In HSCT patients, hematuria is generally considered related to toxic or infectious impairment of urinary mucosae until proven otherwise, and “hematuria” and “hemorrhagic cystitis” are widely used as synonyms.In this study we aimed to verify the risk potential of patients and transplants characteristics in the development of HC.
In our cohort, HC was strongly associated to age both as a continuous increasing risk and with a cut off of at 55 years. The widest available retrospective analysis performed on 1321 patients of all ages identified age lower than 20 years old as being at higher risk of HC 13, whether the biggest prospective study on 450 patients did not found differences in HC from being younger or older than 18 years, despite an incidence of HC in 21% of younger patients compared to an average of 12.2% 3. At the best of our knowledge, there is no other data analyzing the older age as a risk factor for HC in an exclusively adult population.
Cyclophosphamide has been described as having a role in HC when used in conditioning regimens 13. The rationale of this association lies in acrolein, a cyclophosphamide urinary metabolite with toxic effects on bladder mucosae. As some data are available on risk of HC in PTCY treated patients, no comparison has been made between the two triple prophylaxis regimens with post-transplant methotrexate or cyclophosphamide until now. In our population, we report that PTCY treated patients experience more HC, despite not independently from age.
Moderate-to-severe aGVHD was associated to more HC in our population, in partial disagreement to what had been described in 2015 in a small French cohort, where 22 out of 33 haploidentical transplants treated with PTCY experienced HC with no association with GVHD 7. It is possible to hypothesize a role for GVHD in damaging urothelium together with direct or indirect effects of GVHD therapy with high dose steroids and immunosuppression.
Matched transplants had a lower incidence of HC compared to haploidentical transplants. This is similar to what Copelan and colleagues had described in 122 patients uniformly treated with PTCY prophylaxis, where they reported HC in 25% vs 42% of HLA matched and haploidentical transplants, respectively. In that series the authors hypothesized that HLA mismatched donor T cells could impair host antigen presenting cells, thus favoring BKV infections 4. A strong association between HC and BKV detection has been found also in our cohort of patients and was independent from the other risk factor (data not shown). Similarly, Oltolini et al have reported 235 patients who received PTCY as GVHD prophylaxis, where HLA mismatch was found to favor early viral, but not bacterial, infections 15. As this immunological thesis appears interesting, it does not fully explain higher impact of HLA mismatch in BKV negatives HCs.
About the role of gender in development of HC, few and contrasting literature is available: Gargiulo et al found no difference in HC incidence in a prospective population of 450 mixed pediatric and adult patients of both genders (13% vs 11%), while Lunde et al retrospectively revised 1321 consecutive patients and found that male gender was associated with higher incidence of HC (15% vs 23%, p = 0.01) 3,13 In our study, male patients had doubled incidence of HC compared to females. We found that HC was more common as prostatic volume increased and that a cut off of 40 cm^3 was able to discriminate two populations with very different HC risk (16% vs 32%, p = 0.03). Despite association between age and prostatic hyperplasia results obvious, they seem to remain independently associated to HC in multivariate analysis. We argued that prostate may play a part in determining incidence and severity of HC in male patients. Our hypothesis was that toxic metabolites as acrolein may have a prolonged contact with bladder mucosae due to urinary retention in patients with prostatic hyperplasia. This exposure could reasonably contribute to chemical damage and bleeding in a thrombocytopenic and immunocompromised patient. Moreover, urinary retention may enhance viral damage from JCV and BKV on urothelium. Prostatic samples from patients with prostate cancer (PC) and prostatic hyperplasia have been found to be a reservoir both of BKV and JCV in 22–32% cases as well as a possible site of viral replication 16,17. As urinary viral reactivation, especially BKV, are common in several immunodeficiency status, and polyomavirus in urinary tract may contribute to HC, it is reasonable to hypothesize that prostatic hyperplasia, viral reactivation and HC may be connected 18,19.
Patients with HC had worse outcomes. Not only they experienced more prolonged hospitalization, but they also had higher probability of dying for NRM. Prolonged hospitalization was usually due to HC, as far as its acute management requires invasive procedures and an intense transfusion support. On the other side, multi organ worsening condition may associate with infections, severe cytopenia or renal failure, thus identifying HC as the top of an iceberg.
A point of discussion is HC prophylaxis: from GITMO prospective experience and ECIL guidelines on BKV related HC, some prophylactic approaches have been recommended despite no clear efficacy have been demonstrated. In those papers, Mesna associated to cyclophosphamide, urine alkalinization, intravenous hyper-hydration and bladder continuous irrigation are considered, while no clear position is taken on antibiotic prophylaxis 3,20. In 2008 Hadjibabaie et al performed continuous bladder irrigation on 40 consecutive patients receiving HSCT for sibling donor and conditioning including cyclophosphamide, and were compared to an historical cohort. Incidence of HC was 50% in historical cohort vs 32% in patients receiving prophylactic irrigation (p = 0.1), with lower length of HC when occurred (18 vs 10 days) 21. In our population, three patients received continuous bladder irrigation for a history if intolerance to Mesna or previous HC, and none of them experienced HC. At present days, treatment of HC is not formally standardized in the setting of allogeneic transplants, although factors as time from transplant and platelets recovery seem to play a central role.Most patients usually receive intravenous hyper-hydration and intensive platelets transfusion, with continuous bladder irrigation limited to 12–27% patients according to different experiences 13,20. Limited amount of patients require intravesical cauterization or intravesical instillation of hyaluronic acid, fibrin glue or platelet-rich plasma. When viral BKV is detected, systemic or local specific therapy is required and can be curative in up to 70% cases. A possible role may be played by BKV genotype, while the role of JCV need to be further investigated 22,23.
Data on prostatic hyperplasia have never been reported in this setting:a prospective evaluation of post void residual urine and measurement of acrolein and viruses in urines may clarify the pathogenesis of this complication.
In conclusion, age more than 55 is the an independent risk factor for hemorrhagic cystitis in patient treated with allogeneic stem cell transplantation. Mismatch transplants and PTCY based triple GVHD prophylaxis may have a role, but not independently from age. For male patients, prostatic hypertrophy may be an additional risk factor. More intense prophylactic strategies may represent a reasonable option to prevent HC in the setting of high risk adult transplants.