Donor Lymphocyte Infusion for Blood Cancers

Overseen By Amy H Chai

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: Active non-hematopoietic malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

430 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether infusing donor lymphocytes (a type of white blood cell) soon after a blood or bone marrow transplant can reduce relapse risk in certain blood cancers. The focus is on high-risk cases of leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that do not respond well to standard treatments. Participants must have one of these conditions and a high risk of relapse. Healthy relatives of patients, who may serve as donors, are also needed. The trial involves chemotherapy and various tests, with follow-ups over five years. As a Phase 1, Phase 2 trial, the research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on any other investigational drugs, and prior experimental treatments must be completed at least 3 weeks before starting the trial.

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

Research shows that donor lymphocyte infusions (DLIs) are promising and generally safe. Studies have found that DLIs usually have low toxicity, meaning serious side effects are rare, especially when patients receive certain pre-treatments. However, some patients might still experience side effects, which are usually manageable.

This trial is in an early stage, meaning the treatment is still under study to ensure safety and determine the best dose. While researchers are testing DLIs to help prevent cancer recurrence, their use remains experimental. Participants in the trial will be closely monitored for any side effects.

Overall, DLIs seem well-tolerated, but like any treatment, they carry risks. Discussing these risks with the trial team can help clarify what they might mean for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Donor Lymphocyte Infusion (DLI) for blood cancers because it offers a more personalized approach compared to traditional chemotherapy and radiation, such as regimens involving drugs like Busulfan, Cyclophosphamide, and Fludarabine. DLI leverages the body's immune system by using donor immune cells to target and attack cancer cells, potentially reducing the need for harsh chemicals and their side effects. This method not only aims to improve patient outcomes but also seeks to enhance the body's natural defenses, providing a promising alternative to existing treatments.

What evidence suggests that donor lymphocyte infusion could be effective for reducing relapse in blood cancers?

Research has shown that donor lymphocyte infusion (DLI), a treatment under study in this trial, can help prevent cancer recurrence after a blood or bone marrow transplant. Studies have found that DLI strengthens the body's ability to fight cancer cells, particularly in diseases like leukemia and myelodysplastic syndrome. For patients whose cancer returned after their first transplant, DLI improved survival chances compared to chemotherapy alone. This treatment enhances the body's immune response to attack cancer more effectively. While some studies have shown limited success, the overall potential of DLI to reduce the risk of cancer returning makes it a promising option for certain blood cancers. ^{3 6 7 8 9}

Who Is on the Research Team?

Christopher G Kanakry, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults aged 18-65 with high-risk blood cancers like leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma that are hard to treat or likely to come back. They need a healthy relative who can donate bone marrow and white blood cells for the study.

Inclusion Criteria

I have a donor who matches my HLA type.

I can care for myself but may need occasional help.

My related donor is over 12, willing, and able to donate blood, bone marrow, and stool for research.

Exclusion Criteria

I have not undergone intense bone marrow preparation for stem cell transplant.

I do not have any severe illnesses that would make a transplant risky for me.

Recipient must not be actively breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for various exams and tests

Pre-Transplant Conditioning

Participants receive chemotherapy and other drugs starting 6 days before transplant

1 week

Inpatient stay at NIH hospital

Transplantation

Participants undergo allogeneic hematopoietic cell transplantation

1 day

Inpatient procedure

Donor Lymphocyte Infusion (DLI)

Participants receive donor lymphocyte infusion 7 days post-transplant

1 day

Inpatient procedure

Post-Transplant Monitoring

Participants are monitored for development of GVHD and other outcomes

100 days

Frequent follow-up visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Periodic follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Cyclophosphamide
• Donor Lymphocyte Infusion
• Fludarabine
• Mycophenolate mofetil
• Sirolimus

Trial Overview The trial is testing if giving patients donor lymphocytes (white blood cells) from their transplant donor soon after a bone marrow transplant can lower the chance of cancer coming back. It includes chemotherapy drugs and staying near NIH for monitoring.

How Is the Trial Designed?

Group I: Phase II Efficacy, Cohort 2 (haploidentical) Experimental Treatment 6 Interventions

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Group II: Phase II Efficacy, Cohort 1 (matched) Experimental Treatment 6 Interventions

DLI at maximally tolerated, safe dose (from Phase I) to assess secondary clinical outcomes at this dosing level (up to 14 additional evaluable patients in each cohort)

Group III: Phase I Dose Escalation, Cohort 2 (haploidentical) Experimental Treatment 6 Interventions

DLI at escalating doses (1 x 10\^5 CD3+ cells/kg, 3 x 10\^5 CD3+ cells/kg, and 1 x 10\^6 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Group IV: Phase I Dose Escalation, Cohort 1 (matched) Experimental Treatment 6 Interventions

DLI at escalating doses (1 x 10\^6 CD3+ cells/kg, 3 x 10\^6 CD3+ cells/kg, and 1 x 10\^7 CD3+ cells/kg) on day +7 or +21 to assess for safety and determine Phase II dose (up to 18 evaluable patients)

Group V: Donor Arm Active Control 1 Intervention

Donors for Recipients in Arms 1-4

Busulfan is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a study of 42 patients undergoing allogeneic hematopoietic stem cell transplantation, the combination of busulfan and fludarabine (BuFlu) resulted in significantly lower rates of mucositis compared to the traditional busulfan and cyclophosphamide (BuCy) regimen.

