Optimizing GVHD Prophylaxis After Allogeneic Hematopoietic Cell Transplantation (PTCYGVHD)

A Phase II Randomized Trial to Optimize GVHD Prophylaxis After Allogeneic Hematopoietic Cell Transplantation in Older Adults With Hematological Malignancies: the PROMISE Trial

This study will compare post-transplant health-related quality of life following the use of standard versus attenuated dose of post-transplant cyclophosphamide in addition to two-drug graft-versus-host disease (GVHD) prophylaxis among recipients of allogeneic hematopoietic stem cell transplant.

Study Overview

• Status: Recruiting
• Conditions: Hematological Malignancies; Graft-versus-Host Disease (GVHD)
• Intervention / Treatment: Drug: Attenuated-dose Cyclophosphamide; Drug: Sirolimus; Drug: Mycophenolate Mofetil (MMF); Drug: High-dose Cyclophosphamide

Detailed Description

This is a single-center phase II study of 126 participants (63 per arm) with hematological malignancies. Participants will be randomized to receive high doses (standard arm) or attenuated doses of cyclophosphamide in addition to two-drug GVHD prophylaxis. Participants will be monitored for health-related quality of life [Functional Assessment of Cancer Therapy-Bone Marrow Transplant, FACT-BMT(1)], functional outcomes (Karnofsky Performance Scale (KPS), activities of daily living, instrumental activities of daily living, Clock-in-the-Box Test, Fried Frailty Index, fall history, BMI, and Geriatric Depression Scale-15, GVHD, relapse, survival, and toxicities (using Common Terminology Criteria for Adverse Events, CTCAE version 5.0).

• Study Type: Interventional
• Enrollment (Estimated): 126
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Taylor Johnson; Phone Number: 402-559-4596; Email: taylora.johnson@unmc.edu
• Study Contact Backup: Name: IIT OFFICE; Phone Number: 402-559-4596; Email: iitoffice@unmc.edu

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • Recruiting
      • University of Nebraska Medical Center
      • Contact: A
      • Contact: Taylor Johnson; Phone Number: 402-559-4596; Email: taylora.johnson@unmc.edu
      • Principal Investigator: Moataz Ellithi, MBChB

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

• Adults aged 60 years or older
• Diagnosis of a hematological malignancy or other serious hematological disorder that requires an allogeneic hematopoietic cell transplantation
• Planned to receive any reduced-intensity conditioning regimen (any graft source is acceptable) and availability of human leukocyte antigen (HLA)-matched donor at HLA loci A, B, C, and HLA-DR beta chain antigen (DRB1)
• Karnofsky Performance Status (KPS) of 70% or higher.

Exclusion criteria:

