Increasingly, haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been used to treat malignant hematologic diseases. This has been primarily due to recent improvements in conditioning regimens and clinical outcomes, thus overcoming the lack of compatible human leukocyte antigen (HLA) donors.1,2 Nevertheless, haplo-HSCT is not free of complications; hemorrhagic cystitis (HC) is one of the most relevant, with a reported incidence of 10%–70%.3–6 This complication is a common cause of hospitalization, raising post-transplant morbidity and also mortality in these patients.

HC is an inflammatory process of the bladder, with clinical manifestations that vary from mild to severe. Clinically, the condition is characterized by hematuria, dysuria, irritative symptoms of the urinary tract and even renal failure due to hydronephrosis. HC is classified into four grades (I–IV) according to severity.7,8

In patients having received a haplo-HSCT, different risk factors and etiological agents are associated with HC, including alkylating agents, such as cyclophosphamide or busulfan, radiotherapy and infectious agents, such as the Polyomavirus BK.9–13 Cyclophosphamide is associated with early onset HC, usually 24–72 h post-drug administration.14,15

The BK is a DNA virus of the polyomaviridae family, which remains latent in urothelial cells. Primary infections occur during childhood, at a median age of 4–5 years. The worldwide BK seroprevalence in asymptomatic adults is 46%–94%.16 Nevertheless, in immunosuppressed patients, higher virus replication rates are recorded leading to cystitis, which is frequently of late onset, unlike the early-onset caused by alkylating agents.7 Additionally, other infection risk factors have been reported, including myeloablative conditioning regimens, second stem cell transplants and graft vs. host disease (GVHD).3,17

The post-haplo-HSCT HC treatment has not yet been standardized. However, common therapeutic strategies include general measures, such as oral or intravenous hydration, pain relief, cidofovir and quinolones, such as ciprofloxacin. This latter agent has been known to halt BK virus replication. Some patients, without complete response to antimicrobial therapy, benefit from steroids.18–23 In patients with severe or refractory HC, other therapeutic options include the endoscopic application of fibrin glue to damaged bladder mucosa, hyperbaric oxygen therapy, electrocoagulation of bladder mucosa, selective arterial embolization and cystectomy. However, the latter approach is associated with high complication rates and mortality and therefore, should remain as a last resource.24–29 In the literature, information on HC after haplo-HSCT is scarce, in terms of treatment options and clinical outcomes, and this is especially true for the outpatient, reduced-intensity conditioning setting.

We described HC incidences in a group of patients who received a haplo-HSCT on an outpatient basis. We assessed HC risk factors, such as donor and recipient gender, CD34+ doses, GVHD, treatment and outcomes.

One hundred and eleven patients were included, 72 males and 39 females, with a median age of 18 (1–63 years). A total of 85% of the patients had a malignant hematologic disease, the most frequent diagnosis being acute leukemia (71%). All patients received a haplo-HSCT because they did not have fully compatible HLA donors. General patient and clinical characteristics are shown in Table 1. Grades II–IV acute graft vs. host disease (aGVHD) was observed in 40 (36%) of the 111 patients and mild-to-moderate chronic graft vs. host disease (cGVHD) was observed in 27 (24%) patients.

Characteristics of patients with HC

Thirty (27%) of the 111 patients had HC, 19 (63.3%) males and 11 (36.6%) females, with a median age at transplantation of 17.5 (3–61 years). Fifteen (50%) patients were <18 years at the time of transplant. Indications for transplant included malignant disease in 26 (87%) patients and non-malignant disease in four patients. Grades II–IV aGVHD was observed in 13 (43.3%) patients, while eight (26.6%) patients developed cGVHD (Table 1). The skin was the most frequently affected site in both acute and chronic GVHD.

According to the HC classification, one patient (4%) was stratified at Grade I, 21 (70%) at Grade II, four (13%) at Grade III and four (13%) at Grade IV. The median time of HC onset was 30 days (7–149 days) post-transplant, with a median duration of 23.5 days (4–80 days). Late HC was observed in all 30 patients in this group. Using qPCR, BK virus levels were quantified in blood and urine samples from 14 patients; the BK virus was detected in 10 (71%) samples, nine in urine and one in blood, while in four samples, the BK virus was not detected. The median urinary viral load was 50,000,000 copies/µL (50,000,000–833,682,957 copies).

