Reduced-Dose Cyclophosphamide for Leukemia After Stem Cell Transplant

(OPTIMIZE Trial)

Recruiting at 34 trial locations

Overseen By OPTIMIZE Study Team

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Center for International Blood and Marrow Transplant Research

Disqualifiers: Prior allogeneic transplant, uncontrolled infection, 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: 2

313 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether a lower dose of cyclophosphamide (also known as Cytoxan, Neosar, or Endoxan), administered after a stem cell transplant, can reduce infections while still preventing Graft Versus Host Disease (GvHD), a condition where the donor's cells attack the patient's body. The trial involves various treatment plans using different drug combinations before and after receiving stem cells from a mismatched donor. Suitable candidates include those with leukemia or similar blood conditions, showing no active disease signs, and planning to undergo a mismatched, unrelated donor stem cell transplant. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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

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.

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

Previous studies have shown that the combination of busulfan and fludarabine (BuFlu) is safer than similar treatments, such as busulfan with cyclophosphamide, which has higher toxicity. Specifically, BuFlu resulted in fewer transplant-related deaths and is effective for patients with certain blood cancers.

Research on fludarabine combined with total body irradiation (TBI) also indicates good safety results. Patients experienced low rates of severe side effects, such as infections and graft-versus-host disease (GvHD), where new stem cells attack the patient's body.

When paired with melphalan, fludarabine has been shown to be safe and effective, particularly for older patients with acute leukemia and similar conditions. This combination is less toxic compared to other treatments.

Lastly, fludarabine and cyclophosphamide with TBI has been well-tolerated in patients using mismatched donors, proving to be a safe option.

Overall, these treatments offer promising safety profiles, with lower risks of severe side effects compared to other treatments in similar situations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore using reduced-dose cyclophosphamide after a stem cell transplant for leukemia, which could minimize side effects. Traditionally, treatments for leukemia often involve high-intensity chemotherapy and radiation, which can be tough on the body. These trial regimens stand out by combining different chemotherapy drugs like fludarabine, busulfan, and melphalan with varying doses of cyclophosphamide and total body irradiation. The aim is to find a balance that effectively targets leukemia cells while reducing the harsh side effects typically associated with full-dose treatments. This approach could potentially make transplants safer and more tolerable for patients, especially those with mismatched donors.

What evidence suggests that this trial's treatments could be effective for leukemia?

Research has shown that a lower dose of cyclophosphamide can effectively reduce the risk of Graft Versus Host Disease (GvHD), a common issue after a stem cell transplant, while possibly lowering infection rates. In this trial, participants will receive different treatment regimens. For those receiving fludarabine and busulfan together, studies indicate this combination safely and effectively prepares the body for a transplant, offering benefits like quicker recovery of blood cells. Participants in another arm will receive fludarabine with total body irradiation (TBI), which has been well-tolerated and has shown good results in reducing the chances of the disease returning. The mix of fludarabine and melphalan, studied in another arm, has also been effective, particularly for older patients, by helping to lower disease relapse and maintain survival. Lastly, the combination of fludarabine, cyclophosphamide, and TBI, tested in a separate arm, offers a good balance of reducing relapse risks and being well-tolerated. These findings support the potential effectiveness of using a lower dose of cyclophosphamide in this trial for leukemia patients. ^{1 3 6 7 8}

Who Is on the Research Team?

Steven Devine, MD

Principal Investigator

NMDP

Jeffery Auletta, MD

Principal Investigator

NMDP

Are You a Good Fit for This Trial?

Adults aged 18-66 with various blood cancers, who can consent and follow the trial procedures. They must have a partially matched unrelated donor for stem cell transplant and be in good enough health to undergo the procedure. Specific conditions like AML or ALL should be in early remission.

Inclusion Criteria

My leukemia is in its first remission or later, or I have a specific type of myelofibrosis.

I can care for myself but cannot do normal activities or work.

My kidneys work well enough (creatinine clearance ≥ 45mL/min).

Exclusion Criteria

I have a donor who matches me closely for a transplant.

Inability to provide informed consent or comply with protocol

I am receiving treatment to lower my body's reaction to a transplant.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants receive conditioning regimens including Fludarabine, Busulfan, Melphalan, or TBI, followed by a PBSC graft infusion from a mismatched unrelated donor

7 days

Daily visits for conditioning and transplantation

Post-Transplant Cyclophosphamide Treatment

Participants receive a reduced dose of cyclophosphamide on Day 3 and Day 4 post-transplant

2 days

2 visits (in-person)

Follow-up

Participants are monitored for safety, effectiveness, and incidence of infections, GvHD, and other outcomes

1 year

Regular visits as per protocol

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Cyclophosphamide
• Fludarabine
• Melphalan
• Mesna
• Mycophenolate Mofetil
• Patient Reported Outcomes
• PBSC Hematopoietic Stem Cell Transplantation
• Post-Transplant Cyclophosphamide
• Tacrolimus
• Total-body irradiation

Trial Overview The trial tests if a lower dose of Post-Transplant Cyclophosphamide after stem cell transplantation from mismatched donors is effective at preventing Graft Versus Host Disease while reducing infections within the first 100 days post-transplant.