Both BuFlu and BuCy showed similar efficacy in terms of engraftment time, relapse risk, event-free survival, and overall survival, suggesting that BuFlu is a viable alternative to BuCy for this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine-based myeloablative regimen as pretransplant conditioning therapy in adult acute leukemia/myelodysplastic syndrome: comparison with oral or intravenous busulfan with cyclophosphamide. Lee, JH., Choi, J., Kwon, KA., et al.[2021]

In a study of 26 patients undergoing hematopoietic stem cell transplantation, those receiving fludarabine showed a significant reduction in the clearance of orally administered busulfan, indicating that fludarabine affects how the body processes busulfan.

Despite higher plasma levels of busulfan in patients treated with fludarabine, these patients experienced less myelosuppression-related toxicity, suggesting that lower doses of busulfan (about 30% less) may be safer and more effective when used with fludarabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of fludarabine on the pharmacokinetics of oral busulfan during pretransplant conditioning for hematopoietic stem cell transplantation. de Castro, FA., Lanchote, VL., Voltarelli, JC., et al.[2013]

In a study of 95 patients undergoing allogeneic stem cell transplantation, replacing cyclophosphamide with fludarabine in the conditioning regimen (busulfan+fludarabine) led to faster engraftment and significantly lower rates of acute and chronic graft-versus-host disease (GVHD).

The fludarabine regimen also resulted in better event-free survival and overall survival rates compared to the standard busulfan and cyclophosphamide regimen, indicating it may be a more effective option for myeloablative conditioning in allogeneic SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. Chae, YS., Sohn, SK., Kim, JG., et al.[2022]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

The combination of intravenous busulfan and fludarabine as a conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) demonstrated a high complete remission rate of 85% in patients with active disease.

This regimen showed low regimen-related (1%) and treatment-related (3%) mortality rates, indicating improved safety, while achieving a 1-year overall survival rate of 65% and event-free survival rate of 52% for all patients, suggesting it is an effective and reduced-toxicity option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. de Lima, M., Couriel, D., Thall, PF., et al.[2021]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

A population pharmacokinetic/pharmacodynamic model was developed using data from 41 hematopoietic cell transplant recipients to understand how different concentrations of F-ara-A affect lymphocyte suppression.

The model successfully characterized the variability in absolute lymphocyte counts during treatment, indicating that the specific HCT protocol significantly influenced lymphocyte kill rates and could help optimize future fludarabine-based conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic/dynamic model of lymphosuppression after fludarabine administration. McCune, JS., Vicini, P., Salinger, DH., et al.[2021]

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3846289/

Donor lymphocyte infusion for relapsed hematological ... Allogeneic hematopoietic cell transplantation (HCT) has the potential to provide long term survival and even cure in patients with hematological malignancies (1 ...

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324924008843

Outcome of donor lymphocyte infusion after allogeneic ... Some reports indicate that immunotherapy, including DLI, improves prognosis in patients with MDS who relapse after HSCT compared to chemotherapy alone, while ...

3. thelancet.com thelancet.com/journals/lanhae/article/PIIS2352-3026(24)00098-X/abstract

Donor lymphocyte infusion after allogeneic haematopoietic ... Long-term results of adjuvant donor lymphocyte transfusion in AML after allogeneic stem cell transplantation. Bone Marrow Transplant. 2016; 51:663-667.

4. astctjournal.org astctjournal.org/article/S1083-8791(17)30576-1/fulltext

Donor Lymphocyte Infusions Used to Treat Mixed-Chimeric ... Donor lymphocyte infusions (DLI) have the potential to enhance the graft-versus-malignancy (GVM) effect, reducing the risk of relapse in patients with MC.

5. nature.com nature.com/articles/s41409-024-02312-4

Safety but limited efficacy of donor lymphocyte infusion for ... DLIs given to PTCy-treated patients had low toxicity but limited efficacy, although pre-HCT serotherapy may modulate both toxicity and response.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38796194/

Donor lymphocyte infusion after allogeneic haematopoietic ... A set of consensus-based recommendations for the application of unmanipulated DLI after allogeneic HCT for haematological malignancies.

7. astctjournal.org astctjournal.org/article/S1083-8791(18)31074-7/fulltext

Pattern of Use and Outcomes with Donor Lymphocyte ... Cellular therapy with DLI or SCB remains a viable treatment modality with reasonable long-term outcomes for relapsed/refractory hematologic malignancies after ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723016408

Risks of Patient and Donor Genetics in Allogeneic ... Up to 30% of patients relapse after allo-HSCT, of which up to 2% to 5% are donor-derived malignancies (DDMs). DDMs can arise from a germline genetic ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9868208/

Comparison of Outcomes of Donor Lymphocyte Infusions ... Outcomes with DLI alone for post-transplant relapsed hematological malignancies are poor especially in acute leukemias.