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Keywords:

  • graft-versus-host disease;
  • extracorporeal photochemotherapy;
  • ultraviolet;
  • stem cell transplantation;
  • bone marrow

Summary

  1. Top of page
  2. Summary
  3. References

Recent studies suggest that extracorporeal photochemotherapy (ECP) may be beneficial in patients with steroid-refractory chronic graft-versus-host disease (cGvHD). However, it is not yet clear whether certain conditions, such as age, mode of onset of cGvHD etc., influence clinical response and whether certain affected organs are more sensitive to ECP than others. We analysed the main clinical and laboratory parameters related to evolution of the disease in 32 steroid-refractory cGvHD patients, to identify any useful response predictors to ECP. ECP affected the course of the disease positively in 78% (25/32) of our cases.

Graft-versus-host disease (GvHD) is a severe complication of allogeneic haematopoietic stem cell transplantation (HSCT) (Tabbara et al, 2003). Corticosteroids are the mainstay of therapy for GvHD (Vogelsang, 2001; Martin et al, 2004). Those patients developing steroid-refractory disease have a particularly dismal prognosis (Carpenter & Sanders, 2003). To date, no standard first line treatment strategy exists for patients who develop this complication (Ilhan et al, 2004).

Extracorporeal photochemotherapy (ECP) is emerging as a promising alternative therapy for GvHD (Greinix et al, 1998; Apisarnthanarax et al, 2003; Bisaccia et al, 2003; Seaton et al, 2003; Ilhan et al, 2004). Although results of randomised studies are not yet available, a clinical response rate of about 60% has been reported in steroid-refractory cGvHD patients undergoing ECP (Apisarnthanarax et al, 2003; Bisaccia et al, 2003; Ilhan et al, 2004).

The aim of the present study was to evaluate ECP clinical effects on a large sample of steroid-refractory chronic GvHD (cGvHD) patients and to analyse clinical and laboratory parameters to assess the efficacy of ECP for each affected organ.

The data of patients before treatment is given in Table I. Three identical UVAR photopheresis units (Therakos Inc., West Chester, PA, USA) were used for ECP as previously reported (Seaton et al, 2003). On enrolment, patients underwent detailed clinical examination, analysis and other procedures to document and assess the involvement of the various organs and systems. Routine analyses were performed at each cycle of ECP. Skin involvement was assessed every 3 months by the same observer for each patient. Skin biopsies were obtained in respective areas prior to starting ECP and were repeated 6 and 12 months after the start of treatment, when possible near the site of the first biopsy. Activity of cutaneous cGvHD was quantified during treatment on the basis of surface area involved and severity. The measuring technique was adapted from Child's grading method, which associates quantification of skin area involved with qualitative evaluation of clinical manifestations (Child et al, 1999). Unlike Child et al (1999), in sclerodermoid cGvHD, we used a grading scale based on elastometry (Cutometer SEM 474; Courage + Khazaka Electronic GmbH, Cologne, Germany) as previously reported (Fimiani et al, 1997). Diagnosis of oral mucosal cGvHD was based on clinical and histological examination. Ophthalmologic examination and Schirmer test was repeated every 3 months for optical GvHD. Hepatic involvement was diagnosed on the basis of liver function parameters. Liver biopsy was only performed in those patients in whom the liver alone was involved. Liver function parameters were evaluated before each treatment cycle. Pulmonary involvement was assessed by a pneumologist. Lung function tests: forced expiratory volume in 1 s, forced vital capacity and total carbon monoxide transfer (CO transfer) were assessed at the start of treatment in all patients and every 6 months thereafter only in those showing altered respiratory function. These patients also underwent a computerised axial tomography scan before and 12 months after ECP. Thrombocytopenia was evaluated as follows: complete response (CR), when the platelet count returned to the normal range (130–400 × 109/l); partial response, when initial value improved by more than 25% but did not become normal; stabilisation (ST), when an increase did not exceed 25% and progression (P), when the platelet count decreased. To assess the role of ECP in the context of other therapies we introduced the parameter ‘overall outcome’. The contribution of ECP was considered: determinant (++) when CR was observed in all organs involved after the start of ECP and when the dose of immunosuppressants could be reduced by at least 50% with respect to initial therapy; ineffective (−) when P was observed in one of the organs involved, when it was necessary to increase the dose of immunosuppressants, or when CR was not observed in any organ and immunosuppressants were not reduced by more than 50%; good (+) in all other cases. Overall outcome was scored 0 when ECP was ineffective and 1 when ECP was determinant or good. This provided a realistic, although somewhat arbitrary, line between responders and non-responders, which was necessary for meaningful statistical analysis. All the parameters evaluated (numerical and categorical) were analysed with respect to a binary variable, namely overall outcome 0 or 1.

