Stem Cell Transplantation for Osteopetrosis

Overseen By Lisa Burke

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnancy, Myeloablative chemotherapy, Infections, 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: Unknown

100 Participants Needed

Trial Summary

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 treatment for osteopetrosis?

Research shows that using busulfan and fludarabine in stem cell transplantation can lead to successful engraftment and lower toxicity compared to traditional regimens. This combination has been effective in other conditions, suggesting potential benefits for osteopetrosis treatment. ^{1 2 3 4 5}

Is stem cell transplantation using busulfan and fludarabine generally safe for humans?

Stem cell transplantation using busulfan and fludarabine has been studied in various conditions and is generally associated with minimal regimen-related toxicity, but there are risks of complications like graft-versus-host disease (GVHD) and infections. While the treatment allows for adequate engraftment, it can lead to significant morbidity and mortality, particularly due to infections and GVHD. ^{3 4 5 6 7}

What makes the stem cell transplantation treatment for osteopetrosis unique?

This treatment uses a combination of busulfan and fludarabine, which is a novel approach compared to the traditional use of busulfan and cyclophosphamide. The busulfan and fludarabine regimen is associated with a shorter time to engraftment and a lower incidence of graft-versus-host disease (a condition where the donor cells attack the recipient's body), making it potentially safer and more effective for patients. ^{1 3 4 7 8}

What is the purpose of this trial?

This trial tests a treatment using busulfan and fludarabine to prepare patients with certain genetic disorders for a bone marrow transplant. The goal is to safely replace their bone marrow with healthy donor cells by carefully monitoring drug levels. Busulfan is used to clear out bone marrow cells before the transplant, and fludarabine is being tested as a less harmful alternative to another drug.

Research Team

Paul Orchard, M.D.

Principal Investigator

Masonic Cancer Center, University of Minnesota

Eligibility Criteria

This trial is for patients aged 0-55 with various inherited metabolic disorders like Hurler syndrome, Hunter syndrome without severe neurologic disease, and severe osteopetrosis. Participants must have a suitable stem cell donor, good organ function, and no recent myeloablative chemotherapy or uncontrolled infections.

Inclusion Criteria

I have been diagnosed with severe Osteopetrosis.

My condition is listed as eligible for this trial.

I have been diagnosed with MNGIE.

Exclusion Criteria

I do not have any uncontrolled infections, including HIV or mold infections in the last 30 days.

I haven't had intense chemotherapy within the last 4 months.

Pregnancy - menstruating females must have a negative serum or urine pregnancy test within 14 days of study treatment start

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants undergo conditioning with busulfan and fludarabine, with busulfan therapeutic drug monitoring

1-2 weeks

Transplantation

Participants receive allogeneic hematopoietic cell transplantation

1 week

Follow-up

Participants are monitored for donor hematopoietic engraftment and transplant-related outcomes

100 days

Long-term Follow-up

Participants are monitored for post-HSCT changes in disease and other long-term outcomes

1 year

Treatment Details

Interventions

• cALD HR-D (High-Risk, Regimen C)
• cALD HR-D (High-Risk, Regimen D)
• cALD SR-A (Standard-Risk, Regimen A)
• cALD SR-B (Standard-Risk, Regimen B)
• IMD Preparative Regimen
• Osteopetrosis Haploidentical Only Preparative Regimen
• Osteopetrosis Only Preparative Regimen
• Stem Cell Transplantation

Trial Overview The study tests the effectiveness of busulfan- and fludarabine-based conditioning regimens with busulfan drug monitoring in achieving successful stem cell engraftment while minimizing transplant-related mortality in patients with inherited metabolic disorders and osteopetrosis.

Participant Groups

Group I: cALD SR-B (Standard-Risk, Regimen B) Experimental Treatment 3 Interventions

See intervention descriptions.

Group II: cALD SR-A (Standard-Risk, Regimen A) Experimental Treatment 3 Interventions

See intervention descriptions.

Group III: cALD HR-D (High-Risk, Regimen D) Experimental Treatment 3 Interventions

See intervention descriptions.

Group IV: cALD HR-C (High-Risk, Regimen C) Experimental Treatment 3 Interventions

See intervention descriptions.

Group V: OP and IMD -Haplo-Identical Only Experimental Treatment 2 Interventions

Severe Osteopetrosis (OP) and Inhterited Metabolic Disorders (IMD) -Haplo-Identical Only See intervention descriptions.

Group VI: OP - Except Haplo-Identical Experimental Treatment 2 Interventions

Severe Osteoperosis (OP) - Except Haplo-Identical See intervention descriptions.

