GVHD-Reduction Strategies for Blood Cancers

Recruiting at 2 trial locations

Overseen By Marie Bleakley

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Checkpoint inhibitors

Disqualifiers: CNS involvement, HIV, uncontrolled infections, organ dysfunction, pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores ways to reduce graft versus host disease (GVHD) in individuals with certain blood cancers, such as acute leukemia or myelodysplastic syndromes (MDS), who are in remission. It tests two approaches to prepare patients for a donor stem cell transplant, which can generate healthy blood cells and potentially eliminate remaining cancer cells. Suitable participants are those in remission from acute leukemia or MDS with an appropriate stem cell donor. As a Phase 2 trial, it measures the treatment's effectiveness in an initial, smaller group.

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

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

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

Initial research findings provide insights into the safety of the treatments in this trial.

Research shows that busulfan often carries a lower risk of death from treatment-related causes. However, it can cause chronic graft-versus-host disease (GVHD), where donor cells attack the patient's body, in many cases.

Fludarabine is generally well-tolerated. Studies indicate it can lead to longer survival and lower chances of graft failure, where the transplanted cells don't function properly. It is often used due to its lower risk of serious side effects.

Cyclophosphamide is known for reducing the risk of GVHD. Research shows it helps prevent donor cells from attacking the patient's body after a transplant, making transplants safer and more successful.

Methotrexate lowers the chances of severe GVHD without increasing the risk of cancer recurrence. It is considered relatively safe, especially in smaller doses, and is commonly used to protect against GVHD.

Thiotepa has shown promising safety results in studies. One study noted a 10% rate of severe acute GVHD, which is relatively low, suggesting it might be well-tolerated.

Overall, these treatments have been studied before, and most show promising safety profiles. However, it is important to note that this trial is still in a phase where safety is being closely monitored, so new findings could emerge. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for GVHD reduction in blood cancer patients because they explore innovative combinations of drugs and strategies. Unlike traditional approaches that often rely on single methods, this trial investigates the use of multiple drugs like cyclophosphamide, fludarabine, methotrexate, and thiotepa, alongside techniques like total body irradiation (TBI) and donor T-lymphocyte infusion. Each arm of the trial is designed to assess different combinations, which may offer more personalized and effective ways to manage GVHD. By exploring these varied approaches, researchers aim to improve patient outcomes and reduce the severity of GVHD, which is a common complication in bone marrow transplants.

What evidence suggests that this trial's treatments could be effective for reducing graft versus host disease in blood cancer patients?

This trial evaluates different strategies to reduce the risk of graft versus host disease (GVHD) in patients receiving stem cell transplants. One trial arm uses a combination of fludarabine, busulfan, and tacrolimus. Another arm adds cyclophosphamide after the transplant, which studies suggest can further lower the risk of GVHD. A separate arm tests the effectiveness of methotrexate with tacrolimus to decrease the severity of GVHD. Additionally, some trial arms involve treatments like total body irradiation (TBI) and thiotepa to prepare patients for transplants by weakening the immune system. Together, these treatments aim to reduce complications and improve survival rates for people with blood cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Marie Bleakley

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

This trial is for patients with acute leukemia or MDS in remission, aged 1-60, who have a matched donor for stem cell transplant. They must be vaccinated against COVID-19 and cannot participate if they weigh over 100 kg, are HIV positive, have significant organ dysfunction like kidney failure or heart issues, are pregnant/breastfeeding, unwilling to use birth control post-transplant, or have uncontrolled infections.

Inclusion Criteria

I am between 1 and 60 years old.

Must be vaccinated against COVID19. 'COVID vaccinated' is as defined by the NMDP and number of required doses may vary according to vaccine manufacturer and evolving guidelines.

I am between 1 and 50 years old and eligible for a specific treatment plan.

Exclusion Criteria

I weigh less than 100 kg and have an HLA-matched unrelated donor.

I have an organ that is not working properly.

I have had a bone marrow transplant before.

