Bendamustine +/- Cyclophosphamide to Prevent GVHD Post Stem Cell Transplant for Blood Cancers

Overseen By Issa F. Khouri, M D

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Pregnant, HIV positive, Active infection, others

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

Compensation: Varies

Number of Visits: 4

25 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I/II trial studies the side effects and best dose of bendamustine when given with or without cyclophosphamide in preventing graft versus host disease (GVHD) in patients undergoing stem cell transplant. Drugs used in chemotherapy, such as bendamustine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total body irradiation before or after a stem cell transplant helps kills cancer cells that are in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Sometimes, the transplanted cells from a donor can attack the body's normal cells called GVHD. Giving tacrolimus, mycophenolate mofetil, and filgrastim after the transplant may stop this from happening.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug Bendamustine in preventing GVHD after stem cell transplant for blood cancers?

Research shows that Bendamustine, when used after a stem cell transplant, can reduce the risk of graft-versus-host disease (GVHD) while maintaining the beneficial effects against leukemia. It has been found to improve survival rates and is less suppressive on bone marrow compared to other treatments like cyclophosphamide. ^{1 2 3 4 5}

Is Bendamustine with or without Cyclophosphamide safe for humans?

Bendamustine, used alone or with other drugs, has been studied in various conditions and is generally considered safe, though some serious side effects like fever, bone pain, and kidney issues have been reported. Cyclophosphamide is widely used in transplants to prevent complications and is also generally safe, but it can have side effects. Both drugs have been used in clinical settings with careful monitoring for safety. ^{2 4 6 7 8}

How is the drug Bendamustine +/- Cyclophosphamide unique in preventing GVHD after stem cell transplant for blood cancers?

This treatment is unique because Bendamustine, when used after a stem cell transplant, can reduce the risk of graft-versus-host disease (GVHD) while preserving the beneficial graft-versus-leukemia (GvL) effect, and it is less likely to suppress bone marrow compared to the commonly used Cyclophosphamide. ^{1 2 4 7 9}

Research Team

Issa F. Khouri

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for blood cancer patients who need a stem cell transplant and have good lung function (FVC and FEV1 >= 40%), heart function (ejection fraction >= 40%), and kidney function (creatinine clearance >= 30 ml/min). They must have a donor that's mismatched or haplo-identical, be relatively fit (Zubrod performance 0 to 2 or Karnofsky ≥60), not HIV positive, without active hepatitis B/C, unresolved toxicities from prior treatments, certain active diseases/infections, or pregnant/nursing.

Inclusion Criteria

Forced vital capacity (FVC) >= 40%. (at time of study entry)

The donor's tissue type is not a close match to yours.

I can take care of myself but may not be able to do heavy physical work.

Exclusion Criteria

I have no lasting side effects above mild from previous cancer treatments.

I am HIV positive.

I am unable or unwilling to sign the consent form.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-Transplant Conditioning

Patients receive chemotherapy and total body irradiation to prepare for stem cell transplantation

6 days

Daily visits for chemotherapy administration

Stem Cell Transplantation

Patients undergo stem cell transplantation

1 day

1 visit for transplantation procedure

Post-Transplant Treatment

Patients receive post-transplant medications including tacrolimus, mycophenolate mofetil, and filgrastim to prevent GVHD and support recovery

6 months

Regular visits for medication administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Weekly for 3 months, every 3 months in year 1, every 6 months in year 2

Treatment Details

Interventions

• Bendamustine
• Cyclophosphamide

Trial Overview The study tests if bendamustine with/without cyclophosphamide can prevent GVHD after stem cell transplants. It includes chemotherapy drugs like melphalan and fludarabine, total-body irradiation before the transplant to kill cancer cells/make room for new cells in bone marrow, followed by tacrolimus and mycophenolate mofetil to potentially stop GVHD.

Participant Groups

Group I: Schedule II (lymphoid malignancies) Experimental Treatment 9 Interventions

Patients receive fludarabine IV over 1 hour, bendamustine IV over 30-60 minutes on days -5 to -3 and undergo TBI on day -1 and stem cell transplantation over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal. CD20+ patients receive rituximab IV over 4-6 hours on days -13, -6, 1, and 8.

Group II: Schedule I (non-lymphoma) Experimental Treatment 9 Interventions

Patients receive fludarabine IV over 1 hour on days -5 to -2, melphalan IV over 30 minutes on days -5 and -4, and undergo TBI on day -1 and stem cell transplantation IV over 2-6 hours on day 0. Depending on when the trial was joined, patients receive cyclophosphamide IV over 3 hours or bendamustine IV over 30-60 minutes or cyclophosphamide IV over 3 hours and bendamustine IV over 30-60 minutes on day 3. Patients also receive bendamustine IV over 30-60 minutes on day 4. Beginning day 5, patients receive tacrolimus IV followed by PO QD or BID for 6 months and mycophenolate mofetil PO TID until day 100. Beginning day 7, patients receive filgrastim-sndz SC QD until blood cell levels return to normal.

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

Approved in United States as Treanda for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in European Union as Ribomustin for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma
• Multiple myeloma

Approved in Canada as Levact for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Approved in Japan as Bendamustine hydrochloride for:

• Chronic lymphocytic leukemia
• Non-Hodgkin lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Post-transplant bendamustine (PT-BEN) significantly reduces graft-versus-host disease (GvHD) and improves survival rates in murine models of haploidentical bone marrow transplantation (h-BMT), while still preserving the beneficial graft-versus-leukemia (GvL) effect.

