Optimizing GVHD Prophylaxis After Allogeneic Hematopoietic Cell Transplantation

Official title

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

Overview

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.

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).

Interventions

• 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 High-dose Cyclophosphamide
  Cyclophosphamide administered at the standard high dose of 50 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.

Primary outcome measures

• Change in Health-Related Quality of Life as Measured by Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [Time frame: Baseline and 3 months post-transplant]

Secondary outcome measures (12)

• Change in Karnofsky Performance Scale [Time frame: Baseline and 3 months post-transplant]
• Change in Activities of Daily Living [Time frame: Baseline and 3 months post-transplant]
• Change in Instrumental Activities of Daily Living [Time frame: Baseline and 3 months post-transplant]
• Change in Fried Frailty Index [Time frame: Baseline and 3 months post-transplant]
• Change in Clock-in-the-Box Test [Time frame: Baseline and 3 months post-transplant]
• Change in History of Falls [Time frame: Baseline and 3 months post-transplant]
• Change in Body Mass Index [Time frame: Baseline and 3 months post-transplant]
• Change in Geriatric Depression Scale-15 [Time frame: Baseline and 3 months post-transplant]
• Gaft-Versus-Host Disease-Free, Relapse-Free Survival [Time frame: From date of transplant to 1 year post-transplant]
• Overall Survival at 1 Year Post-Transplant and Event-Free Survival [Time frame: From date of transplant to 1 year post-transplant]
• Cumulative Incidence of Transplant-Related Mortality [Time frame: From date of transplant to 1 year post-transplant]
• Cumulative Incidence of Grade II-IV Acute GVHD [Time frame: From date of transplant to 1 year post-transplant]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Nebraska Medical Center — Omaha

Publications

• 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 Hematopoi PMID 34855460
• 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. PMID 363972
• 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. PMID 21464398
• 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. PMID 9051246

Identifiers

NCT: NCT06799195 · 0094-25-FB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