Post-transplant complications Cataracts in patients receiving stem cell transplantation after conditioning with total body irradiation

Transcription

1 (2002) 29, Nature Publishing Group All rights reserved /02 $ Post-transplant complications Cataracts in patients receiving stem cell transplantation after conditioning with total body irradiation C Aristei, M Alessandro, A Santucci 2, F Aversa 2, A Tabillo 2, A Carotti 2, RA Latini, C Cagini 3 and P Latini Institute of Radiotherapy Oncology, General Hospital and Perugia University, Perugia, Italy; 2 Department of Hematology and Bone Marrow Transplantation Unit, General Hospital and Perugia University, Perugia, Italy; and 3 Eye Clinic, General Hospital and Perugia University, Italy Summary: One hundred and ninety-three patients with hematological malignancies and a follow-up year, treated with stem cell transplantation (45 autologous, 99 allogeneic T cell-depleted matched, 49 allogeneic T cell-depleted mismatched) from July 985 to May 998, were considered evaluable for the development of cataracts. Total body irradiation (TBI), administered either according to a hyperfractionated scheme (HTBI) or in a single dose (STBI), was employed in the conditioning regimens. HTBI was prescribed in 94% of patients undergoing allogeneic matched transplant, while STBI was used in 7% of patients receiving allogeneic mismatched and in all patients undergoing autologous transplant. The median follow-up was 7.56 years in the HTBI and 3.02 years in the STBI group. Among the different risk factors analyzed by univariate analysis only the TBI scheme and type of transplant reached statistical significance (P and P 0.00, respectively). By multivariate analysis only the TBI scheme was an independent factor for cataract development (STBI vs HTBI RR 7.2; P 0.0). Our results showed that STBI is more cataractogenic than HTBI. The incidence of cataract we observed was among the lowest described in the literature. T cell depletion, because it prevents graft-versus-host disease and reduces the protracted use of post-transplant steroids, explains the results we obtained. (2002) 29, DOI: 0.038/sj/bmt/ Keywords: cataract; total body irradiation; stem cell transplantation Advances in transplant techniques over the past 20 years have improved long-term survival of patients receiving bone marrow transplant (BMT) and, consequently, have Correspondence: Dr C Aristei, UO Radiotherapy Oncology, Azienda Ospedaliera di Perugia, Policlinico Monteluce, 0622 Perugia, Italy Received 5 June 200; accepted 5 November 200 allowed recognition of the late effects of treatment, such as cataracts. Its incidence has been reported in 3% to 00% of cases. 6 Different risk factors for cataract formation have been described in the literature, these being conditioning regimen, type of transplant, age, acute or chronic graft-versus-host disease (GVHD), steroids and previous prophylactic cranial radiotherapy.,4,5,7,9,0,3,7 Both the use of total body irradiation (TBI) in the pre-transplant regimen and the TBI schedule have been proven to be two of the most important risk factors for the development of cataracts.,4,6,7,9,0,3 Cataract due to radiation is typically posterior, subcapsular, and different from nuclear cataract located in the central part of the lens, which is usually associated with advanced age. Other than the risk factors cited above, the large variability in cataract incidence reported in different studies could depend both on length of follow-up 0 and the generally small number of surviving patients at the end of the longest follow-up. This is because when only a few patients remain, even a small number of cataracts can considerably raise the probability of this late effect. We evaluated the risk of and risk factors for cataract formation in 93 patients receiving two different TBI schedules in their pre-transplant regimen. Patients and methods One hundred and ninety-three patients (33 males, 60 females; median age 33 years, range 2 59) with hematological malignancies who underwent BMT and/or peripheral blood stem cell transplantation (PBSCT) at our institution between July 985 and May 998 were considered evaluable for the development of cataracts. All had a follow-up of at least year and received regular ophthalmological examinations. Written consent was obtained from patients or, in the case of minors, parents, as well as from donors. Forty-five patients received autologous, 99 allogeneic T cell-depleted matched and 49 allogeneic T cell-depleted mismatched BMT and/or PBSCT. Characteristics of patients are detailed in Table. TBI was administered either according to a hyperfractionated scheme (HTBI) or in a single dose (STBI). It was