• Previous history of one or more prior allogeneic stem cell transplants (i.e., second or third allogeneic transplant)
• Planned use of high doses of cyclophosphamide (e.g., a total cyclophosphamide dose of approximately 50 mg/kg or more) as part of the conditioning regimen prior to allogeneic stem cell transplant. A lower dose of cyclophosphamide (e.g., fludarabine, cyclophosphamide, and low-dose total body irradiation regimen that uses 2 doses of cyclophosphamide at 14.5 mg/kg) is acceptable.
• Known diagnosis of liver cirrhosis or other advanced liver disease that may impact cyclophosphamide metabolism.
• Diagnosis of myelofibrosis
• Creatinine clearance less than 40 mL/min/1.73 m², which may increase the risk of hemorrhagic cystitis with post-transplant cyclophosphamide (PTCy)
• Systolic cardiac dysfunction with an ejection fraction of less than 45%.
• Use of a haploidentical or mismatched donor.
• Any other condition judged by the physician to increase the risk of toxicities associated with PTCy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Attenuated-dose post-transplant cyclophosphamide (PTCy) Arm; Participants will receive attenuated-dose post-transplant cyclophosphamide (PTCy) at 25 mg/kg on days +3 and +4 after allogeneic hematopoietic stem cell transplantation. This is in addition to sirolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis.	Drug: Attenuated-dose Cyclophosphamide; Cyclophosphamide administered at an attenuated dose of 25 mg/kg on days +3 and +4 post-transplant for GVHD prophylaxis.; Drug: Sirolimus; Sirolimus is started on day +5 with a loading dose of 6 mg, followed by a maintenance dose of 2 mg daily, adjusted to target trough levels of 8-12 ng/mL. Sirolimus taper is recommended to start at day +90 and to be completed by day +180, provided there is no evidence of acute GVHD.; Drug: Mycophenolate Mofetil (MMF); MMF is started on day +5 at a dose of 15 mg/kg per dose (maximum 1 g per dose) three times daily. MMF is generally discontinued by day +35 in the absence of GVHD.
Active Comparator: High-dose post-transplant cyclophosphamide (PTCy) Arm: Standard of Care; Participants will receive high-dose post-transplant cyclophosphamide (PTCy) at 50 mg/kg on days +3 and +4 after allogeneic hematopoietic stem cell transplantation. This is in addition to sirolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis.	Drug: Sirolimus; Sirolimus is started on day +5 with a loading dose of 6 mg, followed by a maintenance dose of 2 mg daily, adjusted to target trough levels of 8-12 ng/mL. Sirolimus taper is recommended to start at day +90 and to be completed by day +180, provided there is no evidence of acute GVHD.; Drug: Mycophenolate Mofetil (MMF); MMF is started on day +5 at a dose of 15 mg/kg per dose (maximum 1 g per dose) three times daily. MMF is generally discontinued by day +35 in the absence of GVHD.; Drug: High-dose Cyclophosphamide; Cyclophosphamide administered at the standard high dose of 50 mg/kg on days +3 and +4 post-transplant for GVHD prophylaxis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Health-Related Quality of Life as Measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplantation	The health-related quality of life will be assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) trial outcome index (TOI). The FACT-BMT is a validated, patient-reported questionnaire that measures physical and functional well-being specifically in bone marrow transplant recipients. Higher scores indicate better quality of life. The primary outcome is to compare the FACT-BMT TOI scores between the attenuated-dose PTCy arm and the high-dose PTCy arm at 3 months post-transplant.	Baseline and 3 months post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cumulative Incidence of Grade II-IV Acute GVHD	Acute graft-versus-host disease (GVHD) of grade II-IV is assessed using the Mount Sinai acute GVHD grading system. The study will estimate and compare the cumulative incidence of grade II-IV acute GVHD at 1 year post-transplant between the two treatment arms.	From date of transplant to 1 year post-transplant
Cumulative Incidence of Chronic GVHD	Chronic GVHD is assessed using the NIH chronic GVHD grading system, which includes both classical chronic GVHD and overlap syndrome. The study will estimate and compare the cumulative incidence of chronic GVHD at 1 year post-transplant between the two treatment arms.	From date of transplant to 1 year post-transplant
To determine the cumulative incidence and kinetics of hematologic recovery (neutrophil and platelet) among the two treatment arms	Hematologic recovery is evaluated by time to neutrophil engraftment (absolute neutrophil count ≥ 500/mm³ for three consecutive days) and platelet engraftment (platelet count ≥ 20,000/mm³ or ≥ 50,000/mm³ without transfusion for seven days). The study will describe and compare the cumulative incidence and kinetics of neutrophil and platelet recovery by days +28 and +100 post-transplant between the two treatment arms.	From date of transplant to day +28 and day +100 post-transplant
Incidence of Grade III or Higher Adverse Events	Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study will assess and compare the incidence of grade III or higher adverse events by day +100 post-transplant between the two treatment arms.	From date of transplant to day +100 post-transplant
Change in Karnofsky Performance Scale	Karnofsky Performance Scale (KPS) is a validated tool ranging from 0 (death) to 100 (normal activity). Higher scores indicate better functional status.	Baseline and 3 months post-transplant
Change in Activities of Daily Living	Activities of Daily Living (ADL) measures basic self-care tasks such as bathing and dressing. The typical total score ranges from 0 to 6, with higher scores indicating better functional status.	Baseline and 3 months post-transplant
Change in Instrumental Activities of Daily Living	Change in Instrumental Activities of Daily Living (IADL) assesses more complex tasks (e.g., handling finances). Total scores typically range from 0 to 8 or 0 to 14 (depending on the version), with higher scores indicating greater independence.	Baseline and 3 months post-transplant
Change in Fried Frailty Index	The Fried Frailty Index assesses five components (weight loss, exhaustion, grip strength, walking speed, and physical activity). A higher total score indicates greater frailty.	Baseline and 3 months post-transplant
Change in Clock-in-the-Box Test	This is a brief test of visuospatial and executive function, typically scored on accuracy of clock drawing/placement (range 0-8). Higher scores suggest better cognitive performance.	Baseline and 3 months post-transplant
Change in History of Falls	The number of falls, if any, will be collected since baseline. Results will be analyzed as the proportion of participants experiencing ≥1 fall over the time frame, or as the difference in mean (or median) number of falls between arms.	Baseline and 3 months post-transplant
Change in Body Mass Index	Body Mass Index (BMI) is calculated as weight (kg) / [height (m)]² (kg/m²). Higher or lower values do not necessarily indicate "better" or "worse" status by themselves but will be compared between arms for changes from baseline.	Baseline and 3 months post-transplant
Change in Geriatric Depression Scale-15	The Geriatric Depression Scale-15 (GDS-15) is a 15-item screening tool for depression in older adults (scores 0-15). Higher scores indicate more severe depression.	Baseline and 3 months post-transplant
Gaft-Versus-Host Disease-Free, Relapse-Free Survival	Graft-Versus-Host Disease (GRFS) is defined as the time from transplant to the first occurrence of grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death from any cause. An event is counted when any of these conditions are met. The GRFS at 1 year post-transplant will be compared between the two treatment arms.	From date of transplant to 1 year post-transplant
Overall Survival at 1 Year Post-Transplant and Event-Free Survival	Overall Survival (OS) is defined as survival from the date of transplant until death from any cause. Event-Free Survival (EFS) is defined as survival from the date of transplant without disease relapse or progression. The study will compare the proportion of participants alive (for OS) and without relapse or progression (for EFS) at 1 year post-transplant between the two treatment arms	From date of transplant to 1 year post-transplant
Cumulative Incidence of Transplant-Related Mortality	Transplant-related mortality (TRM) is defined as death from causes other than disease relapse or progression. The study will estimate and compare the cumulative incidence of TRM at 1 year post-transplant between the two treatment arms.	From date of transplant to 1 year post-transplant
Cumulative Incidence of Grade II or Higher Infections	Infections will be graded according to Blood and Marrow Transplant Clinical Trials Network (BMT CTN) criteria. The study will estimate and compare the cumulative incidence of grade II or higher infections by 6 months post-transplant between the two treatment arms.	From date of transplant to 6 months post-transplant

