Interferon-γ (IFN-γ) With Donor Leukocyte Infusion to Treat Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndromes Post Allogeneic Hematopoietic Stem Cell Transplantation
- Conditions
- Myelodysplastic SyndromesAcute Myeloid Leukemia
- Interventions
- Biological: Donor Leukocyte Infusion (DLI)
- Registration Number
- NCT06529731
- Lead Sponsor
- Sawa Ito, MD
- Brief Summary
This phase 2 study aims to confirm the efficacy seen in the prior phase 1 trial, and further contribute to this effort through the collection of leukemia cells pre- and post- in vivo IFN-γ therapy. As in the previously conducted phase 1 trial, this trial will test whether leukemia blasts were responsive to IFN-γ in vitro and in vivo, with single-cell RNA sequencing (scRNAseq) conducted to understand the transcriptomic changes induced by IFN-γ in leukemia cell subsets, including those with stem cell characteristics.
- Detailed Description
This novel regimen has the potential to fill a large unmet need for this high-risk population of patients who have few, if any, effective therapeutic options. If this trial confirms the clinical efficacy of IFN-γ/DLI, it will establish a new standard of care for post-transplant AML/MDS relapse. It would also provide a rationale to explore other indications for IFN-γ in the context of an alloSCT, including 1) IFN-γ/DLI for relapsed disease after haploidentical alloSCT; 2) pre-emptive post-alloSCT treatment of patients transplanted with measurable residual disease (MRD) or with poor-risk AML/MDS such as with TP53 mutations; and 3) prevention of relapse in patients who can only tolerate reduced-intensity conditioning regimens which in most studies results in higher rates of post-alloSCT AML/MDS relapse than when intensive conditioning regimens are employed. Together, this work would allow more patients with AML/MDS to be referred for and ultimately benefit from an alloSCT.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 45
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Recipients of an alloSCT for AML or MDS from an HLA-matched donor
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AML/MDS relapsed post-alloSCT with measurable residual disease defined by at least 5% of more myeloblasts based on bone marrow biopsy morphology by pathologist review. Abnormal myeloblasts cannot not exceed 30% overall
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Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
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A DLI is available, or the donor is available and agrees to undergo apheresis to collect lymphocytes for infusion
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If salvage therapy for post-alloSCT relapse was received, the therapy is limited to 1 cycle of the following:
- For hypomethylating agents, venetoclax, and targeted therapies (e.g., tyrosine kinase inhibitors, IDH1/IDH2 inhibitors, or FLT3 inhibitors), the last dose must be > 2 week prior to the initiation of IFN-γ
- For cytotoxic chemotherapy agents, the last dose must be >2 weeks prior to start of treatment for the present study
- For investigational agents, the last dose must be ≥ 4 weeks or 5 half-lives (whichever is longer) prior to the start of treatment for the present study
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Provision of signed and dated informed consent form
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Stated willingness to comply with all study procedures and availability for the duration of the study
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For female subject, who is < 55 years old without hysterectomy, oophorectomy or documented menopause, willingness to use two forms of contraception including one form of highly effective contraception (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
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For male subject, willingness to use highly effective contraception methods including male condoms by male subject and one form of highly effective contraception by his female partner (i.e., long-acting reversible contraception, oral contraceptive pills) for the duration of the study
- Primary engraftment failure after alloSCT
- Grade 3 or 4 aGVHD per Mount Sinai Acute GVHD International Consortium (MAGIC) at the time of planned enrollment
- History of grade 4 aGVHD per the MAGIC criteria
- Moderate or severe cGVHD per NIH Consensus Criteria at time of planned enrollment
- Any systemic immunosuppressive medications taken within 2 weeks before the enrollment
- Grade 3 or higher non-hematologic toxicity related to any prior therapy at the time of enrollment
- A contraindication to receive IFN-γ including a known hypersensitivity to IFN-γ, E. coli derived products or any other component of the product
- Positive pregnancy test or currently breastfeeding on Day 1 of study treatment
- Active cardiac arrhythmia not controlled by medical management or current NYHA class II or higher congestive heart failure within 2 months of enrollment unless it was due to a tachyarrhythmia which is under control at the time of enrollment
- Active ischemic heart disease not controlled with medications within 2 months of enrollment
- Acute or chronic pulmonary disease requiring continuous oxygen treatment
- Seizure disorder not controlled by medications within 2 months of enrollment
- AST or ALT > 5x ULN or total bilirubin >3x ULN at time of enrollment
- Renal function eGFR <30 mL/min at time of enrollment using modified Cockcroft-Gault formula
- Body surface area ≤ 1.5 m2 or ≥ 2.5 m2 so as to minimize variation in IFN-γ exposure based on differences in body surface area
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description IFN-γ + DLI Interferon gamma-1b ACTIMMUNE® (IFN-γ-1b) at a dose of 50 mcg/m\^2 (All participants will receive a 4-week period of IFN-γ monotherapy with ACTIMMUNE 100 mcg 3 times a week. This dose and schedule will be continued for 4 additional weeks and then tapered to 100 mcg weekly for an additional 4 weeks) DLI at a dose of 10\^7 CD3+ cells/kg (DLI doses will be given pending clinical assessment for disease, graft versus host disease (GVHD) and peripheral blood donor chimerism the week prior to DLI. Second DLI dose is only offered to subjects with residual disease not requiring cytotoxic therapy and without GVHD) IFN-γ + DLI Donor Leukocyte Infusion (DLI) ACTIMMUNE® (IFN-γ-1b) at a dose of 50 mcg/m\^2 (All participants will receive a 4-week period of IFN-γ monotherapy with ACTIMMUNE 100 mcg 3 times a week. This dose and schedule will be continued for 4 additional weeks and then tapered to 100 mcg weekly for an additional 4 weeks) DLI at a dose of 10\^7 CD3+ cells/kg (DLI doses will be given pending clinical assessment for disease, graft versus host disease (GVHD) and peripheral blood donor chimerism the week prior to DLI. Second DLI dose is only offered to subjects with residual disease not requiring cytotoxic therapy and without GVHD)
- Primary Outcome Measures
Name Time Method Event-free survival (EFS) At 1 year Occurrence of treatment failure, hematologic relapse from a CR (complete remission)/CRh/Cri), or death observed from start of IFN-γ treatment. Patients alive at 1 year after start of treatment will be censored on the date of last contact.