Table I.  Study population.
Patient no.Age (years)Sex*Time interval between HSCT and first cycle of ECP (months)aGvHDcGVHD (type)Clinical involvementTherapy
CutaneousOral mucosaOcularHepaticThrombocytopeniaLung
  1. P, progressive; Q, quiescent; D, de novo; S, sclerodermoid; L, lichenoid; C, ciclosporin; A, azathioprine; TH, thalidomide; TC, tacrolimus; PR, prednisone; MP, methylprednisolone; MM, mycophenolate mofetile; H, hydroxychloroquine. *(1), <6 months; (2), between 6 and 12 months; (3), >12 months.

135M11 (2)NoDYes (L)YesNoNoYesNoC
237M2 (1)YesPYes (L)NoNoYesYesNoMP
356M11 (2)YesPNoYesYesNoNoYesC, A
460W2 (1)NoDYes (L)YesNoNoNoNoC, TH
535M6 (2)YesPYes (L)NoNoNoYesNoTC
651F2 (1)YesQYes (L)YesYesYesNoNoC, PR
725M3 (1)YesQYes (L)NoNoYesNoYesC, PR
819M2 (1)YesPNoYesNoYesNoNoC, MP
943M13 (3)NoDYes (L)YesNoYesNoNoC, MP
1029M2 (1)NoDYes (S)NoNoNoYesNoC, PR, A
1140F10 (2)NoDYes (S)YesYesYesNoNoC, MP, A, TH
1249M56 (3)YesPYes (L)YesYesYesYesNoP, TH, MM, TC
1319M4 (1)NoDYes (L)NoNoNoNoNoC, A
1435M46 (3)NoDYes (S)YesYesYesNoNoC, P, MM
1542F5 (1)YesPYes (L)YesYesNoNoNoC
1631F13 (3)YesPYes (S)NoNoYesYesYesMP, MM, TC, H
1734M5 (1)YesPYes (L)YesYesYesNoNoC, P, TH
1829F4 (1)NoDNoNoNoYesNoNoP
1918F9 (2)YesPYes (S)YesYesYesYesNoP, C, A
2035M3 (1)YesPYes (L)YesYesNoNoNoC, P, A
2145M7 (2)YesPYes (L)YesNoNoYesNoC, P, TH
2252F1 (1)NoDYes (S)YesYesYesNoNoC, P, TH
2335M4 (1)YesQYes (L)YesNoYesYesYesC, P, TH, MM
2441F14 (3)NoDNoYesNoYesYesNoC
2555F1 (1)YesPYes (L)YesNoYesNoNoC, P, MM
2658M43 (3)YesQNoYesNoYesYesNoC, MP
2758M44 (3)NoDYes (L)YesYesYesNoNoC, P
2821M2 (1)YesQYes (L)YesYesYesYesNoP, TC
2942M2 (1)YesPYes (L)YesYesYesNoNoC, P, MM
3019M8 (2)YesQYes (L)YesYesYesNoNoC, P, MM
3137F2 (1)NoDYes (L)YesYesYesNoNoC, MP
3244F5 (1)NoDYes (S)YesYesNoNoYesC, P

To evaluate the statistical dependence of overall outcome (0, negative; 1, positive) after 1 year of ECP, all clinical and historical variables of each patient before treatment were analysed. Qualitative/categorical variables were studied by means of contingency tables using the Fisher's exact test for 2 × 2 tables and the chi-squared test for larger tables. Univariate anova and the non-parametric Mann–Whitney test were used for quantitative variables. To determine whether there were significant changes in quantitative variables, the t-test for paired data was applied to the sample of all treated patients. Finally, for these six twice-measured variables, multivariate analysis of variance (manova) for repeated measures was also used to evaluate between-subject and within-subject effects. A significance level of 95% (P < 0·05) was adopted for all statistical analyses, which were performed with the Statistical Package for the Social Sciences (spss) software.

