BK-viruria and haemorrhagic cystitis are more frequent in ... - Nature

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ORIGINAL ARTICLE

BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts G Giraud1, P Priftakis1,2, G Bogdanovic1,3, M Remberger4, M Dubrulle1, A Hau1, R Gutmark1,5, J Mattson4,6, B-M Svahn6, O Ringden6, J Winiarski2, P Ljungman7 and T Dalianis1,4,8 1

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; 2Department of Paediatrics, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; 3Department of Clinical Microbiology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; 4Department of Clinical Immunology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; 5Johns Hopkins University School of Medicine, Baltimore, MD, USA; 6Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden; 7Haematology Centre, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden and 8Swedish Institute for Infectious Disease Control, Solna, Sweden

The influence of conditioning regimen, donor background and HLA matching on development of BK virus (BKV)associated haemorrhagic cystitis (HC) was examined in 175 allogeneic haematopoietic stem cell transplant (HSCT) patients, undergoing 179 HSCT events. Twentyseven patients presented late-onset HC, and BK viruria was verified in 23/27 HC events. Seventy-one (40%) HSCTs were performed with myeloablative conditioning (MC), 108 (60%) were performed with reduced intensity conditioning (RIC), 66 (37%) were performed with a related donor (RD) grafts and 113 (63%) with an unrelated donor (URD) graft. BK viruria was more common during HC, than non-HC events, after MC as compared to RIC (both Po0.001), and with an HLA-mismatched donor (Po0.01). By multivariate logistical regression analysis, independent risk factors for HC were BKV (OR 6.7; 95% CI 2.0–21.7; P ¼ 0.001), MC (OR 6.0; 95% CI 2.1–17.3; Po0.001) and URD (OR 3.4; 95% CI 1.1–10.6; P ¼ 0.03). However, when analysing HSCT performed with URD or RD grafts separately, BKV (OR 8.5; 95% CI 1.8–19.3; P ¼ 0.004) and MC (OR 5.9; 95% CI 1.3–11.3; P ¼ 0.009) increased the risk for HC only with a URD, but not with an RD graft. Bone Marrow Transplantation (2008) 41, 737–742; doi:10.1038/sj.bmt.1705962; published online 7 January 2008 Keywords: BK virus; HC; conditioning; donor source; HLA; predictive factors

Correspondence: Dr T Dalianis, Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital CCK, R8:01, Stockholm 171 76, Sweden. E-mail: [email protected] Received 1 August 2007; revised 6 November 2007; accepted 9 November 2007; published online 7 January 2008

Introduction BK virus (BKV) reactivation1,2 in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) has been associated with late-onset haemorrhagic cystitis (HC).3–5 HC can result in significant morbidity and mortality and thereby influence HSCT outcome.6 Roughly 50–100% of all HSCT recipients develop BK viruria, while only 5–40% progress to HC, indicating that BK reactivation alone is not enough to cause HC.6–9 HC has been suggested to be associated with acute graft versus host disease (aGVHD) in some, but not all, reports.9–13 An increased BK-viral load in the urine or plasma of HC patients has also been observed but has not always been prognostic for HC development.12,13–17 Additionally, adenovirus has been shown to cause HC particularly in Japanese patients.18 The influence of having myeloablative conditioning (MC) or reduced intensity conditioning (RIC) prior to HSCT on the development of HC has also been studied.13,19 It was shown that, in HC, where adenovirus dominated (86%) over the presence of BKV (14%), the cumulative incidence of HC was similar after receiving MC and RIC, but HC was milder in the RIC group as compared to the MC group.19 In contrast, in a recent study by us,13 where the presence of BKV was prominent in HC, receiving RIC rather than MC reduced the risk of developing HC. In addition, we and others have reported that allogeneic HSCT patients with unrelated donor (URD) grafts had a higher risk of HC compared to patients with related donor (RD) grafts.13,20,21 A major histocompatibility antigen (HLA-A*, -B* and -DRB1*) mismatch is unfavourable from a transplantation point of view, while a mismatch of a minor histocompatibility antigen (HLA-C*, DQA*, DQB* and DPA* and DPB*) may result in fewer problems. However, no stringent studies have been performed on the effect of recipient–donor HLA matching and the development of HC.

