Stem Cell Response After Traumatic Injury in the Elderly

Overseen By Kalia Sadasivan, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Florida

Must not be taking: Corticosteroids, Immunosuppressants, Chemotherapy

Disqualifiers: Pregnancy, Renal disease, Hematological disease, others

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

Compensation: Varies

Number of Visits: 1

400 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on chronic corticosteroids or immunosuppression therapies.

What evidence supports the effectiveness of the drug Filgrastim in the treatment for stem cell response after traumatic injury in the elderly?

Filgrastim, a drug used to boost white blood cell production, has been shown to be effective in mobilizing stem cells for transplantation in patients with conditions like multiple myeloma and non-Hodgkin lymphoma. This suggests it may help in similar ways for elderly patients recovering from traumatic injuries by supporting stem cell mobilization and recovery. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Filgrastim, a treatment used to prevent infections and help with stem cell collection, has been studied for safety. It has been used since 1991 and is generally considered safe, though some people may experience side effects like fever, muscle pain, or bone pain. These side effects are usually mild and reversible. ^{1 3 5 6 7}

How does the drug plerixafor differ from other treatments for stem cell mobilization after traumatic injury in the elderly?

Plerixafor is unique because it specifically targets the CXCR4 receptor to release stem cells from the bone marrow into the bloodstream, enhancing the collection of stem cells when combined with G-CSF. This mechanism is different from standard treatments that rely solely on G-CSF, making plerixafor particularly useful for patients who have difficulty mobilizing enough stem cells with G-CSF alone. ^{2 4 8 9 10}

What is the purpose of this trial?

Traumatic injury is a leading cause of morbidity and mortality in young adults, and remains a substantial economic and health care burden. Despite decades of promising preclinical and clinical investigations in trauma, investigators understanding of these entities is still incomplete, and few therapies have shown success. During severe trauma, bone marrow granulocyte stores are rapidly released into the peripheral circulation. This release subsequently induces the expansion and repopulation of empty or evacuated space by hematopoietic stem cells (HSCs). Although the patient experiences an early loss of bone marrow myeloid-derived cells, stem cell expansion is largely skewed towards the repopulation of the myeloid lineage/compartment. The hypothesis is that this 'emergency myelopoiesis' is critical for the survival of the severely traumatized and further, failure of the emergency myelopoietic response is associated with global immunosuppression and susceptibility to secondary infection. Also, identifying the release of myeloid derived suppressor cells (MDSCs) in the circulation of human severe trauma subjects. This process is driven by HSCs in the bone marrow of trauma subjects. Additionally, MDSCs may have a profound effect on the nutritional status of the host. The appearance of these MDSCs after trauma is associated with a loss of muscle tissue in these subjects. This muscle loss and possible increased catabolism have huge effects on long term outcomes for these subjects. It is the investigator's goal to understand the differences that occur in these in HSCs and muscle cells as opposed to non-injured and non-infected controls. This work will lead to a better understanding of the myelopoietic and catabolic response following trauma.

Research Team

Philip Efron, MD

Principal Investigator

University of Florida

Eligibility Criteria

This trial is for adults aged 55 and older with severe trauma from blunt or penetrating injuries, showing signs of hemorrhagic shock or having a high injury severity score. It also includes younger adults (18-54) with similar injuries requiring surgery. Excluded are those not expected to survive 48 hours, prisoners, pregnant women, patients with end-stage renal disease, hematological diseases, prior bone marrow transplants, or recent chemotherapy/radiation.

Inclusion Criteria

Ability to obtain Informed Consent prior to operation

Severe Trauma Population:

I have had a serious injury with a severity score of 15 or more.

Exclusion Criteria

I have not had chemotherapy or radiation in the last 6 months.

I have had a bone marrow transplant in the past.

I have end-stage kidney disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Sample Collection and Initial Analysis

Bone marrow and blood samples are collected at the time of surgery for genomic and biochemical analysis

Baseline

1 visit (in-person)

Follow-up

Participants are monitored for genomic response and clinical outcomes, including malunion and additional surgical procedures

8 months

Follow-up surgery and clinical data collection

Treatment Details

Interventions

• Blood collection
• Bone marrow collection
• Clinical data collection

Trial Overview The study investigates how severe injury affects stem cells in the elderly by collecting blood and bone marrow samples and clinical data. Researchers aim to understand 'emergency myelopoiesis'—the body's response to replenish immune cells after trauma—and its link to muscle loss and infection risk post-injury.

Participant Groups

Group I: Severe Trauma Experimental Treatment 3 Interventions

Bone marrow collection. Blood collection. Clinical data collection.

Group II: Healthy Young Bone Marrow Control Experimental Treatment 1 Intervention

Deidentified freshly isolated bone marrow samples from healthy young control subjects will be purchased for a tissue bank.

Group III: Elective Hip Repair Experimental Treatment 3 Interventions

Bone marrow collection. Blood collection. Clinical data collection.

