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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 15  |  Issue : 2  |  Page : 111-117

Role of intravesical granulocyte-macrophage colony-stimulating factor in controlling hemorrhagic cystitis in patients undergoing stem cell transplantation - A retrospective cohort study


Department of Medical and Pediatric Oncology, The Gujarat Cancer and Research Institute, Ahmedabad, Gujarat, India

Date of Submission09-Aug-2020
Date of Decision14-Oct-2020
Date of Acceptance05-Apr-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Dr. Akanksha Garg
Department of Medical and Pediatric Oncology, The Gujarat Cancer and Research Institute, Ahmedabad - 380 016, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_93_20

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  Abstract 

Introduction: Hemorrhagic cystitis (HC) is a well-known complication in patients undergoing hematopoeitic stem cell transplantation (HSCT), contributing considerably to morbidity and prolonged hospital stay. Granulocyte-macrophage colony-stimulating factor (GM-CSF) affects the proliferation and differentiation of hematopoietic stem/progenitor cells and the functioning of monocytes, granulocytes, lymphocytes, and endothelial cells. The objective of this study was to evaluate the efficacy and safety of GM-CSF bladder irrigation for HC post-HSCT. Materials and Methods: We conducted a retrospective cohort study to assess the clinical effects of GM-CSF (GM-CSF group) in controlling HC in patients who had undergone HSCT at our institute. We also compared these patients with those who did not receive GM-CSF. Results: There were 12 patients in the GM-CSF group and seven patients in the non-GM-CSF (control) group. The median ages were 16 years (range: 4–33 years) and 19 years (range; 6–41 years), respectively. Median time-to-resolution of HC from day of onset was 9.5 days in the GM-CSF group versus 59 days in the non GM-CSF group (P = 0.001). Mortality was 85% in the control group as compared to 16% in GM-CSF group (P = 0.008). Among the GM-CSF responders, complete response was seen in eight patients (67%). None of the patients developed any systemic or local side effects to GM-CSF. Overall survival in the two groups was 75% and 14%, respectively (P = 0.043). Conclusion: GM-CSF was shown to be effective in controlling HC in post-HSCT patients, without any major side effects, along with decreased mortality and improved overall survival.

Keywords: Granulocyte-macrophage colony-stimulating factor, hematopoeitic stem cell transplantation, hemorrhagic cystitis


How to cite this article:
Garg A, Dasgupta R, Shah S, Patel K, Shah K. Role of intravesical granulocyte-macrophage colony-stimulating factor in controlling hemorrhagic cystitis in patients undergoing stem cell transplantation - A retrospective cohort study. Indian J Transplant 2021;15:111-7

How to cite this URL:
Garg A, Dasgupta R, Shah S, Patel K, Shah K. Role of intravesical granulocyte-macrophage colony-stimulating factor in controlling hemorrhagic cystitis in patients undergoing stem cell transplantation - A retrospective cohort study. Indian J Transplant [serial online] 2021 [cited 2021 Jul 24];15:111-7. Available from: https://www.ijtonline.in/text.asp?2021/15/2/111/319894


  Introduction Top


Hemorrhagic cystitis (HC) is a commonly encountered complication in patients undergoing hematopoietic stem cell transplantation (HSCT) with the incidence varying from 10% to 60% and morbidity and mortality reaching up to 10%–75%.[1],[2] Symptoms can vary from microscopic hematuria to obstructive renal failure. It can be classified as early-onset HC occurring within a week (in most cases, within 48 h) after the transplant and late-onset HC occurring from 2 weeks up to 6 months post-HSCT. Early-onset HC occurs due to conditioning agents such as cyclophosphamide or radiation toxicity, while late onset HC can be attributed to multiple etiologies such as BK Polyoma virus, cytomegalovirus (CMV), adenovirus, occurrence of graft versus host disease (GVHD), and donor source.[3],[4],[5],[6]

Conventionally, high-dose cyclophosphamide-induced HC is sought to be prevented by bladder irrigation, hyperhydration, and the use of 2-mercaptoethane sulfonate sodium (Mesna). Other interventions used include the intravesical instillation of prostaglandins,[7],[8] silver nitrate,[9] and formalin.[10] Surgical interventions such as cystostomy, temporary urinary diversion, and bladder packing may be necessary in cases with refractory, life-threatening bleeding.[11]

Granulocyte-macrophage colony-stimulating factor (GM-CSF) affects the proliferation and differentiation of hematopoietic stem/progenitor cells and the functioning of monocytes, granulocytes, lymphocytes, and endothelial cells. It has healing effects by regulating acute and chronic inflammation. The pleotropic effects of GM-CSF have been exploited for the treatment of inflammatory and ulcerative conditions such as HSCT-associated mucositis[12] and chronic leg ulcers.[13] There are case reports and studies showing encouraging results for the use of intravesical GM-CSF in HC as well.[14] Since the number of transplants have been increasing each year, the incidence of HC is bound to increase, too. Many transplant centers in India are increasingly doing haploidentical transplants where posttransplant cyclophosphamide is being used, which is associated with higher risks of HC. There is a paucity of data on HC from India. We conducted a retrospective analysis, evaluating the efficacy and safety GM-CSF in resolution of HC in the posttransplant setting.


  Materials and Methods Top


We conducted a retrospective cohort study in the BMT unit of our tertiary care center.

Inclusion and exclusion criteria

Patients developing HC ≥ Grade II during the post-HSCT period between January 2012 to January 2020 were included in the study. Those not meeting these criteria were excluded. Case details were retrieved from patient files. Before January 2015, we did not routinely use GM-CSF bladder irrigation for patients developing HC. After this period, we started using this modality in addition to conventional measures for all patients with HC. A total of 19 patients developed HC, of which 7 received standard care (non-GM-CSF group) and 12 received GM-CSF additionally. The study was approved by the ethics committee of the institute. The patients had been monitored for symptoms of HC both during admission and during outpatient follow-ups. The treatment and conditioning regimens were according to standard protocols mentioned in previous publications.[15],[16]

Objective

The objective of the study was to evaluate the efficacy and safety of GM-CSF bladder irrigation in patients with HC post-HSCT.

Definitions

Very specific definitions are not described in literature as of now, which has led to a wide range in the reported incidence of HC in HSCT patients.[1],[2] HC has however been described as an episode of macroscopic hematuria with symptoms of burning micturition, frequency, and dysuria provided that bacterial cystitis and differentials such as Disseminated intravascular coagulation (DIC), other bleeding diatheses, or sepsis has been ruled out. Severity of HC was as per criteria in [Table 1].[17] Grade II or higher was considered significant, as this was the group that required intervention.
Table 1: Grading of hemorrhagic cystitis[17]

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Definition of response, assessed at 3 days from intravesical granulocyte-macrophage colony-stimulating factor instillation[14]

Complete remission (CR) – Resolution of symptoms and hematuria with no recurrence within 1 week of CR.

Partial remission – Microscopic hematuria with no symptoms and not requiring transfusions.

Failure – No response or recurrence within 1 week of discontinuation of intravesical GM-CSF instillation.

BK viruria of >9 × 106 copies/ml was considered significant.

Transplant protocols and follow-up

All patients were managed according to the standard transplant protocols of the unit. They were regularly followed up posttransplant and investigations were monitored as per unit protocol. Urine microscopic examination and dipstick testing were done for all patients with HC. In addition, imaging, such as sonography of the bladder to look for clots, was done as appropriate. CMV polymerase chain reaction (PCR) was monitored for all patients as per protocol. As PCR for BK virus from serum and urine were not available in-house, these samples were sent to an accredited laboratory outside our institution for a few patients only.

Prophylaxis and treatment of hemorrhagic cystitis

All patients who received cyclophosphamide as a part of their conditioning regimen were given Mesna, hydration, alkalinization, and forced diuresis as prophylaxis. When a patient developed HC, they were started on the following additional measures.

Control group

Patients in the control group received hyperhydration (3 L/m2) and Mesna infusion (20 mg/kg IV q6 hourly for 4 days). Continuous bladder irrigation was done using cold saline if the patient developed clots.

Granulocyte-macrophage colony-stimulating factor group

GM-CSF was infused into the bladder through the Foley's catheter in addition to the above measures. Intravesical GM-CSF was administered at a dose of 500 μg diluted in 50 ml normal saline, followed by direct instillation into the bladder through a triple lumen Foley's catheter for 5 consecutive days. The Foley's catheter was clamped for 1–1.5 h or as tolerated by patient. This was followed by bladder irrigation with 0.9% normal saline.

Patients were given intensive platelet transfusions to maintain platelet counts above 50 × 109/L, and any coagulopathy was corrected with Vitamin K supplementation or fresh frozen plasma to maintain the prothrombin time international normalized ratio (PT-INR) below 1.5 times the upper limit of normal.

Statistical analysis

Mann–Whitney U-test and Chi-square test were used to compare continuous and categorical variables between the two groups, respectively. Probabilities of survival and median follow-up period were measured using Kaplan–Maier method and compared using log-rank test. Event was defined as death due to GVHD, sepsis, or relapse. Cox proportional hazards model was used for the evaluation of risk factors in the development of HC using univariate analysis. Risk factors included recipient age, donor age, gender, graft type, type of conditioning, and use of antithymocyte globulin (ATG). A P < 0.05 was considered statistically significant. IBM SPSS version 23.0 was used (Armonk, USA).

Patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The ethical clearance was taken from institutional review board, with IRB number IRC/2020/P-42. All protocols were followed as per Declaration of Helsinki.


  Results Top


Baseline characteristics

Three hundred and sixty-two transplants were done from January 2008 to January 2020. This included 205 allogenic transplants (matched sibling donor 156, matched unrelated donor 6, umbilical cord blood 16, and haploidentical 27). Median age at transplant was 24 years (range: 1–65 years). Myeloablative conditioning regimens were used in 114 transplants. All the haploidentical transplants used posttransplant cyclophosphamide (PTCy) for preventing GVHD.

A total of 19 patients developed HC during this period. The median age was 15 years (range: 4–41 years), with 63% males. Indications for HSCT ranged from benign disorders such as thalassemia major (n = 6), severe aplastic anemia (AA) (n = 4), paroxysmal nocturnal hemoglobinuria (PNH) (n = 2), PNH/AA overlap (n = 1), or Fanconi anemia (n = 1), to malignant disorders, such as acute myeloid leukemia (n = 1) and acute lymphoblastic leukemia (n = 4). Baseline characteristics of these patients have been highlighted in [Table 2]. The dose of cyclophosphamide used ranged from 120 to 200 mg/kg (latter dose in thalassemia transplants) divided over 3 or 4 days. PTCy as GVHD prophylaxis was used at a dose of 50 mg/kg for 2 days. Rabbit ATG was administered as a part of the conditioning regimen in 11 patients. Majority of the patients developed late onset HC (79%).
Table 2: Baseline characteristics of all patients with hemorrhagic cystitis

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Risk factors for development of hemorrhagic cystitis

The risk of development of HC (Grade III–IV) was higher in males (P = 0.02, Hazard ratio (HR) 3.2) and those receiving myeloablative conditioning (P = 0.038, HR 4.8).

Response to treatment in the granulocyte-macrophage colony-stimulating factor group

Eight patients achieved CR with a median time to response of 4 days which was significantly shorter than the nonresponders (20 days, P = 0.01). Duration of hospital stay was similar in the responders and the nonresponders (P = 0.32) [Table 3]. None of the patients had recurrence during follow-up. The four patients, who did not respond, required additional measures. One patient required alum irrigation, followed by clot removal. Three patients had persistent thrombocytopenia requiring transfusion support.
Table 3: Responders versus nonresponders in granulocyte-macrophage colony-stimulating factor group

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Complications/toxicities

Localized hypogastric pain was the only major side effect reported. No systemic side effects were observed. GM-CSF was well tolerated by the majority of the patients. Two patients had urinary tract infection (Proteus mirabilis and Klebsiella pneumoniae one each) which was treated with appropriate antibiotics.

Comparison of granulocyte-macrophage colony-stimulating factor versus control group

The treatment parameters were comparable in both the groups. More patients received myeloablative conditioning in the GM-CSF group (9 vs. 1, P = 0.01). The median time to resolution of HC was significantly reduced in the treatment group (9.5 vs. 59 days, P = 0.001). The number of deaths were significantly higher in the control group (P = 0.008) [Table 4]. Two patients in the control group required surgical intervention for clot removal.
Table 4: Comparison of the granulocyte-macrophage colony-stimulating factor and nongranulocyte-macrophage colony-stimulating factor group

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Treatment-related mortality and overall survival

The overall survival was 75% in the GM-CSF group and 14% in the control group (P = 0.043) [Figure 1]. Most of the deaths were due to septicemia or GVHD. In the GM-CSF group, the median duration of follow-up was 8.5 months (range: 0.5–33 months). One death in the GM-CSF group was related to progressive HC and other two were due to peritransplant septicemia and GVHD at 1.5 months posttransplant. In the control group, the median duration of follow-up was 3 months (range: 1–93 months). In this group, there were five deaths contributed by HC and one death due to an unrelated cause during follow-up. The mortality was significantly less in the GM-CSF group (P = 0.008).
Figure 1: Overall survival in the two treatment groups (granulocyte-macrophage colony stimulating factor vs. no granulocyte-macrophage colony-stimulating factor)

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  Discussion Top


HC is a serious complication post-HSCT requiring prolonged duration of hospital stay and increased financial burden on the family. Hence, transplant physicians need to tackle this complication at the earliest and reduce the morbidity and mortality associated with it. In this study, we conducted a retrospective analysis of 19 patients who developed HC following HSCT at our institute and tried to establish possible predictive risk factors for developing HC. We also analyzed the therapeutic effects of intravesical GM-CSF in 12 of these patients in treating HC as an addition to the standard of care and compared them to the remaining seven patients who did not receive GM-CSF. This is the only published study on the use of intravesical GM-CSF from India.

Multiple studies have attributed high-dose (120–150 mg/kg) cyclophosphamide used in conditioning regimens as the predominant cause of early-onset HC in transplant patients.[18],[19],[20],[21],[22],[23],[24],[25] Pathogenesis of cyclophosphamide-induced HC involves the effect of its metabolite, acrolein, on bladder mucosa. Other studies have found infections such as BK virus, adenovirus, age of recipient, type of transplant, and GVHD as the predominant causes.[1],[26],[27] Harkensee et al. and Kondo et al. have identified younger age at transplant to be a risk factor for developing HC, with the cut off varying from 7 to 10 years.[4],[28] In a study by Wu et al., age <30 years, type of transplantation, CMV status, and acute GVHD were associated with the occurrence of HC after allo-HSCT. Multivariate analysis showed that acute GVHD was an independent risk factor for HC after allo-HSCT. They concluded that timely treatment of HC showed better prognosis.[29] Copelan et al. showed that higher incidence of HC occurred post haploidentical transplantation. Higher susceptibility to development of HC was shown to occur with greater HLA mismatch.[30] Although our cohort of patients was small, we found that the occurrence of HC was higher in males and associated with the use of myeloablative conditioning.

There are reports suggesting a pleiotropic tissue healing potential of GM-CSF in skin lesions of chronic leg ulcers,[13] burn wounds,[31] Kaposi's sarcoma,[32] and drug-induced mucositis.[12] Vela-Ojeda et al.[14] in their study reported favorable outcomes in controlling HC in HSCT patients using intravesical GM-CSF, with a median time-to-response being 36 h. Decker et al.[33] in their review on pediatric HC recommended the early use of intravesical therapies such as alum, prostaglandins, or cidofovir in addition to conventional therapy for superior control of HC. In our treatment group (GM-CSF group), all patients received GM-CSF within 3 days of HC-onset, along with other supportive measures. The median time to response was 4 days in the responder group as compared to 20 days in the nonresponders (P = 0.001). One possible explanation for this can be the increased use of ATG in the GM-CSF group which can predispose to a virus-related HC and hence a prolonged duration of HC.

Use of other intravesical therapies such as instillation of 1% alum, silver nitrate, prostaglandins, and formalin have been described to have success rates varying from 50% to 100% but are associated with significant side effects. For instance, allergic reactions, central nervous system disturbances, metabolic acidosis and coagulopathy with alum, ureteral obstruction with silver nitrite, severe bladder spasms with prostaglandins, and vesicoureteric reflux, bladder/ureteral fibrosis, and long-term bladder dysfunction with formalin.[10],[34],[35],[36],[37],[38],[39] In our study, localized pain was the only notable side effect of intravesical administration of GM-CSF, without any other major local or systemic effects, in concordance with similar observations made by Vela-Ojeda et al.[14]

HC is known to cause prolonged hospital stay and increased morbidity. Sencer et al.[40] reported an average of delay of 15 days in hospital discharge in patients with HC as compared to patients who did not develop HC during HSCT. Yang et al. observed higher hospitalization costs in patients with HC versus those with no HC.[18] In our study, duration of hospital stay was similar in both the groups although time to resolution of HC was significantly less in the GM-CSF group (P = 0.001). This highlights to benefit of GM-CSF in early control of HC. The overall survival was 75% in the GM CSF group and 14% in the control group (P = 0.043) [Figure 1]. The mortality was also significantly less in the GM-CSF group (P = 0.008). The reduced mortality could partly be explained by improved patient care in the subsequent years at our unit.

Limitations of the study

However, our study has many limitations such as being a retrospective analysis of a small number of patients, with the two cohorts being separated by significant time duration. We could perform BK virus testing only in a minority of our patients due to cost constraints. Larger, prospective studies are however needed to establish its use as a standard of care in controlling HC in patients post-HSCT.


  Conclusion Top


HC is a commonly encountered complication in patients undergoing allogeneic HSCT, especially with the use of high-dose cyclophosphamide-based conditioning regimens. Apart from hyperhydration, Mesna, bladder irrigation, and transfusion support, the early administration of intravesical GM-CSF has shown promise in controlling HC in post-HSCT patients. The administration is simple with manageable side effects, and it results in reduced morbidity, mortality, and improved survival.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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