Haemorrhagic cystitis, conditioning and HLA match G Giraud et al

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We, therefore, studied the impact of donor background, conditioning and HLA matching in BKV-associated HC in a large patient group.

Table 1 Clinical characteristics of all 175 HSCT patientsa, including the distribution of patients during 179 HSCT eventsb with and without HC Patients and diagnosisa,b

Patients, materials and methods Patients From May 2002 to December 2006, 175 successive allogeneic HSCT patients agreed to participate in this study conducted according to the permission 357/01 from the Human Research Ethics Committee of the Karolinska Institute. Of these patients, 85 have been described earlier13 and 4 were transplanted twice; thus, 179 HSCT events were included. The clinical characteristics of the patients are summarized in Table 1, and their HSCT events, their conditioning and donor type and source are summarized in Table 2. Late-onset HC, defined as HC41 week after HSCT, was graded from I to IV as described by Bedi et al., 1994.6 One hundred and eight (60%) HSCT were performed using RIC regimens; fludarabine (90–150 mg/m2) together with 6 Gy fractionated total –body irradiation and 60 mg/kg cyclo phosphamide (Cy), or in combination with 2 Gy fractionated total body irradiation, 8 mg/kg busulphan (Bu), 60 mg/kg Cy, or 120 mg/kg Cy (Table 2). The remaining 71 (40%) HSCT were performed using MC; 12 Gy fractionated total body irradiation and Cy, Bu and Cy and BEAM (Table 2).22–24 BKV detection in urine samples by nested PCR Over 800 urine samples (1–28 samples/patient) were obtained prospectively from the 175 patients during 179 HSCT events. No urine samples were available during four events and these events were excluded from the statistical analyses regarding risk factors for BK viruria. Urine samples were collected, when possible, at weekly intervals during hospitalization starting from the week of conditioning. During follow-up, samples were collected once a month up to 1 year after HSCT. Samples were tested (2.5 and 5 ml), for polyomavirus DNA by nested PCR25 (detection X10 BKV copies/PCR reaction), followed by Hinf-I digestion to differentiate between BK and JC DNA.26 HLA typing and selection of donors All patients were HLA class I and class II typed by allele level PCR-SSP (PCR-sequence specific primers) using DNA from peripheral blood. HLA genotyping was performed using the Olerup SSP HLA Typing Kit (Olerup SSP AB, Stockholm, Sweden). PCR products were separated on a 3% agarose gel, stained with ethidium bromide, by electrophoresis, at 150 V for 30 min and visualized under UV light. For donor selection, an RD was generally preferred prior to a URD. For selection of a URD, an HLA identical donor was considered as the first choice, and thereafter the first priority was given to donors with HLA-A*, -B*, -DRB1* match4HLA-DPA*, -DPB* match4HLA-C*, -DQA* and -DQB* match.25 However, CMV match between recipient and donor was prioritized in some cases before a minor HLA match.27 Bone Marrow Transplantation

Patientsa,b Sex (male/female) Median age (min–max) Underlying diagnosisa,b Leukaemia MDS/Myelo-lymphoproliferative disorder Non-malignant disorder Solid Tumour

Totala

HCb

Non-HCb

106/69a 45 (3–67)

21/6b 32 (3–59)

88/64b 48 (3–67)

