Donor Lymphocyte Infusion for MDS and AML

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: Investigational agents

Disqualifiers: Uncontrolled illness, Pregnancy, Poor functional status, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with myelodysplastic syndrome (MDS) whose initial therapy failed or progressed to acute myeloid leukemia (AML). Researchers aim to determine the safety of using a special type of donor immune cells (CD8-depleted lymphocytes) combined with standard chemotherapy. The trial includes different groups to identify the optimal dose of these donor cells. Eligible participants have MDS or AML, have experienced treatment failure, and are fit enough for chemotherapy. As a Phase 1, Phase 2 trial, it focuses on understanding the treatment's effects and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking research.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had systemic chemotherapy or radiotherapy within 4 weeks before entering the study, except for certain allowed treatments like hydroxyurea.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that a new treatment, called NE-DLI, was well-tolerated in previous studies. Patients did not experience severe side effects that would prevent doctors from increasing the dose. This experimental therapy is being tested for individuals with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), particularly when standard treatments are no longer effective. Although the treatment remains under study, early results suggest it is safe for those considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment because it offers a new approach for tackling Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Unlike the standard chemotherapy treatments, which primarily use drugs like cytarabine to kill cancer cells, this method involves infusing CD8-depleted, non-engrafting HLA-mismatched donor lymphocytes. These donor lymphocytes are engineered to target and potentially eliminate cancerous cells without fully integrating into the patient's immune system. This innovative approach could enhance the effectiveness of chemotherapy, potentially reducing relapse rates and improving patient outcomes.

What evidence suggests that this trial's treatments could be effective for MDS and AML?

Research has shown that a new treatment using special donor immune cells might benefit people with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In this trial, participants will receive CD8-depleted, non-engrafting, HLA-mismatched unrelated donor lymphocytes after standard chemotherapy. These donor cells differ because they don't fully match the patient's immune system, yet they might still reduce cancer cell numbers. This could enhance the effectiveness of other treatments, like a bone marrow transplant. For patients whose standard treatments, such as azacitidine or decitabine, are no longer effective, the average survival time is typically 4-6 months. This new therapy aims to extend survival by boosting the body's immune response. Early studies suggest that using these donor cells might help patients achieve remission, even without a prior transplant. ^{1 2 4 5 6}

Who Is on the Research Team?

Joseph Pidala, MD, PhD

Principal Investigator

Moffitt Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults aged 18-79 with Myelodysplastic Syndrome (MDS) or secondary Acute Myeloid Leukemia (sAML) who have not responded to initial therapy. Participants must be in relatively good health, with a decent performance status and adequate organ function. Pregnant women, those with certain leukemia types, recent chemotherapy or radiotherapy recipients, and individuals with severe concurrent illnesses are excluded.

Inclusion Criteria

- IPSS-R score intermediate, high or very high

My diagnosis of AML is confirmed by lab tests.

My kidneys are functioning well.

Exclusion Criteria

I do not have a blastic phase of chronic myeloid leukemia.

I am not pregnant or breastfeeding.

I haven't had chemotherapy or radiotherapy in the last 4 weeks, or I've recovered from their side effects.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen

1 week

1 visit (in-patient)

CD8-depleted NE-DLI Infusion

Participants receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion at varying dose levels

Up to 60 days per dose level

Multiple visits (in-patient)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

What Are the Treatments Tested in This Trial?

Interventions

• CD8 Depleted, Non-engrafting,HLA mismatched unrelated donor lymphocytes
• Standard of Care Chemotherapy

Trial Overview The study tests the safety of CD8 Depleted donor lymphocytes from mismatched unrelated donors combined with standard chemotherapy in patients whose MDS has progressed after first-line treatment or turned into sAML. The goal is to see if this investigational approach can help control the disease.

How Is the Trial Designed?

Group I: Phase 2 -Treatment at Maximum Tolerated Dose (MTD) Experimental Treatment 2 Interventions

All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at MTD.