Due to financial constraints, BK virus detection was not performed in the remaining 16 patients of this group, thus the etiological HC agent in this subgroup was not identified. Urine cultures were performed for all 30 HC patients, but in all cases, cultures were negative for bacterial and fungal infection. The HC treatment was non-invasive in mild HC cases (Grades I–II) and invasive for severe HC or refractory cases. Non-invasive treatments were performed in an outpatient setting, with oral hydration, quinolone and pain relief in 16 (53%) patients. Fourteen (47%) patients required hospitalization for invasive treatment, which included Foley catheterization, intravenous hydration and pain relief. Additionally, one patient received intravenous cidofovir (5 mg/kg); four patients received intravesical cidofovir (5 mg/kg in saline solution, once a week for two weeks); three patients received continuous bladder irrigation (cystoclysis) with saline solution, using a two-way Foley urethral catheter; one patient needed cystostomy (suprapubic catheter insertion), with clot removal due to repetitive urinary obstruction; one patient required cystoscopy, with clot evacuation due to urinary obstruction, and; six patients required a blood transfusion. Quinolones comprised ciprofloxacin (500 mg, twice daily) or levofloxacin (500 mg, daily). Cidofovir was used for patients with detected BK virus and for those who did not response to quinolones. All patients responded to treatment, except two (6.6%), who died due to HC complications. One patient with cystostomy died due to sepsis, secondary to urinary tract infection and another patient with cystoclysis died due to renal failure and multiple organ failure, secondary to in-hospital pneumonia. In total, 16 (53.3%) patients in this group died, the main causes being relapse of underlying disease and infection. For patients without HC, the median follow-up was 6.6 months (1–41 months) and the overall survival was 46.7%, with no significant differences (p = 0.52) (Fig. 1). A significant correlation was observed between HC incidence and donor-receptor sex mismatch (r = 0.222, p = 0.02). However, no relationship was observed between the HC and patient age (r = −0.016, p = 0.86), total hematopoietic CD34+ cells infused (r = −0.063, p = 0.51), median post-transplant days to myeloid (r = −0.081, p = 0.46) and platelet recovery (r = −0.054, p = 0.63), presence of aGVHD (r = −0.081, p = 0.40) or cGVHD (r = −0.024, p = 0.80) and donor gender (r = −0.091, p = 0.34).

Figure 1.

Overall survival of patients with and without hemorrhagic cystitis (HC).

(0,07MB).

In this study, the HC incidence (27%) was similar to other studies, although reported ranges are wide3,6,22,31 In our outpatient HSCT program, hydration could be not efficiently delivered during the conditioning regimen and post-transplantation cyclophosphamide administration, favoring HC in our patients. To minimize the risk, we used Mesna and hydration, from commencement until six hours after the end of the cyclophosphamide infusion.

Many HC risk factors have been described, including the conditioning regimen, unrelated donor and patient characteristics, such as male gender, older age and clinical conditions, including GVHD.3,32,33 In our study, despite all patients having received an RIC and the hematopoietic cell source having been a related donor in all cases, the HC incidence was similar to previous reports on myeloablative regimens. However, we did not find any relationship between demographic characteristics and the HC incidence.

We observed that donor-recipient sex mismatch was more frequent in the HC group than in the group of patients without HC (60% vs. 41%). This sex mismatch correlated with higher HC incidences (r = 0.222, p = 0.02). The discrepancy between sexes was more frequent from male donors to female recipients (37% vs. 23%). Similar information was found in a previous study.34

Cyclophosphamide is used in haploidentical transplantation to induce T lymphocyte apoptosis, thereby reducing the risk of GVHD, without damaging key hematopoietic cells, which produces high levels of protective aldehyde dehydrogenase.35,36 At recommended post-transplantation cyclophosphamide doses of 50 mg/kg on days +3 and +4, previous studies showed a 6% incidence of Grade 3 aGVHD.13,37 In our study, the aGVHD incidence (36%) was higher than previously reported rates, but no correlations with HC incidence or severity (r = −0.081, p = 0.40) were observed.

Although the BK virus can be detected in the urine of 50%–100% of asymptomatic patients, not presenting HC, it is probable that the coexistence of BK virus with other factors could favor HC (6). It has been suggested that delayed immune reconstitution following haploidentical transplant could contribute to higher rates of BK virus infection in this population and that immune reconstitution leads to more severe BK virus infections, including HC incidences, due to the recognition of bladder viral antigens by emerging, functioning lymphocytes.38

Nevertheless, for associations between the BK virus and conditioning regimens, the BK viruria is more frequent in patients who receive a myeloablative conditioning regimen (57%), than those who receive a non-myeloablative scheme (30%), regardless of the presence of HC. In this study, we observed a high HC incidence associated with the BK virus (71%), bearing in mind all patients had received RIC schemes.6 Characteristically, late onset HC is associated with viral infection, mainly by the BK virus.31,39 All HC cases included here were late onset, with a median time after transplant of 30 days (7–149 days) and a median duration of 23.5 days (4–80 days). The BK virus was the most frequent etiological agent detected. Although virus detection was not performed in all patients due to onset characteristics (late onset) and financial constraints, it is unlikely that the HC was caused by the chemotherapy regimen in these cases. Regarding overall survival, we found no differences between patients with and without HC (46.7% vs. 50%, p = 0.712).

Study limitations included its retrospective nature, the small number of patients with HC and a possible underestimation of virus-associated HC, due to the low numbers of samples analyzed. However, our study provides key information on the HC incidence and evolution in patients who receive their haplo-HSCT on an outpatient basis, including all the care for the administration of the conditioning scheme and the post-transplant cyclophosphamide.

In conclusion, the HC incidence and severity after haplo-HSCT on an outpatient basis was comparable to incidences reported in hospitalized patients after myeloablative conditioning. The only characteristic related to a higher HC incidence was the donor-recipient sex mismatch.

All transplant procedures were performed in accordance with institutional ethical standards after obtaining approval by the transplant committee and signing an informed consent, according to the FACT guidelines. Due to the retrospective nature of the study, it was not necessary to request informed consent from patients; however, patient confidentiality was strictly maintained.

The authors declare no conflicts of interest.