95 35

18 4

77 31

28 21

5

23 21

Abbreviations: HC ¼ haemorrhagic cystitis; HSCT ¼ haematopoietic stem cell transplant; MDS ¼ myelo dysplastic syndrome. a Denotes number of patients, and underlying diagnosis per patient; leukaemia: ALL (20), AML (43), CML (22), CLL (4), MDS/AML (5), AUL (1). MDS/myelo- and lympho-proliferative disorders: MDS (13), myeloma (3), lymphoma (1), NHL (9), HL (1), T-LBL (1), mantle cell lymphoma (1), Hodgkin’s lymphoma (1), PCV (1), ET/MPS (1). Nonmalignant diseases: SAA (8), Fanconi’s anaemia (4), ALD (1), MPS (3), Kostman’s syndrome (2), thalassemia (1), ET/MF (2), erythroporphyria (2), amegakaryocytopenia (1), sickle cell anaemia (1), Waldenstroms agammaglobulinaemia (1), PNH (1). Solid tumours: liver cancer (7), kidney cancer (5), prostate cancer (2), colon cancer (5), rectal cancer (1). b Denotes HSCT events; four patients, one woman with CMML and three men, two with AML and one with NHL, all without HC during their first HSCT, were retransplanted and one patient with AML had HC during the second HSCT event.

Statistical analysis Statistical calculations were made using the w2 test. For multivariate analysis, logistic regression models were constructed with forward selection of variables. A univariate P-value of 0.10 was required for inclusion in the multivariate models. In the univariate analyses, the following variables were included: conditioning, donor type, graft source, aGVHD, age, gender, marrow cell dose and anti-thymocyte globulin. In the final multivariate models, only the reported factors (BKV, conditioning, gender and donor for HC and conditioning, gender and HLA mismatch for BK viruria) entered the final models.

Results HC with a dominance of BKV-associated HC Twenty-seven patients (15%) developed HC between 9 and 158 days after HSCT, indicating a 15% incidence of late-onset HC during the 179 HSCT events (Tables 1 and 3). Twenty-six patients developed HC during their first HSCT event, while one patient did so during the second HSCT event. The majority of HC cases (23/27) were regarded as being BKV associated or ‘verified’, since 22 patients had BK viruria during their HC period, and one additional patient who developed HC on day 42, with no available samples during HC, had BK viruria 2 weeks after HC. In the remaining four HC patients, one patient’s urine was JCV DNA positive by PCR during the HC period and three patients had no samples available during their HC


739 Table 2 Clinical characteristics and donor background of 175 HSCT patients, evaluated during their 179 HSCT eventsa for HC in relation to their conditioning regimen

HSCT events

a

Patients, gender, agea Sex (male/female) Median age (min–max) Underlying diagnosisa Leukaemia MDS/myelo- or lympho-proliferative disorder Non-malignant disorder Solid tumour Donorsa Related Unrelated SC sourcea (BM/PBSC/UCB)

RICa

MCa

108 (60%)

71 (40%)

66/42 52 (3–67)

43/28 31 (3–60)

34 30

61 5

23 21

5 0

43 (65%) 65 (58%)

23 (35%) 48 (42%)

19/86/3

20/45/6

Table 3 Clinical characteristics, donor background, HLA matching and conditioning regimen of 175 HSCT patientsa evaluated during their 179 HSCT eventsb for HC and in relation to HC development HCa,b (BKV+)c

Non-HC (BKV+/BKV/ND)a,b,d

HSCT eventsb

27 (23)

152 (60/88/4)

Donorb Related Unrelated

5 (5) 22 (18)

61 (25/34/2) 91 (35/54/2)

HLA recipient/donor matchingb HLA-matched donore HLA-matched±DPf HLA-ABDRB1 mismatchg HLA C, DR, DQA, DQBh

10 12 7 9

Conditioning regimenb Full myeloablative Reduced intensity

21 (18) 6 (5)

50 (27/21/2) 102 (33/67/2)

aGVHDb Grade 0–I Grade II–IV

15 (12) 12 (11)

109 (46/60/3) 43 (14/28/1)

(9) (11) (6) (6)

92 107 15 36

(28/61/3) (36/67/4) (9/6/0) (19/17/0)

a

Conditioning Flu+f-TBI 6 Gy+Cy Flu+TBI 2 Gy Flu+Bu Flu+Cy Flu+Treosulfan Flu+MSC Flu+Treosulfan+Tiotepa Flu+Mel Flu fTBI 12 Gy+Cy Bu+Cy BEAM ATGa