2 504 Table Patient characteristics HTBI STBI Total Number of patients Median age (range) 3 (6 53) 37.5 (2 59) 33 (2 59) Male/Female 78/29 55/3 33/60 Disease Chronic myeloid leukemia Acute lymphoid leukemia Acute myeloid leukemia Non-Hodgkin s lymphoma Myelodysplasia 2 3 Multiple myeloma Transplant Autologous Allogeneic TCD matched Allogeneic TCD mismatched HTBI = hyperfractionated total body irradiation; STBI = single dose total body irradiation; TCD = T-cell depleted. delivered by a 8 MV linear accelerator to all but the first 33 patients, who received HTBI and were treated with a 60 Cobalt Unit. Details of the TBI techniques adopted have been published previously HTBI was administered three times a day, 5 or 6 h apart, in all but two patients who received 2 Gy twice a day for 3 days. The median single dose was.2 Gy (range.2 2), median total dose 4.4 Gy (range 2 5.6). In the STBI group the median dose was 8 Gy (range 7 8.5). The median instantaneous dose rate was 9.54 cgy/min/midplane (range ) in the HTBI and 6 cgy/min/midplane (range ) in the STBI group. HTBI was employed in almost all patients who underwent allogeneic matched transplantation (93 of 99; 93.94%), while STBI was used in the majority of patients who received allogeneic mismatched (35 of 49; 7%) and in all patients receiving autologous transplantation (Table ). TBI was the first treatment administered to all patients, followed by the chemotherapy schemes described in past studies The rationale behind the use of the different pre-transplant schedules, selected according to the type of transplant, has been explained previously. 8 2,25 Ophthalmological examinations were carried out before transplant, 6 and 2 months after, and subsequently yearly. Each patient underwent visual acuity testing, tonometry, slit-lamp and fundus examination after pupillary dilatation. As in other past reports, posterior subcapsular cataract was defined as the presence of vacuolar opacities beneath the posterior lens capsule. 0 Patients with cataracts prior to transplant, either congenital or acquired, were excluded from the analysis. the 50th percentile in the two schedules. The probability of developing cataracts was calculated applying the Kaplan Meier method and analyzed by the log-rank test. Previous prophylactic cranial radiotherapy, which was given to two acute lymphoid leukemia patients (one in the HTBI, one in the STBI group) as central nervous system prophylaxis, was not analyzed as a risk factor. TBI dose was not examined because 77.6% of patients received 4.4 Gy in the HTBI and 86% of patients received 8 Gy in the STBI group. Multivariate analysis was performed applying the Cox regression model. Results The median follow-up was 7.56 years (range ) in the HTBI and 3.02 years (range ) in the STBI group. Cataracts were observed in 4 of the 07 (3%) patients who had undergone HTBI and in 8 of the 86 (2%) patients who had received STBI; in all but two cases they were bilateral. Median time for development was 7.6 years (range.6 4) after HTBI and 2.52 years (range ) after STBI. The hazard rate of cataract development was distributed throughout years 0 among patients who received HTBI, while it was greatest between the second and third year in patients treated with STBI. Two patients in the HTBI (4.3%) and in the STBI (6.%) group required surgery (P 0.002). The two patients in the HTBI group were 45 and 52 years old, while the median age of the patients in the STBI group was 47 years (range 8 58). The decision to perform surgery was based upon patient vision in the context of lifestyle. Notwithstanding this, all patients receiving surgery had a visual acuity 5/0. Among the different risk factors tested on univariate analysis only the TBI scheme and type of transplant reached statistical significance (Table 2). The probability of developing cataracts was 23 ± 6% at 0 years and 74 ± 2% at 4 years in the HTBI group. In the STBI group the probability at 5 years was 4 ± 9% (P 0.000) (Figure ). The probability was 42 ± 2% at 5 years after autologous, 27 ± 8% at 3 years after allogeneic mismatched, whereas after allogeneic matched transplant it was 25 ± 7% at 0 years, and reached 75 ± 20% at 4 years (P 0.00) (Figure 2). The results observed at 4 years in the HTBI group and in allogeneic matched BMT patients depended on two late events occurring in two of the three remaining patients who survived more than 4 years. Multivariate survival analysis showed that only the TBI scheme reached statistical significance (STBI vs HTBI RR 7.2, P 0.0). Statistical analysis On univariate survival analysis, different risk factors were analyzed: age (categorized as 30 years and 30 years), type of transplant, GVHD, steroid therapy, TBI scheme. Furthermore, for each TBI scheme, a different dose rate value, categorized as 9 and 9 cgy/min in the HTBI and 6 and 6 cgy/min in the STBI group was analyzed. The choice of dose rate cut-off was based on the value at Discussion Different risk factors for cataract formation such as conditioning regimen, type of transplant, age, acute or chronic GVHD, steroids and previous prophylactic cranial radiotherapy have been reported after stem cell transplantation.,4,5,7,9,0,3,7 Among the factors related to conditioning regimen, TBI is the most important and the TBI