Collaborators and Investigators

• Sponsor: University of Nebraska
• Investigators: Principal Investigator: Moataz Ellithi, MBChB, University of Nebraska

Publications and helpful links

General Publications

• Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D, Sorror ML, Horowitz MM, Bolwell B, Rizzo JD, Socie G. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2011 Jun 1;29(16):2230-9. doi: 10.1200/JCO.2010.33.7212. Epub 2011 Apr 4.
• McQuellon RP, Russell GB, Cella DF, Craven BL, Brady M, Bonomi A, Hurd DD. Quality of life measurement in bone marrow transplantation: development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplant. 1997 Feb;19(4):357-68. doi: 10.1038/sj.bmt.1700672.
• Luznik L, Pasquini MC, Logan B, Soiffer RJ, Wu J, Devine SM, Geller N, Giralt S, Heslop HE, Horowitz MM, Jones RJ, Litzow MR, Mendizabal A, Muffly L, Nemecek ER, O'Donnell L, O'Reilly RJ, Palencia R, Schetelig J, Shune L, Solomon SR, Vasu S, Ho VT, Perales MA. Randomized Phase III BMT CTN Trial of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions in Myeloablative Hematopoietic Cell Transplantation for Hematologic Malignancies. J Clin Oncol. 2022 Feb 1;40(4):356-368. doi: 10.1200/JCO.21.02293. Epub 2021 Dec 2.
• Korngold R, Sprent J. Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow. J Exp Med. 1978 Dec 1;148(6):1687-98. doi: 10.1084/jem.148.6.1687.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2025
• Primary Completion (Estimated): April 1, 2031
• Study Completion (Estimated): November 1, 2031

Study Registration Dates

• First Submitted: January 15, 2025
• First Submitted That Met QC Criteria: January 22, 2025
• First Posted (Actual): January 29, 2025

Study Record Updates

• Last Update Posted (Actual): December 15, 2025
• Last Update Submitted That Met QC Criteria: December 8, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Randomized Controlled Trial; Sirolimus; Allogeneic Hematopoietic Stem Cell Transplantation; Health-Related Quality of Life (HRQoL); GVHD Prophylaxis; Mycophenolate Mofetil (MMF)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Immune System Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Hematologic Neoplasms; Graft vs Host Disease; Organic Chemicals; Fatty Acids; Lipids; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Caproates; Sirolimus; Cyclophosphamide; Mycophenolic Acid
• Other Study ID Numbers: 0094-25-FB

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No