PT-BEN is less myelosuppressive than post-transplant cyclophosphamide (PT-CY), leading to an increase in certain immune cells and enhancing the function of myeloid-derived suppressor cells, suggesting it could be a safer and more effective option for patients undergoing h-BMT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. Stokes, J., Hoffman, EA., Zeng, Y., et al.[2021]

A Phase Ia trial involving 44 patients with high-risk hematologic malignancies showed that partially replacing post-transplantation cyclophosphamide (PT-CY) with bendamustine (PT-BEN) was well tolerated and led to significantly earlier trilineage engraftment.

The PT-CY/BEN regimen demonstrated favorable trends in reducing chronic graft-versus-host disease (GVHD) and improving GVHD-free relapse-free survival (GRFS), suggesting it may be a promising alternative to standard PT-CY treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. Katsanis, E., Stea, B., Kovacs, K., et al.[2023]

Bendamustine (BEN) shows promise as an immunomodulatory agent in hematopoietic cell transplantation (HCT), consistently reducing graft-versus-host disease (GvHD) and enhancing graft-versus-leukemia (GvL) effects in murine models.

In vitro studies reveal that BEN alters key immune cell populations and functions, such as enhancing myeloid derived suppressor cells (MDSCs) and dendritic cells (DCs), which may lead to improved clinical outcomes in ongoing clinical trials for allogeneic HCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. Stokes, J., Molina, MS., Hoffman, EA., et al.[2021]

Bendamustine used as a conditioning regimen for autologous stem cell transplantation in 35 lymphoma patients resulted in successful hematopoietic reconstitution, with median times of 11 days for neutrophil and 12 days for platelet engraftment, and a high overall survival rate of 90.97% at 12 and 24 months.

The treatment was associated with manageable side effects, including nausea, vomiting, and diarrhea, with no transplant-related deaths reported, indicating that bendamustine is both effective and tolerable for patients undergoing this procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Bendamustine in the Conditioning Regiment for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma]. Fu, Y., Feng, YF., Liu, F., et al.[2023]

Bendamustine shows promising synergistic effects when combined with other anti-cancer drugs, such as alkylating agents and pyrimidine analogues, for treating resistant lymphoid malignancies, as demonstrated in various cancer cell lines.

The drug enhances the uptake of cytosine arabinoside (Ara-C) and increases the expression of transporters that facilitate this process, suggesting that its unique properties may improve the effectiveness of combination therapies in difficult-to-treat cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. Hiraoka, N., Kikuchi, J., Yamauchi, T., et al.[2022]

Bendamustine hydrochloride is a newer alkylating agent that has shown promise in treating resistant or refractory cancers due to its unique pharmacological properties.

The article reviews clinical trials demonstrating bendamustine's effectiveness both as a standalone treatment and in combination therapies for various solid tumors and blood cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine hydrochloride - a renaissance of alkylating strategies in anticancer medicine. Eichbaum, M., Bischofs, E., Nehls, K., et al.[2017]

Bendamustine is a unique cancer treatment that combines alkylating and antimetabolite properties, making it effective against certain blood cancers like chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

It has been approved by the US FDA for patients whose cancer has not responded to or has progressed after rituximab treatment, and it can be used alone or in combination with other therapies, showing promising efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Ujjani, C., Cheson, BD.[2015]

In a study of 34 patients with multiple myeloma, the combination of bendamustine, etoposide, and dexamethasone (BED) successfully mobilized hematopoietic stem cells in all participants, with a median yield of 21.60 million cells per kg of body weight.

The treatment was effective and safe, with 88% of patients needing only one apheresis session, although six patients experienced serious nonhematologic adverse events, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. Green, DJ., Bensinger, WI., Holmberg, LA., et al.[2023]

In a phase II study involving patients with various types of lymphoid malignancies, bendamustine combined with etoposide and dexamethasone successfully mobilized stem cells, with all patients able to collect sufficient stem cells for transplantation.

The mobilization regimen was found to be safe, with only three non-hematologic significant adverse events reported in one patient, indicating that bendamustine can be an effective option for stem cell mobilization in non-Hodgkin lymphoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. Greenbaum, AM., Green, DJ., Holmberg, LA., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Post-transplant bendamustine reduces GvHD while preserving GvL in experimental haploidentical bone marrow transplantation. [2021]

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

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Bendamustine in the Conditioning Regiment for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma]. [2023]

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

Purine analog-like properties of bendamustine underlie rapid activation of DNA damage response and synergistic effects with pyrimidine analogues in lymphoid malignancies. [2022]

6. Spain pubmed.ncbi.nlm.nih.gov

Bendamustine hydrochloride - a renaissance of alkylating strategies in anticancer medicine. [2017]

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

Bendamustine in chronic lymphocytic leukemia and non-Hodgkin's lymphoma. [2015]

8. England pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in patients with multiple myeloma. [2023]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Bendamustine, etoposide, and dexamethasone to mobilize peripheral blood hematopoietic stem cells for autologous transplantation in non-Hodgkin lymphoma. [2022]