Group II: Phase 1 Dose Level 3 Experimental Treatment 2 Interventions

All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 3: 5 X10\^7 CD4 T Cells/kg

Group III: Phase 1 Dose Level 2 Experimental Treatment 2 Interventions

All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 2: 1X10\^7 CD4 T Cells/kg

Group IV: Phase 1 Dose Level 1 Experimental Treatment 2 Interventions

All participants will receive cytotoxic induction chemotherapy with a standard of care cytarabine-based regimen. 24-36 hours after chemotherapy cessation, participants will receive CD8-depleted non-engrafting HLA-mismatched unrelated donor lymphocyte infusion (NE-DLI) at dose level 1: 1X10\^6 CD4 T Cells/kg

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Published Research Related to This Trial

The study successfully generated leukemia-reactive donor T cells from peripheral blood mononuclear cells, showing that this method can produce cells that specifically target leukemia while sparing non-leukemic cells, which is crucial for reducing the risk of graft-versus-host disease.

In 5 out of 6 donors, the generated T cells demonstrated significant anti-leukemic reactivity, primarily mediated by CD4+ T cells, indicating a promising approach for enhancing post-transplant immunotherapy in patients with acute myeloid leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic HLA-matched donor dendritic cells loaded with patient leukemic blasts preferentially induce CD4-positive leukemia-reactive donor lymphocytes. Thomas-Kaskel, AK., Portugal, TG., Herchenbach, D., et al.[2018]

In a clinical trial involving 25 elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), the combination of non-ablative chemotherapy followed by HLA-mismatched allogeneic T-cell infusion (allo-TLI) resulted in high overall response rates of 94% for AML and 75% for MDS patients.

The treatment demonstrated a favorable safety profile, with a low 60-day treatment-related mortality of 8%, and significantly improved overall survival rates compared to historical controls, suggesting it could be a viable first-line treatment for these patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Ablative Chemotherapy Followed by HLA-Mismatched Allogeneic CD3+ T-Cells Infusion Causes An Augment of T-Cells With Mild CRS: A Multi-Centers Single-Arm Prospective Study on Elderly Acute Myeloid Leukemia and int-2/High Risk Myelodysplastic Syndrome Patients. Huang, Y., Hong, M., Qu, Z., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124048183

Non-Engrafting CD8-Depleted Human Leukocyte Antigen ... In cases that are refractory to HMA or progress to sAML, median survival is only 4-6 months. We designed a first-in-human cellular therapy of CD8-depleted, CD4+ ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04620681

NCT04620681 | CD8 Depleted, Non-engrafting, HLA ... This study is attempting to design a therapy called "non-engrafting, CD8 depleted donor lymphocyte infusion" or "NE-DLI" as a treatment for these diseases.

3. researchgate.net researchgate.net/publication/386474171_Non-Engrafting_CD8-Depleted_Human_Leukocyte_Antigen_HLA_Mismatched_Unrelated_Donor_Lymphocyte_Infusion_DLI_Achieves_Remissions_in_Transplant-Naive_Myelodysplastic_Syndrome_MDS_and_Secondary_Acute_Myel

Non-Engrafting CD8-Depleted Human Leukocyte Antigen ... In cases that are refractory to HMA or progress to sAML, median survival is only 4-6 months. We designed a first-in-human cellular therapy of ...

4. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-11553

Non-engrafting, CD8 Depleted Donor Lymphocyte Infusion ... This phase Ib/II trial identifies the side effects and best dose of non-engrafting, CD8 depleted donor lymphocyte infusion (NE-DLI) and studies its ...

5. vjhemonc.com vjhemonc.com/video/dfejx_xgzrk-phase-i-trial-investigating-cd8-depleted-hla-mismatched-unrelated-dli-in-patients-with-mds-and-aml/

ASH 2022 | Phase I trial investigating CD8-depleted HLA ... In this study we developed a novel cellular therapy that's intended to try to reduce the blast percentage and get patients to transplant.

6. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/81/NCT04620681/Prot_SAP_000.pdf

CD8-depleted non-engrafting HLA antigen-mismatched ... Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer. 2010;117:1463-9. 69. Michelis F ...