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

19 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of the study is to determine the safety of an investigational treatment for myelodysplastic syndrome (MDS) after the first therapy (such as azacitidine or decitabine) stops working or after progression of MDS to acute myeloid leukemia (AML). Funding source - FDA OOPD.

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.

What data supports the effectiveness of the treatment for MDS and AML?

Research shows that donor lymphocyte infusion (DLI) can be effective for treating certain types of leukemia, and combining chemotherapy with HLA-mismatched donor cells has shown promise in elderly patients with AML and high-risk MDS. Additionally, using partially matched donor cells has helped some patients achieve remission without severe side effects. ^{1 2 3 4 5}

Is Donor Lymphocyte Infusion safe for humans?

Research indicates that donor lymphocyte infusions, including those with HLA-mismatched donors, are generally safe with mild side effects like mild cytokine release syndrome (CRS). Other studies show that similar treatments, such as NK-cell and γδ T lymphocyte infusions, are well-tolerated with no serious adverse events reported. ^{2 6 7 8 9}

How is the treatment for MDS and AML using donor lymphocyte infusion different from other treatments?

This treatment is unique because it uses CD8-depleted, non-engrafting, HLA-mismatched donor lymphocytes, which aim to reduce the risk of graft-versus-host disease (a condition where the donor cells attack the patient's body) while still providing an immune response against the cancer. It combines this with standard chemotherapy to enhance the overall effectiveness against myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). ^{1 4 10 11 12}

Research Team

Joseph Pidala, MD, PhD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Donor lymphocyte infusions for acute myeloid leukaemia. [2008]

2. Switzerland 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. [2022]

3. Australia pubmed.ncbi.nlm.nih.gov

Haploidentical peripheral blood stem cell infusion in combination with chemotherapy for acute myeloid leukaemia in elderly patients. [2014]

4. England pubmed.ncbi.nlm.nih.gov

Unrelated HLA mismatched microtransplantation in a patient with refractory secondary acute myeloid leukemia. [2020]

5. United States pubmed.ncbi.nlm.nih.gov

Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Long-term survival with low toxicity after allogeneic transplantation for acute myeloid leukaemia and myelodysplasia using non-myeloablative conditioning without T cell depletion. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

A Phase I Trial of Allogeneic γδ T Lymphocytes From Haploidentical Donors in Patients With Refractory or Relapsed Acute Myeloid Leukemia. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Are matched unrelated donor transplants justified for AML in CR1? [2007]

10. England pubmed.ncbi.nlm.nih.gov

Differential effects of donor lymphocyte infusion upon treatment response and GVHD according to relapse level and donor sources in patients with myelodysplastic syndrome. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Allogeneic HLA-matched donor dendritic cells loaded with patient leukemic blasts preferentially induce CD4-positive leukemia-reactive donor lymphocytes. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Donor lymphocyte infusions. [2019]