24 2 48 27 3 1 1 1 1 30 40 1 77

45

Abbreviations: ATG ¼ anti-thymocyte globulin as part of conditioning; BM ¼ bone marrow; Bu ¼ busulphan; Cy ¼ cyclophosphamide; Flu ¼ fludarabine; f-TBI ¼ fractionated total-body irradiation; MC ¼ myeloablative conditioning; Mel ¼ melphalan; PBSC ¼ peripheral blood stem cells; RC ¼ reduced-intensity conditioning; UCB ¼ umbilical cord blood. a Denotes number of HSCT events, and all other parameters are listed after HSCT events, including underlying diagnosis, donors, conditioning, ATG, SC source.

period. Adenovirus was not identified in any of the HC patients. Most HC patients, that is, 89% (24/27) of all and 90% (21/23) of those with BK viruria, developed HC within the first 2 months after HSCT. Moreover, most patients (70%) had severe grades of HC (III or IV) (that is, 19/27 of all and 16/23 with BK viruria), while HC (grade II) was documented in the remaining HC patients. In addition, BK viruria during the first 6 months after HSCT was more common in HC patients (89%, 24/27) than in non-HC patients (41%, 60/148) Po0.0001.

HC and aGVHD Acute GVHD X grade II was more common in patients with HC, that is, 44% (12/27) in all and 48% (11/23) in patients with BK viruria, than during HSCT events without HC (28%, 43/152). However, these differences were not significant (Table 3).

Abbreviations: HC ¼ haemorrhagic cystitis; HSCT ¼ haematopoietic stem cell transplant. a Denotes number of patients. b Denotes number of HSCT events. c HC (BKV+), denotes, number of HC patients with BK-viruria around the HC episode. d Non-HC (BKV+/BKV/ND) denotes the number of non-HC patients with a BKV-positive urine sample at some time during the study period or without a BKV-positive urine sample at some time during the study period; denotes four patients where urine samples were not available for testing. e Indicates complete HLA matching only. f Denotes complete HLA matching, without taking a DPA and/or a DP mismatch into account. g Indicates an HLA mismatch with regard to HLA-A*, -B* or -DRB1* and can include additional minor HLA mismatches. h Denotes patients with an HLA-C*, -DQA* or -DQB* mismatch and can include a DPA* or a DPB* mismatch.

HC in relation to conditioning regimen HC was significantly more frequent during HSCT performed with MC than with RIC, compared to HSCT events without HC (Po0.0001), both when including all 27 HC patients or the 23 with verified BK viruria (Table 3). More specifically, 78% of HC patients (21/27 in total and 18/23 with verified BK viruria) received MC, while 22% (6/27 in total and 5/23 with BK viruria) received RIC (Table 3). In HSCT events without HC, 33% (50/152) were performed with MC, while 67% (102/152) were performed with RIC (Table 3). There was no difference regarding the type of MC (Bu/Cy or CyTBI). Severity of HC seemed to be related to conditioning, since HC was severe (grade III–IV) in all six HC patients receiving RIC (data not shown). Also of note, BK viruria was more frequent after MC than after RIC, that is, 65% (45/69) and 36% (38/106), respectively (Po0.001; Table 3).

HC in relation to donor source Having a URD rather than an RD graft was significantly more frequent (Po0.05) in the HC patient group, that is, Bone Marrow Transplantation


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81% (22/27) and 19% (5/27), respectively, than during HSCT events without HC, that is, 60% (91/152) and 40% (61/152), respectively (Table 3). Likewise, in patients with verified BKV-associated HC, having a URD (78%, 18/23), was more common than having an RD graft (22%, 5/23; P ¼ 0.051; Table 3). The proportion of patients with BK viruria was, however, similar during HSCT performed with RD, (47%, 30/64) and URD (47%, 53/111) grafts (Table 3).