Timeline for a Trial Participant

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

2 weeks

Daily visits for treatment administration

Transplantation

Infusion of donor peripheral blood stem cells and administration of supportive medications

1 day

In-patient stay for transplantation

Post-Transplant Monitoring

Monitoring for graft versus host disease and other complications, with tapering of immunosuppressive medications if no GVHD is observed

50 days

Regular in-patient and out-patient visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Visits at days 7, 14, 21, 28, 56, 80, 180, 270, and at 1, 1.5, and 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic CD34+-enriched and CD45RA-depleted PBSCs
• Busulfan
• Cyclophosphamide
• Cyclosporine
• Fludarabine
• Methotrexate
• Peripheral Blood Stem Cell
• Sirolimus
• Tacrolimus
• Thiotepa
• Total-Body Irradiation

Trial Overview The trial tests two strategies to reduce graft versus host disease after a donor peripheral blood stem cell transplant. Patients receive chemotherapy and total-body irradiation before the transplant to stop cancer growth and prepare their body to accept the donor's healthy stem cells.

How Is the Trial Designed?

Group I: Arm D2 (busulfan, tacrolimus, methotrexate) [DISCONTINUED NOVEMBER 2021] Experimental Treatment 11 Interventions

Patients receive busulfan IV over 180 minutes on days -8 to -5, cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Group II: Arm D1 (TBI, tacrolimus, methotrexate) [DISCONTINUED NOVEMBER 2021] Experimental Treatment 11 Interventions

Patients undergo TBI BID on days -6 to -4, and receive cyclophosphamide IV over 1 hour on days -3 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, PBSC IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Group III: Arm C2 (busulfan, PTCy, tacrolimus) Experimental Treatment 11 Interventions

Patients receive fludarabine IV over 30 to 60 minutes on days -5 to -2, busulfan IV over 180 minutes on days -5 to -2, PBSC IV on day 0, cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Group IV: Arm C1 (TBI, PTCy, tacrolimus) Experimental Treatment 10 Interventions

Patients undergo TBI BID on days -4 to -2 or -3 to -1, and receive PBSC IV on day 0. Patients also receive cyclophosphamide IV over 1 to 2 hours on days 3 and 4, and tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day 5. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Group V: Arm A2 (busulfan, TnD) Experimental Treatment 11 Interventions

Patients receive fludarabine IV over 30 to 60 minutes on days -6 to -2, busulfan IV over 180 minutes on days -5 to -2, and undergo TBI BID on day -1. Patients also receive tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

Group VI: Arm A1 (TBI, TnD) Experimental Treatment 12 Interventions

Patients undergo TBI BID on days -10 to -7, and receive thiotepa IV over 3 hours on days -6 and -5, fludarabine IV over 30 to 60 minutes on days -6 to -2, tacrolimus (or cyclosporine or sirolimus if toxicities occur) IV continuously starting on day -1, CD34+ enriched CD45RA-depleted donor T-lymphocytes IV on day 0, and methotrexate IV on days 1, 3, 6, and 11. If there is no evidence of grade II-IV acute GVHD on or prior to day 50, tacrolimus (or cyclosporine or sirolimus) is tapered per month for capsules (or per week for liquid). Patients also undergo bone marrow aspiration/biopsy, ECHO or MUGA scan, and collection of blood samples throughout the trial.

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

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a randomized controlled trial involving 52 patients undergoing allogeneic hematopoietic cell transplantation, the use of folinic acid (FA) rescue did not significantly reduce the rates of severe oral mucositis caused by methotrexate (MTX) compared to a placebo.

The study found no differences in acute and chronic graft-versus-host disease (GVHD), disease relapse, nonrelapse mortality, or overall survival between the FA and placebo groups, leading to the conclusion that FA rescue does not improve outcomes after MTX prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study. Yeshurun, M., Rozovski, U., Pasvolsky, O., et al.[2022]

Posttransplant high-dose cyclophosphamide (PTCy) has been shown to effectively reduce the incidence of moderate-to-severe graft-versus-host disease (GvHD) in patients undergoing HLA-matched stem cell transplants, with a 24% incidence of grade II-IV acute GvHD observed in a study of 56 patients.