How Is the Trial Designed?

Group I: Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy Experimental Treatment 9 Interventions

Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Group II: Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy Experimental Treatment 7 Interventions

Patients receive: Fludarabine (125-150 mg/m2 total dose) IV on days -7 to -3 Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Group III: Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy Experimental Treatment 7 Interventions

Patients receive: Fludarabine (150-180 mg/m2 total dose) IV on days -6 to -2 Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Group IV: Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy Experimental Treatment 7 Interventions

Patients receive: Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Group V: Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy Experimental Treatment 7 Interventions

Patients Receive: Patients receive: Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

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?

Center for International Blood and Marrow Transplant Research

Lead Sponsor

Trials

40

Recruited

200,190,000+

National Marrow Donor Program

Collaborator

Trials

63

Recruited

202,000+

Published Research Related to This Trial

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]

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 involving 105 patients, substituting fludarabine for cyclophosphamide in the modified busulfan-cyclophosphamide (mBuCy) regimen led to a significantly higher incidence of severe pneumonia (31.1%) compared to the mBuCy regimen (11.6%).

Due to the increased risk of severe pneumonia, the trial was suspended, indicating that fludarabine may not be a safe substitute for cyclophosphamide in this myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Substitution of cyclophosphamide in the modified BuCy regimen with fludarabine is associated with increased incidence of severe pneumonia: a prospective, randomized study. Liu, DH., Xu, LP., Zhang, XH., et al.[2022]

In a study comparing two preconditioning regimens for allogeneic hematopoietic stem cell transplantation, patients receiving busulfan and fludarabine (Bu-Flu) showed improved overall survival and event-free survival rates, particularly in those treated in the first complete remission (CR1).

The Bu-Flu regimen was associated with better outcomes than the traditional busulfan and cyclophosphamide (BuCy) regimen, suggesting it may enhance safety and maintain antileukemic efficacy, warranting further prospective studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Andersson, BS., de Lima, M., Thall, PF., et al.[2022]

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 of 30 adult patients undergoing allogeneic hematopoietic stem cell transplant, fludarabine combined with full-dose busulfan (FluBu) and fludarabine with melphalan (FluMel) showed similar levels of hematological toxicity, indicating that both regimens are comparably safe.

The timing and duration of severe neutropenia were similar between the two groups, with both regimens resulting in a comparable recovery time for neutrophils and platelets post-transplant, suggesting that FluBu can be an effective alternative to standard reduced intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. Chunduri, S., Dobogai, LC., Peace, D., et al.[2013]

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]

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

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 study evaluated a myeloablative conditioning regimen using fludarabine and busulfan in 70 patients with acute leukemia, showing similar efficacy to the traditional BuCy regimen with overall survival at 71% and disease-free survival at 64%.

Fludarabine and busulfan resulted in a high incidence of mucositis (93%) but lower transplant-related adverse effects compared to BuCy, suggesting it could be a safer alternative, although modifications may be needed for optimal anti-leukemic effects in specific leukemia types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and busulfan as a myeloablative conditioning regimen for allogeneic stem cell transplantation in high- and standard-risk leukemic patients. Iravani, M., Evazi, MR., Mousavi, SA., et al.[2013]

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 30 patients with various malignant hematological diseases undergoing allogeneic bone marrow transplantation using a Busulphan and Cyclophosphamide (Bu-Cy) conditioning regimen, sustained disease-free survival (DFS) was achieved in 5 out of 7 patients with acute leukemia in remission and 6 out of 9 patients with chronic myelogenous leukemia (CML) in the chronic phase.

The Bu-Cy protocol demonstrated a strong tumor ablative capability while maintaining toxicity levels similar to other conditioning regimens, making it a promising option for patients with significant bone marrow involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic bone marrow transplantation for hematological malignancies following therapy with high doses of busulphan and cyclophosphamide. Angelucci, E., Polchi, P., Lucarelli, G., et al.[2013]

Citations

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PMC Search Update Consequently, overall survival at 1 year was similar between both treatment arms, meaning no survival advantage was observed with adding TBI to ...

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long term analysis of GITMO AML-R2 trial - PubMed Central With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after ...

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Comparative effectiveness of busulfan/cyclophosphamide... Amongst AML patients, those receiving Bu/Flu had more rapid neutrophil and platelet recovery and a shorter length of hospital stay (LOS); there were no ...

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Long-term Outcomes After Treatment with Clofarabine ... The 1-year OS, DFS and NRM rates were 63%, 57% and 3.3%, respectively. A subgroup analysis showed that OS, DFS and leukemia relapse favored the patients with ...

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an open-label, multicentre, randomised, phase 3 trial The myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide.

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Once-daily IV Busulfan & Fludarabine for Stem Cell Transplant Recently, safety and efficacy data were obtained with a once-daily intravenous busulfan and fludarabine conditioning regimen for allogeneic HSCT in patients ...