HC in relation to HLA matching between recipient and donor Having an HLA-matched donor (with and without DP-match) was more frequent (Po0.05) during HSCT events without HC than with HC, and this tendency was borderline significant (P ¼ 0.07 and P ¼ 0.054, respectively) when restricted to BKV-verified HC (Table 3). More specifically, the respective proportions of HLA-matched grafts (with and without DP match) were as follows: 37% (10/27) and 44% (12/27) among all HC patients; 39% (9/23) and 48% (11/23) in BKV-verified HC; and 61% (92/152) and 70% (107/152) in events without HC (Table 3). BK viruria was less common during HSCT with HLAmatched donors compared to those with mismatched donors, that is, 37% (37/99) and 61% (46/76), respectively (Po0.01) (Table 3). HC and non-HC HSCT events were also compared with regard to more detailed HLA matching (Table 3). A graft with a major HLA mismatch (HLA-A*, -B* or -DRB1*) was more common in HC cases, that is, in 26% (7/27 of all and 6/23 with BK viruria), than in HSCT events without HC, that is, 10% (15/152), P ¼ 0.054 and P ¼ 0.047, respectively (Table 3). Having minor mismatches, including HLA-C*, HLA-DQA* and HLA-DQB*, but not DPA* and DPB*, with regard to HSCT events with and without HC and with and without BK viruria, revealed no statistically significant differences between any of the groups (Table 3). Notably, however, all six patients receiving RIC with HC had URD grafts, and 5/6 of these URD grafts were HLA-mismatched, four with minor HLA mismatches and one with a major HLA mismatch (data not shown).

HC and BK viruria in relation to RD or URD grafts, MC or RIC and other factors We constructed multivariate logistic regression models for factors influencing the risk for BK viruria and HC. Factors significantly influencing the risk for BK viruria were MC (OR 2.9; 95% CI 2.5–5.6; P ¼ 0.001) and HLA mismatch (OR 2.3; 95% CI 1.2–4.4; P ¼ 0.01), while male gender had a borderline effect (OR 1.9; 95% CI 0.99–3.6; P ¼ 0.055). Significant risk factors for HC were BKV (OR 6.7; 95% CI 2.0–21.7; P ¼ 0.001), MC (OR 6.0; 95% CI 2.1–17.3; Po0.001) and URD (OR 3.4; 95% CI 1.1–10.6; P ¼ 0.03), while male gender, again, had a borderline effect (OR 2.8; 95% CI 0.95–8.4; P40.06). Since the use of an unrelated donor was a risk factor for HC, we also constructed multivariate models separately for patients receiving RD or URD grafts. In patients Bone Marrow Transplantation

receiving URD grafts, BKV (OR 5.5; 95% CI 1.6–18.3) and MC (OR 4.4; 95% CI 1.4–13.2; P ¼ 0.009) increased the risk for HC in patients, while no factor was identified as increasing the risk for HC in patients receiving RD grafts.