The introduction of mini-thiotepa in the conditioning regimen significantly reduced the graft failure rate to 0% after its implementation, indicating that PTCy can be a feasible standard of care for preventing GvHD in HLA-matched transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incorporating posttransplant cyclophosphamide-based prophylaxis as standard-of-care outside the haploidentical setting: challenges and review of the literature. García-Cadenas, I., Awol, R., Esquirol, A., et al.[2021]

The novel reduced conditioning regimen using fludarabine, carmustine, and melphalan (FBM) followed by allogeneic stem cell transplantation resulted in rapid hematopoietic engraftment, with significant improvements in white blood cell and platelet counts within days after treatment.

The protocol was well tolerated with low toxicity, even in patients with advanced disease or previous transplants, leading to a high response rate where 90% of patients achieved complete or partial remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid achievement of complete donor chimerism and low regimen-related toxicity after reduced conditioning with fludarabine, carmustine, melphalan and allogeneic transplantation. Wäsch, R., Reisser, S., Hahn, J., et al.[2013]

Fludarabine phosphate significantly reduced the incidence of leukemia in mice after stem cell transplantation, with only 32% of treated mice developing leukemia compared to 76% in the control group, indicating its potential efficacy in preventing leukemia post-transplant.

The treatment with fludarabine also resulted in a marked decrease in the severity of graft-versus-host disease (GVHD), suggesting that it not only helps in controlling leukemia but also mitigates the adverse effects associated with stem cell transplants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine in combination with cyclophosphamide decreases incidence of GVHD and maintains effective graft-versus-leukemia effect after allogeneic stem cell transplantation in murine lymphocytic leukemia. Weiss, L., Abdul-Hai, A., Or, R., et al.[2013]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a meta-analysis of nine randomized trials involving 1107 patients, administering four doses of methotrexate (MTX) during allogeneic stem cell transplantation significantly improved survival rates compared to three doses, with a death odds ratio of 0.67.

Patients receiving four doses of MTX also had lower relapse rates (19.2% for PBSC vs. 36.6% for BM), suggesting that the additional dose may enhance immunosuppression but could also reduce the anti-leukemic effect, warranting further investigation through prospective trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Individual patient data meta-analysis of allogeneic peripheral blood stem cell transplant vs bone marrow transplant in the management of hematological malignancies: indirect assessment of the effect of day 11 methotrexate administration. Bensinger, W.[2018]

In a study of 56 patients with hematological malignancies, a reduced intensity conditioning regimen using fludarabine phosphate and melphalan resulted in over 95% donor chimerism at 3 months post-transplant, indicating successful donor cell engraftment.

The combination of CyA and MTX for immunosuppression led to a significantly lower incidence of acute graft-versus-host disease (aGVHD) at 18% compared to 53% in patients receiving CyA alone, suggesting a safer approach with acceptable toxicity and good disease control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine phosphate and melphalan: a reduced intensity conditioning regimen suitable for allogeneic transplantation that maintains the graft versus malignancy effect. Dasgupta, RK., Rule, S., Johnson, P., et al.[2021]

New GVHD prophylaxis methods, such as anti-thymocyte globulin and post-transplant cyclophosphamide, have been effective in reducing severe graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation, which is crucial for improving patient outcomes.

While these strategies have expanded donor options, especially for non-Caucasian patients, they also carry risks such as increased relapse rates and infections, highlighting the need for careful management in transplant protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controversies and expectations for the prevention of GVHD: A biological and clinical perspective. Watkins, B., Williams, KM.[2022]

In a study of 102 patients undergoing hematopoietic cell transplantation (HCT) with fludarabine and low-dose total body irradiation, significant variability was observed in pharmacological biomarkers related to fludarabine metabolism, indicating that individual responses to the drug can differ widely.

Despite the variability in biomarkers such as F-ara-A area under the curve and F-ara-ATP accumulation, no significant associations were found between these biomarkers and clinical outcomes like acute graft-versus-host disease or overall mortality, suggesting that these pharmacological measures may not predict treatment success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. McCune, JS., Mager, DE., Bemer, MJ., et al.[2018]

The combination of methotrexate (MTX) and cyclosporine (CSP) with the busulfan and cyclophosphamide regimen (BuCy4) in 101 patients significantly reduced the incidence of acute graft-versus-host disease (GVHD) to 9.2%, especially in those receiving optimal immunosuppressive therapy.

