Post-Transplant Complications

Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation

Summary:

To establish the most appropriate prophylactic therapy and risk factors for predicting hemorrhagic cystitis (HC) after stem cell transplantation (SCT), we retrospectively analyzed the clinical records of 450 transplant patients treated from 1982 to 2002. In all, 81 patients developed early- and/or late-onset HC (early=29, late=48, both=4). For the incidence of early-onset HC, administration of cyclophosphamide (CY) (p=0.0079, odds ratio (OD)=5.109, 95% confidence interval (CI)=1.533–17.030), busulfan (BU) (p=0.0015, OD=3.336, 95% CI=1.584–7.027), BU+CY (p=0.0001, OD=4.369, 95% CI=2.055–9.292), antithymocyte globulin (p=0.0009, OD=3.368, 95% CI=1.642–6.911), nonradiation (p=0.0163, OD=2.564, 95% CI=0.181–0.841), 2-mercaptoethane sodium sulfonate (Mesna) (p=0.0001, OD=7.519, 95% CI=2.847–19.858), and bladder irrigation (p=0.0001, OD=4.950, 95% CI=2.328–10.523) were risk factors. By Fisher's exact test, the combination of BU and Mesna was a more significant risk factor (P<0.001) than Mesna alone (p=0.008) compared to the administration of neither agent. By multivariate analysis, prophylactic administration of Mesna (p=0.0105, OD=5.301, 95% CI=1.477–19.026) and bladder irrigation (p=0.0001, OD=9.469, 95% CI=3.872–23.156) were significant risk factors of early-onset HC. We conclude that (i) high-dose BU as well as CY is a cause of HC, (ii) protective bladder irrigation has an opposite effect, and (iii) Mesna possibly has a toxic effect on bladder mucosa.

Main

Hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic stem cell transplantation (SCT). In cases with progression of HC, renal failure has occurred and occasionally resulted in death. Early-onset HC, which might be defined as HC occurring within 48 h of the preparative regimen,1 is thought to be a complication of high-dose cyclophosphamide (CY)-containing preparative regimens, while late-onset HC, occurring beyond 48 h from the preparative regimen, is reported to be associated with viral infections.2,3,4,5,6

Acrolein, a CY-derived metabolite, is one of the causes of early-onset HC associated with the administration of high-dose CY.7,8,9 Increased risks of HC have also been recognized in association with busulfan (BU) or total body irradiation (TBI) that act on bladder mucosa.10 Various protective measures have been taken to reduce the risks of HC, that is, polyuric diuresis, frequent voiding, urethral catheterization, bladder irrigation, and the use of the anti-crosslinking agent 2-mercaptoethane sodium sulfonate (Mesna), but some of these procedures were considered ineffective.1,11,12

To further define the risk factors for early-onset HC, we conducted a retrospective analysis of the clinical records of 450 transplant patients at Tokai University Hospital.

Materials and methods

Patients

A total of 450 allogeneic transplants were carried out on 428 patients at Tokai University School of Medicine from March 1982 to March 2002. Patient characteristics are summarized in Table 1. In total, 326 patients were diagnosed as having various malignancies: 301 had leukemia/myelodysplastic syndrome, 24 had malignant lymphoma, and one had multiple myeloma. The other 124 patients had nonmalignant diseases: aplastic anemia in 68 patients, congenital metabolic disorders in 44, and congenital immunodeficiencies in 12 patients.

Table 1 Patient characteristics and risk factors for early-onset HC by univariate analysis

Among the 147 patients who received a transplant from a mismatched donor, 78 were from a single HLA-locus mismatched donor, and the rest from two- or more-loci mismatched donors.

As prophylaxis for HC, all patients receiving high-dose CY were hyperhydrated. Among the 239 patients who received high-dose CY, 138 (58%) were treated with Mesna when it was available. Mesna was used in 60 patients (90%) of 67 who received high-dose CY and BU.

Onset and grading of HC

Because a distinction between early- and late-onset HC had not been reported previously other than by Russell et al,1 we accepted their criteria as follows: early-onset HC was defined as that occurring within 48 h after administration of CY, and late-onset HC as that occurring later on. HC was graded as mild, moderate, or severe;13 mild HC was defined as sustained (7 days) microscopic hematuria; moderate HC was defined by the presence of clots, dysuria, or gross hematuria; and severe HC by the presence of complications such as urinary obstruction, renal failure, uncontrollable bleeding requiring bladder irrigation, topical instillations by alum or formalin, hyperbaric oxygen therapy, cauterization, or surgical intervention.

Statistical analysis

All statistics were performed with SAS® for Windows® (Release 6.12). We set up 15 parameters for univariate analysis (Table 1) and analyzed the relationship between HC and these by logistic regression. We then enforced a relationship between Mesna and BU by Fisher's exact test. As each parameter must be independent for multivariate analysis, we excluded three parameters (radiation+CY, BU, and CY).

Results were presented by P-value, odds ratio (OD) and its 95% confidence intervals (CIs).

Results

In all, 81 patients among 450 transplants developed early- and/or late-onset HC. Of 81 patients, 33 developed early-onset HC: mild HC in 13, moderate HC in 13, and severe HC in seven patients.

Risk factors for early-onset HC were studied by univariate analysis. A nonmalignant diagnosis (p=0.0006, OD=3.521, 95% CI=1.715–7.246), and an HLA mismatched transplant (p=0.0023, OD=3.064, 95% CI=1.490–6.302) were risk factors on univariate analysis (Table 1). When each preconditioning regimen was compared for its influence on the occurrence of early-onset HC, CY (p=0.0079, OD=5.109, 95% CI=1.533–17.030) as well as BU (p=0.0015, OD=3.336, 95% CI=1.584–7.027), antithymocyte globulin (ATG) (p=0.0009, OD=3.368, 95% CI=1.642–6.911) and nonradiation (p=0.0163, OD=2.564, 95% CI=1.189–5.525) were significant risk factors. While a combination of BU+CY was an obvious risk factor (p=0.0001, OD=4.369, 95% CI=2.055–9.292), radiation+CY was not.

Both HC prophylactic procedures, Mesna (p=0.0001, OD=7.519, 95% CI=2.847–19.858) and bladder irrigation (p=0.0001, OD=4.950, 95% CI=2.328–10.523), were risk factors of early-onset HC.

Because Mesna, as a prophylactic agent for early-onset HC, was unexpectedly a risk factor for HC, we hypothesized that there is a synergistic toxic effect of BU and Mesna, although Mesna without BU was a risk factor for early-onset HC (p=0.008). The combination of BU and Mesna was a more significant risk factor (P<0.001) compared with no BU Mesna (Table 2).

Table 2 Synergistic effect of busulfan and Mesna on early-onset HC by Fisher's test

We also examined risk factors for early-onset HC by multivariate analysis (Table 3). Prophylactic Mesna and bladder irrigation increased early-onset HC by an OD of 5.3 (p=0.0105, 95% CI=1.477–19.026) and 9.5 times (p=0.0001, 95% CI=3.872–23.156), respectively. We analyzed the relations between grading of early-onset HC and Mesna and/or bladder irrigation, but there was no relationship between them.

Table 3 Risk factors for early-onset HC by multivariate analysis

When we analyzed the risk factors for late-onset HC, only CY (p=0.007, OD=2.855), GVHD grade II–IV (p=0.010, OD=2.176) and corticosteroid administration (p=0.009, OD=2.513) were significant on univariate analysis, but no risk factor was determined by multivariate analysis.

Discussion

HC is a frequent and potentially serious complication after SCT. In general,1 post-SCT-HC is classified into two types by time of appearance and causes: early-onset HC caused by RRT and late-onset HC caused by viral infection. Sencer et al14 retrospectively analyzed risk factors after BMT and found a high frequency in recipients with aplastic anemia who were treated with high-dose CY and total lymphoid irradiation. They also found a higher rate of HC in allogeneic recipients than in autologous recipients. After this study they showed that use of BU, higher grade acute GVHD, and older age are significant risk factors of severe HC.15

In this report, we investigated the risk factors for HC following SCT, from our 450 transplant cases. The overall frequency of HC was 19% (7% early onset, 12% late onset), and comparable with that found in previous studies.3,6 We selected several clinical parameters to compare the development of HC.

On univariate analysis, recipients conditioned with CY, BU, or BU+CY were more likely to develop early-onset HC. Our results also revealed nonmalignant diagnosis and HLA mismatched transplant to be risk factors for early-onset HC. Although the former may be caused by the higher dose of CY administered to patients with aplastic anemia as described, the latter cannot be explained except by the fact that mismatched stem cell recipients tend to be sicker. Busulfan was also reported as a risk factor for HC based on the retrospective comparison of SCT patients treated with radiation+CY and BU+CY.16,17 The results of these previous reports are consistent with our results, indicating that high-dose BU as well as CY are toxic to the bladder mucosa.

As the pharmacokinetics of CY indicate that its metabolite excreted into the urine will injure the bladder mucosa, most prophylactic procedures are intended to eliminate this metabolite. Hyperhydration, Mesna, and bladder irrigation have all been recommended as prophylaxis for CY-induced HC in early reviews of BMT,18,19 and each procedure has been reappraised. A randomized trial showed that Mesna and hyperhydration were equally effective in preventing CY-induced HC in SCT patients.7 Another randomized study showed that continuous bladder irrigation and Mesna were equally effective in preventing severe HC associated with high-dose CY.18 However, bladder irrigation entailed the risk of causing urethra injury by catheterization and was associated with significantly more discomfort and a higher occurrence of urinary tract infections.18 Atkinson et al12 have already reported that bladder irrigation is a risk factor for early-onset HC, and this is consistent with our results on univariate and multivariate analysis.

Our results showed that both bladder irrigation and Mesna had the unexpected effect of increasing frequency of early-onset HC. Mesna is usually used in patients treated by CY, which is a primary cause of HC, but our results by multivariate analysis also revealed Mesna to be an independent risk factor. Our univariate and multivariate analysis showed both BU+CY and Mesna to be risk factors for early-onset HC. When we took these results into consideration, we hypothesized a pharmacological synergistic effect of BU and Mesna on the bladder mucosa. A higher frequency of HC was observed with Mesna+BU, but no statistical significance was observed compared with Mesna alone. A prospective randomized study is necessary to prove this point.

Our studies on late-onset HC by univariate analysis reveal only GVHD and corticosteroids to be risk factors. These findings are consistent with previous reports describing viral infections as the main cause of late-onset HC.

We conclude that (i) high-dose BU as well as CY is a cause of HC, (ii) protective bladder irrigation is detrimental, and (iii) Mesna may have a toxic effect on the bladder mucosa.

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Acknowledgements

We are grateful to Mr Hiroki Akiyama (Meiji Seika Kaisha, Ltd) for performing the statistical analysis of the data.

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Correspondence to K Kishi.

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Tsuboi, K., Kishi, K., Ohmachi, K. et al. Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplant 32, 903–907 (2003). https://doi.org/10.1038/sj.bmt.1704240

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Keywords

  • hemorrhagic cystitis
  • stem cell transplantation
  • risk factor
  • Mesna
  • bladder irrigation

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