Discussion Late-onset HC is a serious complication of allogeneic HSCT, and several previous studies have evaluated risk factors for late onset HC in addition to BK viruria.3–12,17,28 In this study, the intensity of the conditioning regimen, patient gender, donor source and HLA matching between recipient and donor, as well as aGVHD, were analysed as risk factors for the development of BKV-associated HC. BK viruria was predominantly found in HC patients, as compared to patients undergoing HSCT without HC, and this is completely in line with earlier investigations.1–5 BK viruria was also more common in patients receiving MC (63%) as compared to those receiving RIC (36%), and conditioning intensity was an independent risk factor for both BK viruria and HC on multivariate analysis. In this study, we confirm MC to be an important risk factor for the development of HC. Furthermore, there was no difference in the risk of developing HC with regard to whether the patient had received Cy/TBI or Bu/Cy, and having an RIC did not reduce the intensity of HC. In addition, analogous to previous studies,13,17 having a URD was associated with HC by both univariate and multivariate analysis. Similarly, having an HLA-mismatched donor was more common in HSCT patients developing HC. However, there was no significant difference in BK viruria between patients receiving an RD (47%) or a URD (47%) graft. Nonetheless, HLA mismatch was an independent risk factor for BK viruria. The latter finding could, however, possibly be explained by the fact that anti-thymocyte globulin treatment was more frequently used if the donors were HLA-mismatched and that BK viruria could be stimulated by anti-thymocyte globulin therapy rather than by the fact that a mismatched graft was used. Male gender tended to be associated with the development of HC, which has been occasionally reported previously by others and by us.12,20,29 When analysing HSCT events separately in patients receiving URD or RD grafts, we disclosed some important differences. Having BK viruria and being transplanted after MC posed an increased risk of HC only in the URD setting and not when undergoing HSCT with an RD graft. In addition, HLA mismatch was identified as an independent risk factor for HC, when patients receiving URD grafts were analysed separately. On the other hand, when correcting for donor type and HLA mismatch, there was no influence of aGVHD on the risk for HC in patients receiving either RD or URD grafts. The pathogenesis of late-onset HC after HSCT is still poorly understood. Possibly, some of our present findings can add some pieces to the puzzle. In the past, we have shown that allogeneic HSCT carries a higher risk for HC than does autologous HSCT.23 We have also previously suggested that the immunosuppressed status of the patient is important, since patients transplanted with URD grafts


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have a higher HC risk than RD-graft recipients.13 Whether this is a direct effect of HLA mismatching, or because different transplant regimens with increased immunosuppression are used with URD grafts, is unknown and cannot be clarified by our study size. We can only speculate why MC in patients receiving URD grafts is associated with HC. One possible explanation is that the combination of a harsher regimen increases the risk for BK viruria, which, together with HLA disparities or more intensive immunosuppression, in turn, increases the risk for HC. Another possibility is that it is due to the stronger immunosuppressive effect of MC, since after RIC there is a greater retention of the recipient’s immunity early after HSCT and, thereafter, a more gradual switch to complete donor chimerism. The latter could facilitate a gradual adaptation of the immune response to BKV. The fact that BK viruria was significantly less common during HSCT events with RIC, as compared to those with MC both now and previously,13 also supported this. Nevertheless, the combination of MC immunosuppression inducing BK viruria and the combination of an HLA mismatch between recipient and donor may also make the immune response to a BKV-infected cell less stringent, causing more cell damage and, thus, further adding to the risk of developing HC. In summary, our results show that patients who have received MC and an HLA-mismatched URD graft have an increased risk for HC and may benefit from being monitored for BK viral load in serum and urine for prediction of HC.

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Acknowledgements We acknowledge the Children’s Cancer Foundation, the Swedish Cancer Foundation, the Stockholm Cancer Society, Karolinska Institutet and the Stockholm City Council for their financial support. We also thank the patients and the staff at the Centre of Allogeneic Stem Cell Transplantation and the Departments of Haematology and Paediatrics for participating in this project.

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26 Priftakis P, Bogdanovic G, Hjerpe A, Dalianis T. Presence of simian virus 40 (SV40) is not a frequent finding in Swedish malignant Mesotheliomas. Anticancer Res 2002; 22: 1357–1360. 27 Ringden O, Schaffer M, Le Blanc K, Persson U, Hauzenberger D, Abedi MR et al. Which donor should be chosen for hematopoietic stem cell transplantation among unrelated HLA-A, -B, and -DRB1 genomically identical volunteers? Biol Blood Marrow Transplant 2004; 10: 128–134. 28 Bogdanovic G, Ljungman P, Wang F, Dalianis T. Presence of human polyomavirus DNA in the peripheral circulation of bone marrow transplant patients with and without hemorrhagic cystitis. Bone Marrow Transplant 1996; 17: 573–576. 29 Asano Y, Kanda Y, Ogawa N, Sakata-Yanagimoto M, Nakagawa M, Kawazu M et al. Male predominance among Japanese adult patients with late-onset hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplant 2004; 32: 1175–1179.