TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT

Stanford University

Status and phase: Not yet enrolling; Phase 1

Conditions: Chronic Myeloid Leukemia (CML); Myelofibrosis (MF); Hematopoietic Cell Transplantation (HCT); Acute Myeloid Leukemia (AML); Chronic Myelomonocytic Leukemia (CMML); GVHD; Myelodysplastic Syndromes

Treatments: Other: Early Tacrolimus Taper Strategy; Drug: Tacrolimus

Study type: Interventional

Funder types: Other

Identifiers

NCT07302776

IRB-82367

Details and patient eligibility

About

The purpose of this study is to test the feasibility and safety of early cessation of tacrolimus following allogeneic hematopoietic cell transplantation (HCT). Post-HCT tacrolimus is given to prevent graft-vs-host-disease (GVHD), but with the use of post-transplant cyclophosphamide (PTCy), the modern approach to GVHD prevention, GVHD rates have reduced markedly.

Enrollment: 50 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Eligible diseases:

  • Acute myeloid leukemia (AML) in complete remission (CR), CR with incomplete hematologic recovery (CRi), or MLFS.
  • Myelodysplasic syndrome (MDS) myelodysplastic syndromes eligible for alloHSCT based on IPSS-M of intermediate or higher, or IPSS-R of intermediate or higher, or refractory disease to standard growth factor or hypomethylating agent-based therapy
  • Myelofibrosis (MF)
  • Chronic myeloid leukemia (CML) in chronic phase with a prior history of accelerated phase or blast crisis or CML in chronic phase refractory to standard TKI therapy
  • Chronic myelomonocytic leukemia (CMML)

• Age ≥ 18 and ≤ 80 years at the time of enrollment.

• Planned for first myeloablative or reduced intensity allogenic transplant using a conditioning regimen listed in Appendix B.

• Has a related or unrelated donor available who is 8/8 HLA match at HLA-A, -B, -C, and -DRB1, all typed using DNA-based high-resolution methods.

• Estimated glomerular filtration rate (eGFR) ≥ 50 mL/minute or creatinine < 2 mg/dL.

Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA).

• Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50%.
• Total bilirubin < 2 times upper limit of normal (ULN) (patients with Gilbert's syndrome may be included once hemolysis has been excluded).
• Karnofsky Performance Score ≥70%
• Negative serum or urine beta-HCG test in females of childbearing potential (FCBP) within 3 weeks of enrollment.

A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Ability to understand and the willingness to provide written informed consent.

Exclusion criteria

• Prior allogeneic HCT.

• Planned donor lymphocyte infusion (DLI).

• Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:

  1. Positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing), or
  2. Presence of anti-donor HLA antibody to any of the following HLA loci: HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, or -DPA1, with mean fluorescence intensity (MFI) >1000 by solid phase immunoassay.

• Uncontrolled bacterial, viral, or fungal infections at time of enrollment including known, active tuberculosis infection.

• Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, and/or Hepatitis C antibody.

  *History of hepatitis B or hepatitis C is permitted if viral load is undetectable per quantitative PCR and/or NAT.

Known allergy or hypersensitivity to planned GVHD prophylactic medications including PTCy, tacrolimus

• Any uncontrolled autoimmune disease requiring active immunosuppressive treatment.
• Concurrent malignancy diagnosed within 12 months of enrollment, except non-melanoma skin cancers or other early-stage solid tumors that have been curatively resected or treated to curative intent. Patients with history of low grade concurrent blood cancers that are controlled will be eligible.
• Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation.

(FCBP definition: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the recipient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.

* All subject files must include supporting documentation to confirm subject eligibility.

Trial design

Primary purpose: Supportive Care

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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50 participants in 1 patient group

Risk-Adapted Early Tacrolimus Taper Strategy

Experimental group

Description:

Initial tacrolimus dosing will be as per Standard of Care protocol. Tacrolimus is initiated at day 5 post-HCT at with initial dosing as described in Section 6.2.3, and converted to oral formulation as soon as appropriate level is achieved and the patient are able to tolerate oral dosing. Oral tacrolimus is dosed in 0.5mg increments up to two times daily. Tacrolimus levels are assessed up to three times weekly in the inpatient or outpatient setting starting 1 - 3 days after initiation to target a level of 5 - 10 ng/mL. Trough levels will be assessed as close to 12 (twice daily dosing) or 24 (daily dosing) hours as feasible after most recent dose. Starting on day 60, patients on Stratum A will taper tacrolimus by approximately 20% of pre-taper dose per week, rounded to the nearest 0.5 mg. Participants who meet criteria and will be completely off tacrolimus by day 88 (+/- 5 days).

Treatment:

Drug: Tacrolimus

Other: Early Tacrolimus Taper Strategy