- Secondary Outcome Measures
Name Time Method Complete Remission (CR) At 6 months Proportion of patients who experience Complete Remission (CR). CR is defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients.
Complete remission with partial hematologic recovery (CRh) At 6 months Proportion of patients who experience Complete remission with partial hematologic recovery (CRh). CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients.
Complete remission with incomplete count recovery (CRi) At 6 months Proportion of patients who experience complete remission with incomplete count recovery (CRi). CRi is defined by all CR criteria except for residual neutropenia less than 1,000/mL or thrombocytopenia less than 100,000/mL51. The proportion of responders (CR, CRh, or CRi) will be calculated as the number of responders divided by the number of evaluable patients. The proportion of responders will be calculated as the number of responders divided by the number of evaluable patients.
Overall survival Up to 1 year Time from start of IFN-γ to death by any cause or censored on the date of last contact.
Event-free survival (EFS) - Landmark 1-year Up to 1 year Time from start of IFN-γ treatment until event of death, date of treatment failure, or hematologic relapse from a CR/CRh/Cri. CR is defined by blasts less than 5% by morphology defined by bone marrow blasts less than 5%; absence of circulating blasts; absence of extramedullary disease; absolute neutrophil count (ANC) at or greater than 1,000/mL; platelet count at or greater than 100,000/mL CRh is defined by ANC at or greater than 500/mL and platelet count at or greater than 50,000/mL otherwise all other CR criteria met. CRi is defined by all CR criteria except for residual neutropenia less than 1,000/mL or thrombocytopenia less than 100,000/mL Treatment failure is not achieving either CR, CRh or CRi by 6 months. Patients evaluable for response without CR, CRh or CRi by 6 months and patients who die before 6 months without response assessments are considered an event at day 1 of IFN-γ treatment
Frequency and severity of adverse events (AEs) Up to 6 months Number of patients who experience an Adverse Event or Serious Adverse Event related to study treatment, per CTCAE v5.0 criteria. Distinct number of patients will be determined per each event type by highest grade experienced.
Minimal residual disease (MRD) At 6 months Rate of complete remission (CR) with no measurable disease at 6 months. CR is defined as
Rate of donor chimerism At 6 months Proportion of the efficacy population with ≥95% peripheral blood CD3+ and CD33+ cells and of unfractionated bone marrow being donor-derived
Frequency of new onset grade 3 or 4 acute graft-versus-host disease (aGVHD) Up to 12 months number of patients meeting criteria for grade 3 or 4 aGVHD per MAGIC divided by the number of evaluable patients. The MAGIC criteria as follows: Overall clinical grade (based on most severe target organ involvement): Grade 0: No stage 1-4 of any organ; Grade I: Stage 1-2 skin without liver, upper GI, or lower GI involvement; Grade II: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 lower GI; Grade Ill: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 0-1 upper GI; Grade IV: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI.
Rate of transfusion independence At 1 year Proportion of the subjects who achieve the absence of a red-cell or platelet transfusion for at least 56 days between the first and last day of treatment.
Frequency of new onset moderate or severe chronic GVDH (cGVHD) Up to 12 months The number of patients meeting criteria for moderate or severe cGVHD per NIH Consensus Criteria divided by the number of evaluable patients. The NIH Consensus Criteria is a diagnostic assessment that evaluates hair, skin, nails, eyes, mouth, genitalia, GI tract, liver, lung, muscles and joints, hematopoietic and immune system, cardiac and neurological condition/function, to determine whether or not the GVHD is chronic.
Trial Locations
- Locations (2)
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States
UPMC Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States