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Preventive Measures for Cyclophosphamide-Related Hemorrhagic Cystitis in Blood and Bone Marrow Transplantation: An Italian Multicenter Retrospective Study

Silvia Gonella
Tania di Pasquale
Alvisa Palese
CJON 2015, 19(1), E8-E14 DOI: 10.1188/15.CJON.E8-E14

Background: Hemorrhagic cystitis (HC) is a troublesome and potentially life-threatening complication of bone marrow transplantation (BMT). HC can appear within a few hours after chemotherapy or after weeks or months. Early-onset HC (EOHC) is usually associated with the conditioning regimen.

Objectives: The main aim of this study was to describe the incidence of EOHC in patients undergoing BMT regimens including high-dose cyclophosphamide (CY) and the effects of the main preventive measures adopted in Italian nursing practice.

Methods: The authors retrospectively analyzed the clinical records of 158 Italian patients who underwent BMT from 2006–2008.

Findings: Thirty-one patients (19.6%) developed EOHC. One hundred and forty-seven patients (93%) given high-dose CY were treated with hyperhydration combined with 2-mercaptoethane sulphonate (mesna) and diuresis alkalinization, and only 51 (32.3%) patients were preventively catheterized and received continuous bladder irrigation (CBI). By univariate analysis, prophylactic urethral catheterization and CBI did not decrease EOHC incidence questioning if these measures were to be routinely recommended. Previous studies showed increased discomfort and urinary tract infection in catheterized patients; therefore, nurses may fulfill an important role in balancing the benefits and harms of preventive catheterization and CBI in patients who received BMT conditioning including high-dose CY.

Hemorrhagic cystitis (HC) is a troublesome and potentially life-threatening complication of bone marrow transplantation (BMT) (Xu et al., 2007). This condition significantly affects patients’ quality of life, increases the length of hospitalization, and can lead to death if the condition is intractable (Xu et al., 2007). The Karolinska Center for Allogeneic Stem Cell Transplantation in Sweden has defined HC as painful hematuria with negative urine culture for bacteria or fungus and without any other explanation, such as general bleeding diathesis, urinary tract catheterization for reasons other than HC, urinary calculi, and bladder neoplasm (Hassan et al., 2007). Similarly, Lee et al. (2003) defined HC as the presence of microscopic or macroscopic hematuria in the absence of other clinical conditions, such as menstruation, general bleeding diathesis, disseminated intravascular coagulation, multiple organ dysfunction syndrome, and sepsis.

The urologic manifestations range from microscopic hematuria to severe hemorrhage with obstructive renal failure. Four grades have been identified: grade 1 (microscopic hematuria), grade 2 (macroscopic hematuria), grade 3 (hematuria with clots), and grade 4 (macroscopic hematuria with clots and impaired renal function secondary to urinary tract obstruction) (Leung et al., 2002). HC may be graded as mild, moderate, or severe according to the degree of pain and amount of hematuria (El-Zimaity et al., 2004; Leung et al., 2002).

HC can be classified into early-onset HC (EOHC) or late-onset HC (LOHC). The former has been defined to occur within 48 hours after receiving chemotherapy (Russel, Vowels, & Vale, 1994) or within 21 days post-transplantation (Lee et al., 2003). Different definitions also exist for LOHC, including cases occurring 48 hours after chemotherapy (Russel et al., 1994) or weeks to months post-transplantation (Lee et al., 2003; Russel et al., 1994).

The incidence of HC in BMT recipients varies from 18%–40% (El-Zimaity et al., 2004; Hadjibabaie et al., 2008; Tsuboi et al., 2003) and, in 4%–8% of cases, HC was severe (Korkmaz, Topal, & Oter, 2007; Lee et al., 2003; Xu et al., 2007). This wide range of reported incidence and severity of complications may be partially from a different definition criteria adopted by researchers and different types of prophylaxis for graft-versus-host disease (GVHD). In addition, some studies showed HC incidence only in the overall period (Bedi et al., 1995; Hadjibabaie et al., 2008; Hassan et al., 2007; Shepherd et al., 1991; Vose et al., 1993), and others considered EOHC and LOHC separately (El-Zimaity et al., 2004; Lee et al., 2003; Tsuboi et al., 2003; Xu et al., 2007).