3 Table 2 analysis Risk factors for the development of cataracts: univariate Factors No. patients Cataracts P Age 30 years 8 NS 30 years 2 2 Type of transplant Autologous 45 0 Allogeneic TCD M Allogeneic TCD MM 49 8 Allogeneic TCD MM 49 8 GVHD No 79 3 NS Yes 4 Steroids No NS Yes 29 3 TBI scheme HTBI STBI 86 8 Dose rate HTBI NS STBI NS TCD = T cell depleted; M = matched; MM = mismatched; HTBI = hyperfractionated total body irradiation; STBI = single dose total body irradiation; NS = not significant. Probability STBI (n = 86) HTBI (n = 07) P < Years Figure Probability estimates of developing cataract according to the TBI scheme. parameters that can influence cataract development are fractionation, total dose, and dose rate.,4,6,7,9,0,3,26 28 In our series, of all the risk factors analyzed on univariate analysis only the TBI scheme and type of transplant proved to be statistically significant. Regarding the TBI scheme, administration in a single dose was more cataractogenic and was associated with an increased need for surgery. Furthermore, the hazard rate of cataract development was very different between the two groups; it was greatest between years 2 and 3 among patients who received STBI, while in the HTBI group it was distributed throughout years 0. Probability autologous (n = 45) allogeneic MM (n = 49) allogeneic M (n = 99) P < Years Figure 2 Probability estimates of developing cataract according to the kind of transplant. M = matched; MM = mismatched. It should be noted that estimates in the final years were calculated on a very small number of patients and consequently the standard deviation was high. The median follow-up of 3.02 years in the STBI group did not permit longterm evaluation, as was possible in the HTBI group, where the follow-up was longer and two late events were observed at 4 years. This strongly suggests that patients risk developing cataracts at any time following TBI. In the HTBI group the probability of developing cataracts at 0 years was lower than reported by others over the same period. 9,0 We believe that the hyperfractionated scheme we selected, which utilized a median of 2 fractions of.2 Gy, allowed sparing of the lens. In fact more than six fractions were associated with a lower risk of cataract formation in the European Group for Blood and Marrow Transplantation (EBMT) Registry series. 3 Furthermore, the low incidence of GVHD observed, due to the T cell depletion technique adopted, and the small number of patients treated with steroids, explain the results we obtained. The low incidence of GVHD and the small number of patients treated with steroids also influenced the results observed in the STBI group, where the probability of cataracts at 5 years was in line with the lowest reported in the literature at the same time. 8,3 In other reports, a lower incidence of cataracts was seen with the selection of a low dose rate, after both fractionated TBI and STBI In our study dose rate was not shown to be a risk factor by univariate analysis, after either HTBI, or STBI. This could have depended on the fact that the median dose rate value was higher than those used in other studies. Moreover, in the HTBI group the number of fractions employed could have influenced the results obtained. In fact, more than six fractions was linked to the disappearance of the importance of dose rate in the EBMT Registry series. 3 Very few studies have analyzed type of transplant as a risk factor for cataracts and the results obtained by univariate analysis have been contradictory. 0,7,28 In our series, type of transplant, which was significant by univariate analysis, lost its significance by multivariate analysis, where it emerged as a confounding factor due to its strong association with the TBI schedule. Therefore, only the TBI scheme proved to be an independent factor for cataract development by multivariate analysis, which showed STBI to be more cataractogenic than HTBI (RR 7.2; P 0.0). 505

4 506 In some studies, GVHD and steroids proved to be risk factors for cataracts.,5,8 0,7 The lack of significance seen in our study is due to the small number of patients who developed GVHD and/or were treated with steroids for a long time and the small number of patients who developed cataracts. In our series, as in most others, age at transplant did not influence the incidence of cataracts,,4,9,0,28 30 while the opposite was found in the EBMT Group study. 3 The results of our study identified, among all the tested risk factors, TBI as the sole cause of cataract formation. Both HTBI and STBI triggered cataracts but after STBI the risk of developing this late effect was significantly higher and the latent period between transplant and cataract formation was shorter. Furthermore, cataracts observed after STBI required surgery more frequently. Nevertheless, the incidence of cataracts that we observed was among the lowest described in the literature, after either HTBI or STBI. T cell depletion, because it prevents GVHD and reduces the protracted use of post-transplant steroids, explains the results we obtained. Acknowledgements This work was supported in part by AIRC (Associazione Italiana Ricerca sul Cancro). References Deeg HJ, Flournoy N, Sullivan KM et al. Cataracts after total body irradiation and marrow transplantation: a sparing effect of dose fractionation. Int J Radiat Oncol Biol Phys 984; 0: Barret A, Nicholls J, Gibson B. Late effects of total body irradiation. Radiother Oncol 987; 9: Kim TH, McGlave PB, Ramsay N et al. Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission. Int J Radiat Oncol Biol Phys 990; 9: Calissendorff B, Bolme P, el Azazi M. The development of cataract in children as a late side-effect of bone marrow transplantation. Bone Marrow Transplant 99; 7: Fyles GM, Messner HA, Lockwood G et al. Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cgy delivered with a high dose rate. Bone Marrow Transplant 99; 8: Bray LC, Carey PJ, Proctor SJ et al. Ocular complications of bone marrow transplantation. Br J Ophthalmol 99; 75: Calissendorff BM, Bolme P. Cataract development and outcome of surgery in bone marrow transplanted children. Br J Ophthalmol 993; 77: Hamon MD, Gale RF, Macdonald ID et al. Incidence of cataracts after single fraction total body irradiation: the role of steroids and graft versus host disease. Bone Marrow Transplant 993; 2: Tichelli A, Gratwohl A, Egger T et al. Cataract formation after bone marrow transplantation. Ann Intern Med 993; 9: Benyunes MC, Sullivan KM, Deeg HJ et al. Cataracts after bone marrow transplantation: long-term follow-up of adults treated with fractionated total body irradiation. Int J Radiat Oncol Biol Phys 995; 32: Chou RH, Wong GB, Kramer JH et al. Toxicities of totalbody irradiation for pediatric bone marrow transplantation. Int J Radiat Oncol Biol Phys 996; 34: Michel G, Socié G, Gebhard F et al. Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation. A report from the Société Française de Greffe de Moelle. J Clin Oncol 997; 5: Belkacemi Y, Labopin M, Vernant JP et al. Cataracts after total body irradiation and bone marrow transplantation in patients with acute leukemia in complete remission: a study of the European Group for Blood and Marrow Transplantation. Int J Radiat Oncol Biol Phys 998; 4: Ringdén O, Remberger M, Ruutu T et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: longterm results of a randomized trial in allogeneic marrow recipients with leukemia. Blood 999; 93: Zierhut D, Lohr F, Schraube P et al. Cataract incidence after total-body irradiation. Int J Radiat Oncol Biol Phys 2000; 46: Vaidya SJ, Atra A, Bahl S et al. Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission long-term follow-up. Bone Marrow Transplant 2000; 25: van Kempen-Harteveld ML, Struikmans H, Kal HB et al. Cataract-free interval and severity of cataract after total body irradiation and bone marrow transplantation: influence of treatment parameters. Int J Radiat Oncol Biol Phys 2000; 48: Latini P, Aristei C, Aversa F et al. Lung damage following bone marrow transplantation after hyperfractionated total body irradiation. Radiother Oncol 99; 22: Latini P, Aristei C, Aversa F et al. Interstitial pneumonitis after hyperfractionated total body irradiation in HLA-matched T-depleted bone marrow transplantation. Int J Radiat Oncol Biol Phys 992; 23: Aristei C, Aversa F, Chionne F et al. Interstitial pneumonitis in acute leukemia patients submitted to T-depleted matched and mismatched bone marrow transplantation. Int J Radiat Oncol Biol Phys 998; 4: Aristei C, Aversa F, Raymondi C et al. Allogeneic matched T- cell-depleted bone marrow transplantation for acute leukemia patients. Cancer J Sci Am 996; 2: Aversa F, Tabilio A, Velardi A et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. New Engl JMed998; 339: Aristei C, Tabilio A. Total-body irradiation in the conditioning regimens for autologous stem cell transplantation in lymphoproliferative disease. Oncologist 999; 4: Aversa F, Tabilio A, Velardi A et al. Transplantation of highly purified peripheral blood CD34+ cells from HLA-identical donors results in rapid engraftment and no GVHD. Blood 2000; 96: 409a (Abstr.). 25 Aristei C, Latini P, Terenzi A et al. Total body irradiationbased regimen in the conditioning of patients submitted to haploidentical stem cell transplantation. Radiother Oncol 200; 58: Ozsahin M, Pène F, Touboul E et al. Total body irradiation before bone marrow transplantation. Results ot two randomized instantaneous dose rates in 57 patients. Cancer 992; 69: Ozsahin M, Belkacemi Y, Pene F et al. Total-body irradiation

5 and cataract incidence: a randomized comparison of two instantaneous dose rates. Int J Radiat Oncol Biol Phys 993; 28: Belkacemi Y, Ozsahin M, Pène F et al. Cataractogenesis after total body irradiation. Int J Radiat Oncol Biol Phys 996; 35: Thomas O, Mahé M-A, Campion L et al. Long-term complications of total body irradiation in adults. Int J Radiat Oncol Biol Phys 200; 49: Schmidt GM, Niland JC, Forman SJ et al. Extended follow-up in 22 long-term allogeneic bone marrow transplant survivors. Issues of quality of life. Transplantation 993; 55: