Influence of Timing PTCy in AlloSCT

Evaluation of the Influence of Timing of Post-transplant Cyclophosphamide in Allogeneic Haematopoietic Stem Cell Transplant Patients.

Cyclophosphamide, administered after the infusion of haematopoietic progenitor cells, is used to prevent graft-versus-recipient disease (GVHD) in patients undergoing allogeneic haematopoietic stem cell transplantation (allogeneic HSCT) and has been shown to reduce the incidence of GVHD.

Cyclophosphamide can cause haemorrhagic cystitis as a result of the direct toxicity of its metabolite acrolein to the bladder mucosa or urothelium upon accumulation in the urine. Hyperhydration and the administration of mesna, which forms a non-urotoxic compound with acrolein, are among the most commonly used strategies to prevent this. The administration of cyclophosphamide in the morning is also recommended.

The protocol for post-transplant cyclophosphamide states that it should be started at least 72 hours (days +3 and +4) after haematopoietic progenitor infusion, but this interval can be extended to 84 hours (day +3.5). After reviewing the recommendations to reduce the risk of haemorrhagic cystitis, it was recommended to delay the infusion of cyclophosphamide to the early morning of days +4 and +5, although in reality, taking into account the hours since the infusion of haematopoietic progenitors, it would be days +3.5 and +4.5 instead of days +3 and +4 in the afternoon/evening. This change will mean a delay of 12 hours in the start of cyclophosphamide, so the investigators will refer to day +3.5 from the infusion of the haematopoietic precursors.

Study Overview

• Status: Recruiting
• Conditions: Cyclophosphamide Toxicity; Allogenic Haematopoetic Transplantation
• Intervention / Treatment: Drug: Cyclophosphamide

Detailed Description

Cyclophosphamide administered after haematopoietic stem cell infusion is used for the prevention of graft-versus-recipient disease (GVHD) in patients undergoing allogeneic haematopoietic stem cell transplantation (allo-SCT) and has been shown to reduce the incidence of GVHD.

However, cyclophosphamide can cause haemorrhagic cystitis (HC) as one of the best known adverse effects. This is due to the direct toxicity of the cyclophosphamide metabolite, acrolein, to the bladder mucosa or urothelium as it accumulates in the urine. The incidence of HC can vary from 10 to 70% of patients and increases the number of days spent in hospital as well as morbidity and mortality after transplantation. Among the most common risk factors and causative agents, in addition to cyclophosphamide, are BK polyomavirus infections, with cyclophosphamide-induced HC often occurring within 72 hours of the administration of cyclophosphamide.

There are several strategies to prevent cyclophosphamide-induced HC, such as hyperhydration with saline and forcing diuresis with furosemide, alkalinisation of diuresis or administration of mesna, which forms a non-urotoxic complex with acrolein in the urinary tract and prevents tissue damage. However, further studies are needed to understand the best strategy to prevent HC, especially in the setting of allo-SCT.

In order to ensure proper hydration, to promote diuresis during the day and to reduce the time that acrolein is in contact with the mucosa, the administration of cyclophosphamide in the morning is recommended.

There are several strategies to prevent cyclophosphamide-induced HC, such as hyperhydration with saline and forcing diuresis with furosemide, alkalinisation of diuresis or administration of mesna, which forms a non-urotoxic complex with acrolein in the urinary tract and prevents tissue damage. However, further studies are needed to understand the best strategy to prevent HC, especially in the setting of allo-SCT.

In order to ensure proper hydration, to promote diuresis during the day and to reduce the time that acrolein is in contact with the mucosa, the administration of cyclophosphamide in the morning is recommended.

The usual protocol for the administration of cyclophosphamide (PTCy) after transplantation states that it should be started at least 72 hours (days +3 and +4) after the infusion of haematopoietic progenitors, but this interval can be extended to 84 hours (days +3.5) and the days of administration have been changed to days +3 and +5 with optimal results. In some patients, the infusion of haematopoietic precursors is carried out in the afternoon because of the need for nursing care. This meant that cyclophosphamide had to be administered in the evening, 72 hours after the infusion of the precursors. After review of the recommendations to reduce the risk of haemorrhagic cystitis, it was recommended that cyclophosphamide infusion be delayed in the morning on days +4 and +5, although in reality, taking into account the hours since haematopoietic progenitor infusion, these would be days +3.5 and +4.5 instead of days +3 and +4 in the afternoon/evening. This change means a 12-hour delay in the start of cyclophosphamide. Therefore, the investigators refer to day +3.5 from the infusion of haematopoietic progenitors.

• Study Type: Observational
• Enrollment (Estimated): 200

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08025
    • Recruiting
    • Hospital de La Santa Creu I Sant Pau
    • Contact: Estela Moreno; Phone Number: +34618954147; Email: Mmorenoma@santpau.cat

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: N/A

• Sampling Method: Probability Sample

Study Population

Patients who received cyclophosphamide after haematopoietic progenitor transplantation, consecutively, at the HSCSP, between January 2014 and December 2022.

Description

Inclusion Criteria:

• Adult recipients (>18 years old) of Allo-SCT
• Allo SCT between January 1, 2014 and December 31, 2022
• PTCy dose 50 mg/kg x 2 days

Exclusion Criteria:

• Patients with no record of time of administration of PTCy
• PTCy dose of 30 mg/kg x 2 days

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cystitis hemorrhagic; Cystitis hemorrhagic grade II-III	Drug: Cyclophosphamide; Time of administration
Non Cystitis hemorrhagic; Non cystitis hemorrhagic or grade I	Drug: Cyclophosphamide; Time of administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
incidence haemorrhagic cystitis Grade II-IV	To compare the incidence of grade II to IV haemorrhagic cystitis, according to the CTCAE classification, depending on the schedule of post-transplant cyclophosphamide administration in consecutive patients.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GVHD acute and chronic	To compare the incidence of acute and chronic graft-versus-host disease.	6 months
Mortality and relapsed	To compare the incidence of transplant-related mortality and recurrence.	6 months

Collaborators and Investigators

• Sponsor: Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2023
• Primary Completion (Estimated): October 1, 2023
• Study Completion (Estimated): December 1, 2023

Study Registration Dates

• First Submitted: May 23, 2023
• First Submitted That Met QC Criteria: May 23, 2023
• First Posted (Actual): June 2, 2023

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 26, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: cyclophosphamide; allogenic haematopoetic transplantation; haemorrhagic cystitis
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: IIBSP-CFM-2023-45

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No