EOHC is usually associated with the conditioning regimen, particularly oxazaphosphorines (e.g., cyclophosphamide [CY], ifosfamide) belonging to alkylating agents widely used in the BMT setting (Dobrek & Thor, 2012). Acrolein, a urinary metabolite of CY and ifosfamide, is thought to be responsible for the urothelial toxicity (Dobrek & Thor, 2012). Another alkylating agent, busulfan, may also induce EOHC, increasing urotoxicity when used together with CY (Atkinson et al., 1991; Tsuboi et al., 2003). The multivariate analysis by Tsuboi et al. (2003) did not confirm any role of busulfan-cyclophosphamide (BU-CY) as a risk factor (n = 67 of 450 patients using the BU-CY conditioning regimen had HC, odds ratio [OR] = 2.055, 95% confidence interval [CI] [0.564, 7.491], p = 0.28).

The etiology of LOHC is heterogeneous and less clear. Cytomegalovirus (Hassan et al., 2007; Xu et al., 2007) and BK virus (Bedi et al., 1995; Erard et al., 2005; Miller et al., 2011) reactivation, GVHD (Hadjibabaie et al., 2008; Lee et al., 2003; Xu et al., 2007), high-dose antithymocyte globulin (Fu et al., 2013), and donor type (El-Zimaity et al., 2004; Xu et al., 2007) have been recognized as LOHC-related risk factors, but data are conflicting. Bedi et al. (1995) and Turkeri et al. (1995) did not find any association between HC and GVHD.

Previous reports (El-Zimaity et al., 2004; Lee et al., 2003; Tsuboi et al., 2003; Xu et al., 2007) mainly focused on the incidence and risk factors of HC. Very few studies (Hadjibabaie et al., 2008; Shepherd et al., 1991; Turkeri et al., 1995; Vose et al., 1993) explored preventive measures for EOHC. These prophylactic strategies were investigated two by two, and no study has given a complete view of the EOHC preventive methods adopted in daily practice. The best treatment suggested by Hadjibabaie et al. (2008) for HC remains prevention because severe HC may be difficult to manage, requiring more intensive transfusion support and invasive treatment, such as cystoscopy with clot evacuation, nephrostomy, or dialysis, that are not always lifesaving. Hassan et al. (2007) found higher transplantation-related mortality in patients with severe HC (n = 11 of 20 participants in grade 3 and n = 5 of 7 participants in grade 4) compared with patients without HC (n = 150 of 726 participants) 300 days after transplantation.

Hemorrhagic Cystitis Chemoprevention

Measures to prevent chemotherapy-related HC have focused on decreasing the concentration of acrolein and its contact time with the urothelium (Dobrek & Thor, 2012). The main prophylactic approaches have been hyperhydration with forced diuresis and frequent voiding; diuresis alkalization; 2- mercaptoethane sodium sulphonate (mesna), a sulphydryl agent that interacts with acrolein and other oxazaphosphorine metabolites to create nontoxic compounds; antibiotic prophylaxis with fluoroquinolones; urethral catheterization; and continuous bladder irrigation (CBI) (Hadjibabaie et al., 2008; Miller et al., 2011; Tsuboi et al., 2003). The effectiveness of these procedures has not always been confirmed and some measures, such as CBI (Hadjibabaie et al., 2008) and mesna (Bedi et al., 1995; Shepherd et al., 1991), were considered ineffective.

In addition, Tsuboi et al. (2003) found mesna and CBI to be risk factors for EOHC by multivariate analysis. In a retrospective study involving 450 transplantation patients, of which 81 (18%) developed HC, mesna and CBI increased EOHC by an OR of 5.3 (95% CI [1.477, 19.026], p = 0.0105) and 9.5 times (95% CI [3.872, 23.156], p = 0.0001), respectively. However, hyperhydration with alkalinizated polyuric diuresis combined with mesna represents the current most widespread strategy in preventing EOHC (El-Zimaity et al., 2004; Hassan et al., 2007; Tsuboi et al., 2003).

Variability between centers concerning the preventive EOHC measures offered to patients still exists in several countries. Evaluating the effectiveness of these preventive measures is the general intent of the current article. In addition, the aim of this study is to describe the incidence of EOHC in patients undergoing BMT regimens, including high-dose CY and the effects of the main preventive measures adopted in daily practice in Italy.

Preventive Measures and Efficacy Data

Hyperhydration With Forced Diuresis and Frequent Voiding Versus Mesna

Several studies (Bedi et al., 1995; Shepherd et al., 1991) found no difference in HC incidence and severity when patients were treated with mesna compared with hyperhydration. In Shepherd et al. (1991), 100 patients were randomized to receive mesna (daily dose of 160% of the daily CY dose) or forced saline diuresis while undergoing BMT conditioning with regimens including high-dose CY. Thirteen patients treated with sodium mercaptoethanesulphonate had severe hematuria, compared with eight hyperhydrated patients (p = 0.31). Similarly, no difference was found in incidence of severe HC (mesna, n = 5 of 40 versus hyperhydration, n = 3 of 40; p = 0.71)

These results were confirmed by Bedi et al. (1995) in a randomized, controlled trial. One hundred and forty-seven patients receiving preparative regimens with high-dose CY before BMT were randomized to the mesna arm (daily dose of 120% of the daily CY dose, n = 71) or hydration with forced diuresis (n = 76). The frequency of HC in patients given mesna (n = 19) was similar to that in recipients of forced diuresis (n = 18, p = 0.41).

Fluoroquinolones

The retrospective study by Miller et al. (2011) showed only one case of BK virus–induced HC (BKHC) in the group receiving ciprofloxacin (n = 44), compared with 11 of 48 patients without prophylaxis. The competing risk analysis (with death in the absence of severe BKHC as a competing risk) found a significant difference in the cumulative incidence of severe BKHC (20.9%, SD = 5.9% without versus 2.6%, SD = 2.6% with; p = 0.01) during the first four years following transplantation.

Hyperhydration With Forced Diuresis and Frequent Voiding Versus Continuous Bladder Irrigation

In a nonrandomized controlled clinical study (Hadjibabaie et al., 2008), 40 patients undergoing allogeneic BMT regimens including high-dose CY started CBI with 300 ml per hour normal saline through a three-way Foley catheter 12 hours before the first dose of CY until 48 hours after the last drug dose. All patients, in addition to a historic control group of 40 consecutive patients, received hyperhydration, diuresis alkalization, and mesna. HC occurred in 13 patients in the continuous irrigation group compared with half (n = 20) in the group without irrigation (p = 0.11). Similarly, six patients with and nine patients without CBI had severe HC (p = 0.77). In contrast, the retrospective analysis by Turkeri et al. (1995) on 199 recipients of BMT conditioned with high-dose CY found CBI to be effective in decreasing chemotherapy-related HC. All patients received hydration, and 149 patients underwent CBI with 180 ml/m2/h normal saline through a three-way Foley catheter. The catheter was inserted 12 hours before the first dose of CY and removed 36 hours after the last dose. Thirty-three patients in the CBI group developed HC compared with 19 patients who did not receive CBI (p < 0.04).

Continuous Bladder Irrigation Versus Mesna

Vose et al. (1993) randomized 200 patients to receive CBI with 200 ml per hour normal saline through a three-way Foley catheter or mesna (daily dose of 100% of the daily CY dose) in addition to hydration. Seventy-three of 97 patients randomized to CBI had hematuria compared with 56 of 103 patients receiving mesna (p = 0.007), but no difference between the two prophylaxis measures was found in the incidence of severe HC (n = 18 in CBI versus n = 18 in mesna).

Methods

The authors conducted a retrospective study in two Italian BMT centers. One center routinely used CBI in all patients undergoing BMT regimens, including high-dose CY. All patients started CBI with 300 ml per hour normal saline through a three-way urinary catheter on the day of the first dose of CY until 48–72 hours after the last drug dose. Another center employed this measure only to manage clinically evident HC (macroscopic hematuria clots).

All adult patients (aged 18 years or older) undergoing autologous or allogeneic BMT regimens, including high-dose CY (greater than 120 mg/kg), in the period from January 2006 to December 2008 were included in the study. All patients were treated according to institutional protocols, and the study was approved by the review board at the University of Udine in Italy.

According to Lee et al. (2003), HC was defined as the presence of microscopic or macroscopic hematuria in the absence of other clinical conditions such as menstruation, general bleeding diathesis, disseminated intravascular coagulation, multiple organ dysfunction syndrome, and sepsis. HC was clinically graded according to the criteria of Leung et al. (2002) and defined as early when occurring within the 21 days post-transplantation.

Data Collection

Data were collected by an experienced researcher through medical records. Data collected included demographic and clinical characteristics, underlying disease, source of hematopoietic stem cell (HSC) (bone marrow, peripheral blood stem cell, and umbilical cord), treatment (chemotherapy agents, total body irradiation, and therapy length), HC preventive measures (hyperhydration, diuresis alkalization, mesna, fluoroquinolone antibiotic prophylaxis, urethral catheterization and its reasons, and CBI).

Data Analysis

Continuous variables were expressed as mean and 95% CI and were compared between groups using the Mann-Whitney U test. Categorical variables were summarized as sums and percentages and the chi-square test with Yates’ correction (or Fisher’s exact test) was used for comparison.

Logistic regression was used to evaluate risk factors for the development of EOHC. Occurrence of EOHC was used as the dependent variable and the following parameters as potential explanatory covariates: gender, age, smoking habits, type of transplantation (autologous or allogeneic), stem cell donor (sibling, unrelated, or umbilical cord blood), CY dose, urethral catheterization, and CBI.

Previous studies did not find any association between HC and the underlying disease or between HC and the conditioning regimen (Bedi et al., 1995; Lee et al., 2003; Tsuboi et al., 2003). Therefore, these variables were not entered into the univariate model.

All univariate analysis parameters were entered into the multivariate regression model and the authors then applied a backward stepwise selection algorithm. The center was not included in the multivariate analysis because a strong overlap between center and CBI was registered. Statistical analyses were performed using SPSS®, version 20.0, and p values of less than 0.05 (two-tailed) were considered significant.

Results

Clinical Features

One hundred and fifty-eight patients were included. Almost 60% of patients were males, and about 40% suffered from acute myeloid leukemia (AML). Only five patients had an autologous transplantation, and 91 of those undergoing allogeneic BMT had a human leukocyte antigen–matched unrelated donor (HLA-MUD). Ninety-four patients received conditioning regimens based on BU-CY and 53 had CY-thiotepa therapy (see Table 1).

Thirty-one patients (19%) developed EOHC that was scored as grade 1 in two patients (6%), grade 2 in 20 patients (65%), and grade 3 in four patients (13%). No patients developed grade 4, and data were not available in five cases. Twenty-two patients with hematuria complained of pain.

EOHC developed only in patients receiving allogeneic BMT. The stem cell donor was HLA-MUD in 22 patients, and 22 patients with EOHC received conditioning regimens based on BU-CY.

Preventive Measures for Early-Onset Hemorrhagic Cystitis

All but one patient, who was allergic to the drug, received mesna and hyperhydration. One hundred and forty-seven patients had diuresis alkalinization and 139 patients (88%) received antibiotic prophylaxis. In all, less than 40% of patients (n = 60) were catheterized. In the center, only 9 of 107 patients were catheterized for macrohematuria (n = 2), clots (n = 1), or other complications (n = 6), and four received CBI to manage clinically evident EOHC. In all, 55 of 158 (35%) transplantation recipients underwent CBI, but only 51 patients (32%) received preventive CBI, and one of five developed EOHC (see Table 2).

The daily mesna dose was the only significant difference in preventive measures between patients with and without EOHC (median = 4,463, 95% CI [4,004, 49,229] in the EOHC group versus median = 3,701, 95% CI [3,422, 3,980] in the non-EOHC group, p = 0.01). The univariate analysis (see Table 3) showed allogeneic transplantation to be a risk factor for EOHC (OR = 2.581, 95% CI [1.2, 5.551], p = 0.015). Results at the multivariate level found that only female gender (OR = 4.057, 95% CI [1.23, 12.88], p = 0.024) and daily dose of CY (OR = 1.001, 95% CI [1, 1.002], p = 0.016) were independent risk factors for EOHC. The authors’ model explained moderate variability (R2 = 9.4%–15.4%).

Discussion

To the authors’ knowledge, this study is the first to simultaneously describe all of the main preventive measures for CY-related EOHC in patients undergoing BMT. The study reports a widespread use of hyperhydration in combination with diuresis alkalization and mesna, according to the generally accepted gold standard (Hensley et al., 2009). In contrast to previous studies (Bedi et al., 1995; Shepherd et al., 1991; Vose et al., 1993), the authors could not explore mesna efficacy because all patients received this prophylactic measure. However, the authors noted a higher daily dose of mesna in patients with EOHC compared with non-EOHC ones, which is consistent with the higher average CY daily dose in patients with EOHC compared with patients without EOHC (3,914 mg in the EOHC group versus 3,599 mg in the non-EOHC group, p = 0.07). Daily dose of CY was confirmed as an independent risk factor for EOHC in the multivariate analysis (Dobrek & Thor, 2012).

In contrast to previous studies (Turkeri et al., 1995; Vose et al., 1993), preventive urethral catheterization and CBI did not seem to decrease CY-related urotoxicity. However, Turkeri et al. (1995) did not define the observation period in their retrospective analysis, and Vose et al. (1993) observed every patient until discharge. In addition, neither Turkeri et al. (1995) nor Vose et al. (1993) adjusted for potential confounders. The authors’ findings showed that six catheterized patients had EOHC, compared with 45 recipients without a urethral catheter (p = 0.098). Similarly, 10 patients receiving CBI developed EOHC versus 41 who did not undergo CBI (p = 0.739). However, a non-randomized study (Hadjibabaie et al., 2008) found no difference in HC incidence (n = 13 with CBI versus n = 20 without CBI, p = 0.1) or grades 3–4 (n = 6 with CBI versus n = 9 without CBI) between patients with or without CBI. Tsuboi et al. (2003) showed that prophylactic CBI could increase EOHC by about 10 times. However, CBI entailed the risk of urethra injury by catheterization and was associated with more bladder spasms, discomfort, prolonged periods of being bedridden, and a higher occurrence of urinary tract infection (UTI) (Hadjibabaie et al., 2008; Turkeri et al., 1995; Vose et al., 1993).

The overall incidence of EOHC in the current study is slightly higher than that reported by Lee et al. (2003) (19% versus 11%), potentially because of the current study containing more patients receiving unrelated transplantation (60% versus 21%) because HLA-MUD stem cell donor was demonstrated as a risk factor for HC (El-Zimaity et al., 2004; Xu et al., 2007). A trend toward a higher incidence of EOHC among patients who had a HLA-MUD (71%) was registered compared with patients with sibling donors (23%), suggesting that more intense immunosuppression may contribute to an increased risk of HC, as previously suggested by Xu et al. (2007) and El-Zimaity et al. (2004). The current study recorded fewer cases of grade 3 EOHC compared to Lee et al. (2003) (13% versus 24%, respectively), which may be because of differences in GVHD prophylaxis, reducing the chance of opportunistic infection that would subsequently cause EOHC, but this hypothesis cannot be confirmed because the authors did not record immunosuppressive therapy.

Similar to previous analyses (Leung et al., 2002; Vose et al., 1993), patients undergoing allogeneic BMT were more likely to develop EOHC. Vose et al. (1993) showed a higher incidence of grade 3 and 4 hematuria in patients receiving an allogeneic transplantation compared with those receiving an autologous transplantation (23% versus 6%, respectively, p = 0.002). A subsequent retrospective study (Leung et al., 2002) reported a significantly higher incidence of HC in allogeneic BMT (84% in allogeneic BMT versus 16% in autologous BMT, p = 0.05).

This study is the first to find a significant association between female gender and EOHC, confirming a trend that emerged in a previous retrospective analysis (Tsuboi et al., 2003) of a numerically but not significantly higher EOHC incidence in women compared with men (7.4% in women versus 7.3% in men, p = 0.9724). However, evidence is conflicting because Lee et al. (2003) reported a higher HC incidence in men (27%) compared with women (25%). However, Lee et al. (2003) did not specifically explore the association between gender and HC incidence in the early post-transplantation period, and gender was not entered into the multivariate model.

Limitations

The study has several limitations because of its retrospective nature. In addition, UTI data were not collected; therefore, the association between preventive measures and UTI were not explored. The current study focused on the early post-transplantation period. Therefore, the authors did not collect information such as GVHD (Hadjibabaie et al., 2008; Lee et al., 2003; Xu et al., 2007), cytomegalovirus (Hassan et al., 2007; Xu et al., 2007), and BK virus (Erard et al., 2005; Miller et al., 2011) infection, which are known risk factors for LOHC. The period of analysis covered three weeks after transplantation, and the bulk of studies exploring EOHC considered the first 48–72 hours postengraftment; therefore, the authors hypothesize that some HC cases labeled as EOHC could have had a late-onset etiology, such as GVHD or viral infection.

Conclusion

Although several improvements have been made in preventing BMT conditioning regimen–related side effects, HC continues to be a frequent and potentially life-threatening complication after transplantation. Severe HC was shown to increase transplantation-related mortality and invasive treatment is not always successful. Therefore, the current best treatment for HC remains prevention.

Hyperhydration associated with diuresis alkalinization and mesna represents the current gold standard for preventing EOHC in BMT regimens containing CY or ifosfamide. However, preventive urethral catheterization and CBI showed conflicting data and the authors’ results do not support their routine use as it occurs in Italian practice. Previous studies showed increased discomfort and UTI in patients with a catheter. In addition, the findings that emerged in this study have confirmed the preventive practice suggested by the American Society of Clinical Oncology (Hensley et al., 2009) based on a high level of evidence. Therefore, nursing practice should consider the benefits and harms of preventive catheterization and CBI in patients who received BMT conditioning including high-dose CY. Further systematic review is warranted, and additional prospective multicenter studies with larger samples are needed to explore the balance between benefits and harms for these invasive measures.

References

Atkinson, K., Biggs, J.C., Golovsky, D., Concannon, A., Dodds, A., Downs, K., & Ashby, M. (1991). Bladder irrigation does not prevent haemorrhagic cystitis in bone marrow transplant recipients. Bone Marrow Transplantation, 7, 351–354.

Bedi, A., Miller, C.B., Hanson, J.L., Goodman, S., Ambinder, R.F., Charache, P., . . . Jones, R.L. (1995). Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. Journal of Clinical Oncology, 13, 1103–1109.

Dobrek, L., & Thor, P.J. (2012). Bladder urotoxicity pathophysiology induced by the oxazaphosphorine alkylating agents and its chemoprevention. Postepy Higieny i Medycyny Doswiadczalnej, 66, 592–602.

El-Zimaity, M., Saliba, R., Chan, K., Shahjahan, M., Carrasco, A., Khorshid, O., . . . de Lima, M. (2004). Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: Donor type matters. Blood, 103, 4674–4680. doi:10.1182/blood-2003-08-2815

Erard, V., Kim, H.W., Corey, L., Limaye, A., Huang, M.L., Myerson, D., . . . Boeckh, M. (2005). BK DNA viral load in plasma: Evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood, 106, 1130–1132. doi:10.1182/blood-2004-12-4988

Fu, H., Xu, L., Liu, D., Zhang, X., Liu, K., Chen, H., . . . Huang, X. (2013). Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: Differences in ATG dosage are key. International Journal of Hematology, 98, 89–95. doi:10.1007/s12185-013-1350-8

Hadjibabaie, M., Alimoghaddam, K., Shamshiri, A.D., Iravani, M., Bahar, B., Mousavi, A., . . . Ghavamzadeh, A. (2008). Continuous bladder irrigation prevents hemorrhagic cystitis after allogenic hematopoietic cell transplantation. Urologic Oncology, 26, 43–46. doi:10.1016/j.urolonc.2006.12.015

Hassan, Z., Remberger, M., Svenberg, P., Elbander, M., Omazic, B., Mattsson, J., . . . Ringdén, O. (2007). Hemorrhagic cystitis: A retrospective single-center survey. Clinical Transplantation, 21, 659–667. doi:10.1111/j.1399-0012.2007.00705.x

Hensley, M.L., Hagerty, K.L., Kewalramani, T., Green, D.M., Meropol, N.J., Wasserman, T.H., . . . Schuchter, L.M. (2009). American Society of Clinical Oncology 2008 clinical practice guideline update: Use of chemotherapy and radiation therapy protectants. Journal of Clinical Oncology, 27, 127–145.

Korkmaz, A., Topal, T., & Oter, S. (2007). Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation. Cell Biology and Toxicology, 23, 303–312.

Lee, G.W., Lee, J.H., Choi, S.J., Kim, S., Seol, M., Kim, W.K., . . . Lee, K.H. (2003). Hemorrhagic cystitis following allogeneic hematopoietic cell transplantation. Journal of Korean Medical Science, 18, 191–195.

