to Article
Oscarson  MMcLellan  RAGullsten  H  et al.  Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett 1999;460321- 327
PubMed Link to Article
Pitarque  Mvon Richter  OOke  BBerkkan  HOscarson  MIngelman-Sundberg  M Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem Biophys Res Commun 2001;284455- 460
PubMed Link to Article
Barker  FMDayhaw-Barker  PForbes  PDDavies  RE Ocular effects of treatment with various psoralen derivatives and ultraviolet-A (UVA) radiation in HRA/Skh hairless mice. Acta Ophthalmol (Copenh) 1986;64471- 478
PubMed Link to Article
Calzavara-Pinton  PGCarlino  AManfredi  ESemeraro  FZane  CDe Panfilis  G Ocular side effects of PUVA-treated patients refusing eye sun protection. Acta Derm Venereol Suppl (Stockh) 1994;186164- 165
PubMed
Souêtre  EDe Galeani  BGastaud  PSalvati  EDarcourt  G 5-Methoxypsoralen increases the sensitivity of the retina to light in humans. Eur J Clin Pharmacol 1989;3659- 61
PubMed Link to Article
Andreu  GLeon  AHeshmati  F  et al.  Extracorporeal photochemotherapy: evaluation of two techniques and use in connective tissue disorders. Transfus Sci 1994;15443- 454
PubMed Link to Article
Xie  HGWood  AJKim  RBStein  CMWilkinson  GR Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 2004;5243- 272
PubMed Link to Article
Yamauchi  AIeiri  IKataoka  Y  et al.  Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002;74571- 572
PubMed Link to Article
Marzolini  CPaus  EBuclin  TKim  RB Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004;7513- 33
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

A, Clinical complications of extracorporeal photochemotherapy (ECP): images of solar erythema and the first chorioretinitis episode; B, cycles of ECP and corticosteroid treatment; and C, clinical evolution of lymphoma evaluated by skin score and percentage of pathological phenotype lymphocytes. PK indicates pharmacokinetics.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Psoralen Plasma Levels Shown by the Patient After Receiving the Sixth Cycle of Extracorporeal Photochemotherapy (ECP)

References

Vagace Valero  JMAlonso Escobar  NDe Argila Fernandez-Duran  D  et al.  Fotoféresis: nueva terapia inmunomoduladora para enfermedades mediadas por linfocitos T. An Med Interna 2003;20421- 426
PubMed
Salvaneschi  LPerotti  CTorretta  L Adverse effects associated with extracorporeal photochemotherapy [letter]. Transfusion 2000;40121
PubMed Link to Article
Staberg  BHueg  B Interaction between 8-methoxypsoralen and phenytoin: consequence for PUVA therapy. Acta Derm Venereol 1985;65553- 555
PubMed
Edwards  DJBellevue  FH  IIIWoster  PM Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice. Drug Metab Dispos 1996;241287- 1290
PubMed
Mäenpää  JSigusch  HRaunio  H  et al.  Differential inhibition of coumarin 7-hydroxylase activity in mouse and human liver microsomes. Biochem Pharmacol 1993;451035- 1042
PubMed Link to Article
Koenigs  LLPeter  RMThompson  SJRettie  AETrager  WF Mechanism-based inactivation of human liver cytochrome P450 2A6 by 8-methoxypsoralen. Drug Metab Dispos 1997;251407- 1415
PubMed
Barthomeuf  CGrassi  JDemeule  MFournier  CBoivin  DBeliveau  R Inhibition of P-glycoprotein transport function and reversion of MDR1 multidrug resistance by cnidiadin. Cancer Chemother Pharmacol 2005;56173- 181
PubMed Link to Article
Edelson  RBerger  CGasparro  F  et al.  Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy: preliminary results. N Engl J Med 1987;316297- 303
PubMed Link to Article
Perotti  CTorretta  LViarengo  G  et al.  Feasibility and safety of a new technique of extracorporeal photochemotherapy: experience of 240 procedures. Haematologica 1999;84237- 241
PubMed
Vagace  JMVargas  MLMelero  J  et al.  Un Nuevo Sistema de Irradiación Ultravioleta (UVAFEC) para Fotoféresis.  Valencia, Spain Congreso Sociedad Española de Transfusión Sanguínea2004;
Gómez  MIAzana  JMArranz  IHarto  ALedo  A Plasma levels of 8-methoxypsoralen after bath-PUVA for psoriasis: relationship to disease severity. Br J Dermatol 1995;13337- 40
PubMed Link to Article
Cavalli  SAHirata  MHHirata  RD Detection of MboII polymorphism at the 5′ promoter region of CYP3A4. Clin Chem 2001;47348- 351
PubMed
van Schaik  RHvan der Heiden  IPvan den Anker  JNLindemans  J CYP3A5 variant allele frequencies in Dutch Caucasians. Clin Chem 2002;481668- 1671
PubMed
Oscarson  MGullsten  HRautio  A  et al.  Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase. FEBS Lett 1998;438201- 205
PubMed Link to Article
Oscarson  MMcLellan  RAGullsten  H  et al.  Characterisation and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population. FEBS Lett 1999;448105- 110
PubMed Link to Article
Oscarson  MMcLellan  RAGullsten  H  et al.  Identification and characterisation of novel polymorphisms in the CYP2A locus: implications for nicotine metabolism. FEBS Lett 1999;460321- 327
PubMed Link to Article
Pitarque  Mvon Richter  OOke  BBerkkan  HOscarson  MIngelman-Sundberg  M Identification of a single nucleotide polymorphism in the TATA box of the CYP2A6 gene: impairment of its promoter activity. Biochem Biophys Res Commun 2001;284455- 460
PubMed Link to Article
Barker  FMDayhaw-Barker  PForbes  PDDavies  RE Ocular effects of treatment with various psoralen derivatives and ultraviolet-A (UVA) radiation in HRA/Skh hairless mice. Acta Ophthalmol (Copenh) 1986;64471- 478
PubMed Link to Article
Calzavara-Pinton  PGCarlino  AManfredi  ESemeraro  FZane  CDe Panfilis  G Ocular side effects of PUVA-treated patients refusing eye sun protection. Acta Derm Venereol Suppl (Stockh) 1994;186164- 165
PubMed
Souêtre  EDe Galeani  BGastaud  PSalvati  EDarcourt  G 5-Methoxypsoralen increases the sensitivity of the retina to light in humans. Eur J Clin Pharmacol 1989;3659- 61
PubMed Link to Article
Andreu  GLeon  AHeshmati  F  et al.  Extracorporeal photochemotherapy: evaluation of two techniques and use in connective tissue disorders. Transfus Sci 1994;15443- 454
PubMed Link to Article
Xie  HGWood  AJKim  RBStein  CMWilkinson  GR Genetic variability in CYP3A5 and its possible consequences. Pharmacogenomics 2004;5243- 272
PubMed Link to Article
Yamauchi  AIeiri  IKataoka  Y  et al.  Neurotoxicity induced by tacrolimus after liver transplantation: relation to genetic polymorphisms of the ABCB1 (MDR1) gene. Transplantation 2002;74571- 572
PubMed Link to Article
Marzolini  CPaus  EBuclin  TKim  RB Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004;7513- 33
PubMed Link to Article

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