Group VII: IMD - Except Haplo-identical Experimental Treatment 2 Interventions

Inherited Metabolic Disease (IMD) - Except Haplo-Identical See intervention descriptions.

cALD HR-D (High-Risk, Regimen C) is already approved in United States, European Union for the following indications:

Approved in United States as Busulfan and Fludarabine Conditioning Regimen for:

• Inherited Metabolic Disorders
• Severe Osteopetrosis

Approved in European Union as Busulfan and Fludarabine Conditioning Regimen for:

• Inherited Metabolic Disorders
• Severe Osteopetrosis

Who Is Running the Clinical Trial?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Findings from Research

In a study of 70 patients undergoing allogeneic hematopoietic stem cell transplantation, targeting a higher busulfan area under the curve (AUC) of ≥19.7 mg*h/L did not improve overall survival (OS) or relapse-free survival (RFS) compared to a lower AUC of <19.7 mg*h/L.

There were no significant differences in non-relapsed mortality or the incidence of acute and chronic graft-versus-host disease between the two dosing groups, indicating that increasing busulfan intensity may not enhance safety or efficacy in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation. Mori, S., Guo, M., Rivera-Robles, N., et al.[2023]

The reduced intensity conditioning regimen using busulfan, fludarabine, and rabbit ATG (Bu/Flu/rATG) was well tolerated in 19 pediatric patients, leading to an excellent overall survival rate of 89% and event-free survival of 74% after 2 years.

However, the study faced a significant challenge with a 21% graft failure rate, particularly in patients receiving transplants from mismatched unrelated donors, which ultimately led to the premature closure of the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML. Horn, B., Baxter-Lowe, LA., Englert, L., 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]

A new preparative regimen for allogeneic stem cell transplantation was tested on 30 patients, primarily aimed at reducing regimen-related toxicity (RRT) while ensuring effective engraftment; 89% of evaluable patients achieved over 90% donor cell chimerism by day 100.

While the regimen showed minimal RRT and a low transplant-related mortality rate of 7% at 3 months, complications such as graft-versus-host disease (GVHD) occurred in 56% of patients, highlighting the need for further research to balance efficacy with safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience. Shaughnessy, PJ., Ornstein, D., Ririe, D., et al.[2019]

In a study of 9 pediatric patients with hemophagocytic lymphohistiocytosis (HLH) treated with a busulfan and fludarabine-based reduced-intensity conditioning (RIC) regimen, all patients achieved successful neutrophil and platelet engraftment, indicating effective treatment.

The 8-year overall survival rate was 78%, with no early treatment-related mortality within 100 days, suggesting that this RIC regimen is a safe and effective option for HCT in pediatric HLH patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis. Suh, JK., Koh, YK., Kang, SH., et al.[2022]

In a study of 378 high-risk non-Hodgkin lymphoma patients undergoing allogeneic stem-cell transplantation, the outcomes of reduced-intensity conditioning (FB2) were similar to those of myeloablative reduced-toxicity conditioning (FB3/FB4) in terms of overall survival and lymphoma-free survival.

The study found no significant advantage in using a myeloablative reduced-toxicity regimen, as both conditioning types showed comparable rates of severe acute graft versus host disease and overall survival, suggesting that reduced-intensity conditioning may be just as effective for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. Le Bourgeois, A., Labopin, M., Blaise, D., et al.[2022]

In a study of 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

In a study of adult patients with acute myeloid leukemia (AML) receiving reduced-intensity conditioning (RIC) before allogeneic hematopoietic cell transplantation (allo-HCT), the Flu+Mel regimen showed a significantly lower risk of relapse compared to the Flu+ivBu regimen, indicating better disease control potential.

Patients receiving the Flu+ivBu regimen experienced significantly lower non-relapse mortality compared to those on Flu+poBu and Flu+Mel, suggesting that while both RIC regimens are effective, Flu+ivBu may be less toxic for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan. Yamashita, T., Takami, A., Uchida, N., et al.[2022]

References

1. Germany pubmed.ncbi.nlm.nih.gov

Evaluation of different pharmacokinetically guided IV busulfan exposure ranges on adult patient outcomes after hematopoietic stem cell transplantation. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML. [2013]

3. England pubmed.ncbi.nlm.nih.gov

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation: comparison with BuCy2. [2022]

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

Phase II study of a moderate-intensity preparative regimen with allogeneic peripheral blood stem cell transplantation for hematologic diseases: the Texas Transplant Consortium experience. [2019]

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

Favorable outcomes with durable chimerism after hematopoietic cell transplantation using busulfan and fludarabine-based reduced-intensity conditioning for pediatric patients with hemophagocytic lymphohistiocytosis. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire. [2022]

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

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. [2015]

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

Reduced-intensity stem cell transplantation for acute myeloid leukemia with fludarabine-based conditioning with intravenous busulfan versus melphalan. [2022]