Leung, A.Y., Mak, R., Lie, A.K., Yuen, K.Y., Cheng, V.C., Liang, R., & Kwong, Y.L. (2002). Clinicopathological features and risk factors of clinically overt haemorrhagic cystitis complicating bone marrow transplantation. Bone Marrow Transplantation, 29, 509–513. doi:10.1038/sj.bmt.1703415

Miller, A.N., Glode, A., Hogan, K.R., Schaub, C., Kramer, C., Stuart, R.K., & Costa, L.J. (2011). Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients. Biology of Blood and Marrow Transplantation, 17, 1176–1181. doi:10.1016/j.bbmt.2010.12.700

Russell, S.J., Vowels, M.R., & Vale, T. (1994). Haemorragic cystitis in paediatric bone marrow transplant patients: An association with infective agents, GVHD, and prior cyclophosphamide. Bone Marrow Transplantation, 13, 533–539.

Shepherd, J.D., Pringle, L.E., Barnett, M.J., Klingemann, H.G., Reece, D.E., & Phillips, G.L. (1991). Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. Journal of Clinical Oncology, 9, 2016–2020.

Tsuboi, K., Kishi, K., Ohmachi, K., Yasuda, Y., Shimizu, T., Inoue, H., . . . Hotta, T. (2003). Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplantation, 32, 903–907.

Turkeri, L.N., Lum, L.G., Uberti, J.P., Abella, E., Momin, F., Karanes, C., . . . Haas, G.P. (1995). Prevention of hemorrhagic cystitis following allogeneic bone marrow transplant preparative regimens with cyclophosphamide and busulfan: Role of continuous bladder irrigation. Journal of Urology, 153, 637–640.

Vose, J.M., Reed, E.C., Pippert, G.C., Anderson, J.R., Bierman, P.J., Kessinger, A., . . . Armitage, J.O. (1993). Mesna compared with continuous bladder irrigation as uroprotection during high-dose chemotherapy and transplantation: A randomized trial. Journal of Clinical Oncology, 11, 1306–1310.

Xu, L., Zhang, H., Huang, X.J., Liu, K.Y., Liu, D.H., Han, W., . . . Lu, D.P. (2007). Hemorrhagic cystitis following hematopoietic stem cell transplantation: Incidence, risk factors and association with CMV reactivation and graft-versus-host-disease. Chinese Medical Journal, 120, 1666–1671.

About the Author(s)

Silvia Gonella, MSc, BNS, RN, is a nurse in the Department of Public Health and Community Medicine at the University of Verona; and Tania di Pasquale, BNS, RN, is an RN and Alvisa Palese, MSc, is an associate professor, both in the School of Nursing at Udine University, all in Italy. The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or editorial staff. Palese can be reached at alvisa.palese@uniud.it, with copy to editor at CJONEditor@ons.org. (Submitted March 2014. Revision submitted May 2014. Accepted for publication May 30, 2014.)

 

References 

Atkinson, K., Biggs, J.C., Golovsky, D., Concannon, A., Dodds, A., Downs, K., & Ashby, M. (1991). Bladder irrigation does not prevent haemorrhagic cystitis in bone marrow transplant recipients. Bone Marrow Transplantation, 7, 351–354.

Bedi, A., Miller, C.B., Hanson, J.L., Goodman, S., Ambinder, R.F., Charache, P., . . . Jones, R.L. (1995). Association of BK virus with failure of prophylaxis against hemorrhagic cystitis following bone marrow transplantation. Journal of Clinical Oncology, 13, 1103–1109.

Dobrek, L., & Thor, P.J. (2012). Bladder urotoxicity pathophysiology induced by the oxazaphosphorine alkylating agents and its chemoprevention. Postepy Higieny i Medycyny Doswiadczalnej, 66, 592–602.

El-Zimaity, M., Saliba, R., Chan, K., Shahjahan, M., Carrasco, A., Khorshid, O., . . . de Lima, M. (2004). Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: Donor type matters. Blood, 103, 4674–4680. doi:10.1182/blood-2003-08-2815

Erard, V., Kim, H.W., Corey, L., Limaye, A., Huang, M.L., Myerson, D., . . . Boeckh, M. (2005). BK DNA viral load in plasma: Evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients. Blood, 106, 1130–1132. doi:10.1182/blood-2004-12-4988

Fu, H., Xu, L., Liu, D., Zhang, X., Liu, K., Chen, H., . . . Huang, X. (2013). Late-onset hemorrhagic cystitis after haploidentical hematopoietic stem cell transplantation in patients with advanced leukemia: Differences in ATG dosage are key. International Journal of Hematology, 98, 89–95. doi:10.1007/s12185-013-1350-8

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