What is the mechanism of action of this treatment?

Shwachman-Diamond Syndrome (SDS) treatments often involve chemotherapy and immunosuppression to manage bone marrow failure and enhance the success of bone marrow transplants. Treosulfan and fludarabine are chemotherapy agents used to eradicate diseased cells and suppress the immune system, allowing healthy donor cells to engraft. Rabbit antithymocyte globulin (rATG) is an immunosuppressive agent that reduces the risk of graft rejection and improves bone marrow function. These treatments are vital for SDS patients as they address bone marrow failure and support successful transplantation, which can be life-saving.

What side effects are associated with this type of intervention?

Common treatments for Shwachman-Diamond Syndrome (SDS) involving chemotherapy and immunosuppression, such as Treosulfan, Fludarabine, and Rabbit Antithymocyte Globulin (rATG), have notable side effects. Treosulfan can cause myelosuppression, leading to increased risks of infection, anemia, and bleeding. Fludarabine is associated with immunosuppression and neurotoxicity, increasing infection risk. rATG can cause infusion-related reactions like fever, chills, and serum sickness, as well as long-term immunosuppression, further heightening infection risk. These side effects are critical in the treatment planning for SDS.

What prior FDA approvals exist?

Shwachman-Diamond Syndrome (SDS) is a rare genetic disorder primarily affecting the bone marrow, pancreas, and skeletal system. While there are no specific FDA-approved treatments exclusively for SDS, management often involves supportive care and treatments used for bone marrow failure syndromes. Chemotherapy agents like Treosulfan and Fludarabine, along with immunosuppressive agents such as Rabbit Antithymocyte Globulin (rATG), are used in conditioning regimens before hematopoietic stem cell transplantation (HSCT) to treat bone marrow failure in SDS patients. These agents help reduce the risk of transplant-related complications and improve outcomes by targeting the underlying bone marrow dysfunction.

What other types of research exist?

Promising novel alternatives for Shwachman-Diamond Syndrome patients considering treatment in 2024 include the use of targeted therapies such as Eltrombopag, which has shown efficacy in improving blood counts in bone marrow failure syndromes, and newer immunosuppressive agents like Alemtuzumab, which may offer a better safety profile. Additionally, gene therapy approaches and the use of CRISPR-Cas9 for genetic correction are emerging as potential curative treatments for SDS.

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Anti-metabolites

Treosulfan-Based Conditioning for Bone Marrow Failure

Phase 2

Recruiting

Research Sponsored by Fred Hutchinson Cancer Research Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

SAMD9 or SAMD9L disorders with a pathogenic mutation(s)

Underlying BMFD treatable by allogenic HCT

Must not have

Positive for human immunodeficiency virus (HIV)

Prior solid organ transplant

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 1 year post-hct

Awards & highlights

No Placebo-Only Group

Summary

This trial tests if a combination of three drugs can reduce complications for patients with bone marrow failure diseases. The drugs work by killing harmful cells, stopping their growth, and reducing immune reactions.

Who is the study for?

This trial is for people aged 1 to under 50 with bone marrow failure diseases treatable by transplant, who have specific genetic mutations or meet diagnostic criteria. Excluded are those with certain other conditions, previous transplants, severe lung function impairment, liver issues, uncontrolled infections, HIV positive status or unwillingness to use contraception.

What is being tested?

The study tests a pre-transplant conditioning regimen using treosulfan combined with fludarabine and rabbit antithymocyte globulin (rATG) in patients with bone marrow failure diseases. The goal is to see if this combination reduces complications post-transplant.

What are the potential side effects?

Potential side effects include immune system reactions due to rATG, organ inflammation from chemotherapy drugs like treosulfan and fludarabine phosphate, increased risk of infection and possible negative impact on fertility.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have a SAMD9 or SAMD9L disorder with a confirmed mutation.

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My bone marrow failure disorder can be treated with a stem cell transplant from a donor.

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I have Shwachman-Diamond syndrome with a confirmed genetic mutation.

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My condition involves a GATA2 mutation causing bone marrow failure.

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I have been diagnosed with paroxysmal nocturnal hemoglobinuria.

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I am between 1 and 49 years old.

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I have Diamond Blackfan Anemia with a confirmed genetic mutation.

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I have a genetic form of anemia known as Sideroblastic anemia.

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I have a genetic condition that affects my platelets.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am HIV positive.

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I have had a solid organ transplant.

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I have been diagnosed with MDS or leukemia according to WHO standards.

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My kidney function is reduced, with a creatinine clearance rate under 60 mL/min.

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I have a diagnosed blood disorder such as aplastic anemia, Fanconi anemia, dyskeratosis congenita, or congenital neutropenia.

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I have had a stem cell transplant from a donor.

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My weight is 10 kg or less at the time of joining the study.

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I have too much iron in my body due to my condition.

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I am not pregnant or breastfeeding.

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I agree to use birth control or abstain from sex for 12 months post-transplant.

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I do not have any ongoing serious infections.

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I am mostly unable to care for myself due to my health condition.

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I am using supplemental oxygen.

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I rely on dialysis for kidney function.

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My liver enzymes are more than four times the normal limit, or I have severe liver disease.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 1 year post-hct

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~1 year post-hct

This trial's timeline: 3 weeks for screening, Varies for treatment, and 1 year post-hct for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Graft-Versus Host-Disease (GVHD)-Free Event-Free Survival (EFS)

Secondary study objectives

Chronic GVHD

Donor Chimerism (CD3 and Myeloid)

Event-Free Survival

+10 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (conditioning regimen; transplant; GVHD prophylaxis)Experimental Treatment15 Interventions

CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2. TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Bone Marrow Aspiration

2011

Completed Phase 2

~1740

Echocardiography

2013

Completed Phase 4

~11580

Bone Marrow Biopsy

2021

Completed Phase 3

~230

Biospecimen Collection

2004

Completed Phase 3

~2030

Methotrexate

2019

Completed Phase 4

~4400

Multigated Acquisition Scan

2015

Completed Phase 3

~270

Allogeneic Bone Marrow Transplantation

2009

Completed Phase 2

~530

Peripheral Blood Stem Cell Transplantation

1997

Completed Phase 3

~1330

Computed Tomography

2017

Completed Phase 2

~2790

Treosulfan

2009

Completed Phase 3

~2320

Fludarabine Phosphate

1997

Completed Phase 3

~2390

Tacrolimus

2019

Completed Phase 4

~5510

0 / 24Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Shwachman-Diamond Syndrome (SDS) treatments often involve chemotherapy and immunosuppression to manage bone marrow failure and enhance the success of bone marrow transplants. Treosulfan and fludarabine are chemotherapy agents used to eradicate diseased cells and suppress the immune system, allowing healthy donor cells to engraft. Rabbit antithymocyte globulin (rATG) is an immunosuppressive agent that reduces the risk of graft rejection and improves bone marrow function. These treatments are vital for SDS patients as they address bone marrow failure and support successful transplantation, which can be life-saving.

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