Patients receiving optimal treatment had a projected 2-year disease-free survival rate of 52.3%, which improved to 65.2% in low-risk patients, highlighting the efficacy of this immunosuppressive strategy in enhancing post-transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute graft-versus-host disease prophylaxis with methotrexate and cyclosporine after busulfan and cyclophosphamide in patients with hematologic malignancies. von Bueltzingsloewen, A., Belanger, R., Perreault, C., et al.[2021]

The new conditioning regimen using thiotepa and fludarabine (TT-FLUDA) was well tolerated in six patients undergoing allogeneic bone marrow transplantation, with successful engraftment and stable donor chimerism in most cases.

Despite the patients being poor candidates for standard treatments, the TT-FLUDA regimen showed no major toxicity, although one patient died from acute graft-versus-host disease (GVHD), indicating a need for careful monitoring of GVHD prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa and fludarabine (TT-FLUDA) as conditioning regimen in poor candidates for conventional allogeneic hemopoietic stem cell transplant. Alessandrino, EP., Bernasconi, P., Colombo, AA., et al.[2019]

In a study of 35 patients undergoing allogeneic peripheral blood stem cell transplantation (alloPBSCT), a combination of post-transplant cyclophosphamide and standard immunosuppressants effectively reduced the incidence of acute and chronic graft-versus-host disease (GVHD) to 17% and 7%, respectively, with no severe grade IV GVHD cases reported.

The approach resulted in an impressive 2-year nonrelapse mortality rate of just 3% and maintained overall survival at 77%, demonstrating that this strategy not only controls GVHD but also preserves the beneficial graft-versus-tumor effect essential for combating hematologic malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. Carnevale-Schianca, F., Caravelli, D., Gallo, S., et al.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5743624/

Fludarabine and Busulfan versus ... Using the CIBMTR database, we report the outcomes of two most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) vs. fludarabine, ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2503189

Graft-versus-Host Disease Prophylaxis with ... Data from two randomized trials have suggested that post-transplantation cyclophosphamide can reduce the risk of GVHD after SCT from a matched ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11452337/

a study from the acute leukemia working party (EBMT) - PMC Tacrolimus versus cyclosporine a combined with post-transplantation cyclophosphamide for AML In first complete remission: a study from the acute leukemia ...

4. astctjournal.org astctjournal.org/article/S1083-8791(20)30227-5/fulltext

Long-Term Outcomes of Allogeneic Hematopoietic Cell ... Improved outcomes using tacrolimus/sirolimus for graft-versus-host disease prophylaxis with a reduced-intensity conditioning regimen for allogeneic ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S108387911500107X

Phase II Trial of Graft-versus-Host Disease Prophylaxis ... A matched cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II to IV (46% versus 19%; ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10500467/

Association between busulfan exposure and survival in ... Busulfan exposure is associated with OS; 5-year survival with an exposure of ≥59.5 vs <59.5 mg × h/L was 67% (95% CI, 59-76) vs 40%.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18546

Efficacy and safety of busulfan-fludarabine versus ... While BuCy demonstrated higher 5-year event-free survival and lower rates of Grade III-IV aGVHD, BuFlu was associated with significantly lower ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4261630/

Myeloablative reduced-toxicity IV busulfan-fludarabine and ... In this analysis of 79 patients with AML or MDS who were ≥ 55 years of age at time of allo-SCT, we showed good outcomes including OS, EFS, TRM and GvHD rates ...

9. ashpublications.org ashpublications.org/blood/article/142/Supplement%201/6958/505472/Outcomes-of-Treosulfan-Vs-Busulfan-Based

Outcomes of Treosulfan Vs. Busulfan Based Conditioning ... Extensive chronic GVHD was encountered in 15.7% of the patients in the treosulfan group compared to 32.1% in the busulfan group (p < 0.001).

10. sciencedirect.com sciencedirect.com/science/article/pii/S2473952923004676

Myeloablative fractionated busulfan for allogeneic stem cell ... Myeloablative fractionated busulfan regimen results in low nonrelapse mortality without a higher relapse rate.