The 32 patients in this study received a total of 1128 cycles of ECP, with only minor side-effects (slight hypotension, haematomas at antecubital venepuncture sites), none of which required interruption of treatment. The response obtained for each organ/apparatus level are reported in Table II. We observed a negative outcome in eight patients and a positive outcome in 24 patients (78%) (Table II). No statistical differences (P > 0·05) in outcome were found for any categorical variable, except for the number of immunosuppressant drugs at the start of ECP and time interval between HSCT and first cycle of ECP. Univariate anova and Mann–Whitney test gave no significant differences (P > 0·05) in outcome for these three analysed variables except for the interval between transplant and first cycle of ECP. Paired t-test of the six quantitative variables before and after 1 year of treatment showed significant differences only for skin score, platelet count and levels of transaminases, gamma glutamyl transferase and bilirubin. The multivariate analysis of variance (manova) for repeated measures applied to all subjects indeterminate for outcome (within-subject analysis) confirmed the univariate t-test analysis, giving a statistically significant change in time (P < 0·05) for the five variables (skin score, transaminases, gamma glutamyl transferase, bilirubin and platelet count). When these changes were compared between responders and non-responders (between-subject analysis), no statistical significance was found for the time changes of any variable, nor were interactions between time and outcome found.

Table II.  Results of the study population.
Patient no.Cutaneous cGvHDOral mucosal cGvHDOcular cGvHD responseHepatic cGvHD responseThrombocytopeniaLung cGvHD responseNeuromuscular cGvHD responseOverall outcome
HistoSkin score before ECPSkin score after ECPResponseGradeResponsePlatelet count before ECP*Platelet count after ECP*Response
  1. S, sclerodermoid; L, lichenoid; CR, complete response; PR, partial response; ST, stabilisation; P, progression. * Platelet count (×109/l)

1L1000CR2CR68201CR++ (1)
2L1600CR0PR51248CR++ (1)
32CRCRPR++ (1)
4L300CR2CR++ (1)
5L1200CR0101263CR++ (1)
6L400CR2PRCRCR+ (1)
7L500CR0PRPR++ (1)
81CRCR++ (1)
9L700CR2CRCR++ (1)
10S6020PR058147CR++ (1)
11S12080PR1CRPRPR    PR++ (1)
12L16050PR2PRPRP58215CR− (0)
13L–S8020PR0+ (1)
14S210190ST2PRPRPR− (0)
15L400CR2PRPR ++ (1)
16S120110ST0ST9897STP− (0)
17L300CR2CRCRCR++ (1)
180CR++ (1)
19S120100ST2CRCRPR113155CR+ (1)
20L800CR2CRCR++ (1)
21L500CR2CR76189CR++ (1)
22S120100ST1CRCRPRPR+ (1)
23L800CR1CRPR41205CRST+ (1)
242CRPR104180CR− (0)
25L6030PR2PRPR+ (1)
261CRPR27136CR++ (1)
27L14090PR2PRPRPR− (0)
28L900CR1STPRST25130CR+ (1)
29L18070PR2STPRPR+ (1)
30L14040PR2PRSTP− (0)
31L800CR2CRCRST+ (1)
32S210180ST2CRCRP − (0)

In recent years ECP has proven to have a positive effect on the course of GvHD, with few or no side-effects (Greinix et al, 1998; Child et al, 1999; Apisarnthanarax et al, 2003; Bisaccia et al, 2003; Seaton et al, 2003; Ilhan et al, 2004). Our experience seems to confirm that ECP is indeed useful in the treatment of patients with steroid-refractory cGvHD. In our study ECP was determinant in 22% of cases, good in 56% and ineffective in 22% of patients. On this basis we can say that ECP affected the course of the disease positively in 78% (25/32) of our cases. Our statistical analysis did not uncover clinical or historical parameters that could predict those patients that may be more responsive to ECP except for the number of immunosuppressant drugs at first cycle of ECP, which seemed to show an inverse correlation with therapeutic response, and interval between HSCT and first cycle of photopheresis. These findings can be interpreted in two ways. The first is that patients whose immune system is less suppressed (fewer drugs) respond better to ECP (Fimiani et al, 2004). Of course we cannot exclude that patients initially on fewer immunosuppressants had less aggressive cGvHD, and responded better only for this reason. With regard to the response of the various organs to ECP, our good results/improvements in skin, oral mucosal, liver and conjunctival manifestations are in line with those of other authors (Greinix et al, 1998; Child et al, 1999; Apisarnthanarax et al, 2003; Bisaccia et al, 2003; Seaton et al, 2003; Ilhan et al, 2004). In our series ECP was particularly effective in patients with thrombocytopenia (platelet count <100 × 109/l), producing CR in more than 90% of cases. If these findings are confirmed in larger series of patients, ECP should be immediately considered in all subjects with major or refractory thrombocytopenia. The response of lung involvement to ECP, like that of muscle, is perhaps the least encouraging aspect of our study. This finding, together with that in sclerodermoid forms, suggests that patients with cGvHD and advanced fibrosis have low sensitivity to ECP.

References

  1. Top of page
  2. Summary
  3. References
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