Who Is Running the Clinical Trial?

University of Florida

Lead Sponsor

Trials

1,428

Recruited

987,000+

National Institute of General Medical Sciences (NIGMS)

Collaborator

Trials

315

Recruited

251,000+

Findings from Research

Filgrastim significantly reduces the incidence of febrile neutropenia and severe neutropenia in patients undergoing chemotherapy, with relative risks of 0.63 and 0.50, respectively, based on a systematic review of 25 studies involving 1194 articles.

The most common adverse effect reported with filgrastim treatment is bone pain, which has a relative risk of 2.61, indicating it is a notable side effect to consider when using this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim. Dale, DC., Crawford, J., Klippel, Z., et al.[2022]

Plerixafor effectively mobilizes hematopoietic stem cells by blocking the CXCR4 receptor, leading to a significant increase in CD34+ cells in the peripheral blood, peaking about 10 hours after administration.

A predictive model developed from data of 45 pediatric patients shows a strong correlation between peripheral blood CD34+ counts and the volume of CD34+ cells collected during apheresis, allowing for better planning and assurance of successful stem cell collection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development and validation of a predictive model to guide the use of plerixafor in pediatric population. Sebastien, B., Cheverton, P., Magnin, C., et al.[2022]

In a prospective randomized trial involving 97 patients with multiple myeloma and non-Hodgkin lymphoma, tbo-filgrastim was found to be not inferior to filgrastim in terms of stem cell mobilization efficacy, with a mean collection of 11.6 CD34+ cells/kg compared to 10.0 CD34+ cells/kg for filgrastim.

Both tbo-filgrastim and filgrastim showed similar safety profiles, indicating that tbo-filgrastim can be a safe and effective alternative to filgrastim for stem cell mobilization in patients undergoing autologous hematopoietic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a Prospective Randomized, Open-Label, Noninferiority Study of Tbo-Filgrastim (Granix) versus Filgrastim (Neupogen) in Combination with Plerixafor for Autologous Stem Cell Mobilization in Patients with Multiple Myeloma and Non-Hodgkin Lymphoma. Bhamidipati, PK., Fiala, MA., Grossman, BJ., et al.[2021]

In a clinical trial involving 37 allogeneic PBSC donors, the addition of plerixafor (P) significantly improved the mobilization of CD34+ stem cells, with median counts increasing from 15/µl after G-CSF alone to 44/µl after G-CSF plus P (p < 0.001).

Plerixafor treatment led to a median yield of 3.74 × 10^6 CD34+/kg recipient body weight on Day 2, compared to only 1.31 × 10^6 CD34+/kg on Day 1, with 57% of donors reaching the target cell count, and no severe adverse events reported, indicating its safety and efficacy for donors with poor mobilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial. Hölig, K., Schmidt, H., Hütter, G., et al.[2022]

The study found that both ior®LeukoCIM and Neupogen® had similar safety profiles, with mild to severe swelling of the hock-joint observed in rats, but all adverse effects were fully reversible.

Both products effectively increased white blood cell and neutrophil levels to a comparable extent, indicating similar pharmacodynamic and pharmacokinetic properties, supporting their classification as biosimilars.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Biosimilarity of ior&#174;LeukoCIM Compared to Neupogen&#174; Based on Toxicity, Pharmacodynamic, and Pharmacokinetic Studies in the Sprague-Dawley Rat. Licollari, A., Riddle, K., Taylor, SR., et al.[2018]

A retrospective study of adverse drug reactions from 1991 to 2018 found that filgrastim biosimilars, such as Grasin® and Zarzio®, reported higher rates of specific side effects compared to the originator Neupogen®, indicating potential differences in safety profiles.

The study revealed that some biosimilars, like Zarzio® and Tevagrastim®, had significant reports of drug ineffectiveness, suggesting that their efficacy may not match that of the original filgrastim, highlighting the need for further large-scale studies to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data. Rastogi, S., Shukla, S., Sharma, AK., et al.[2020]

The biosimilar filgrastim-sndz (Zarxio) offers significant cost savings compared to reference filgrastim and pegfilgrastim for preventing chemotherapy-induced neutropenia, with savings ranging from $65 to $3,666 depending on the administration scenario and duration of treatment.

Filgrastim-sndz consistently demonstrated lower costs across various administration methods, making it a cost-effective option for patients undergoing chemotherapy, while maintaining the same efficacy as its reference counterparts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia. McBride, A., Campbell, K., Bikkina, M., et al.[2022]

Plerixafor, when used as a rescue treatment after chemotherapy and G-CSF mobilization, successfully allowed 69% of patients to achieve the target dose of CD34+ cells needed for stem cell collection on the first attempt.

Pre-apheresis factors, specifically the CD34+ cell count and platelet count, were significant predictors of successful stem cell collection, indicating that higher counts can reduce the need for additional apheresis procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Day -1 CD34+ Cells and Platelet Count Predict the Number of Apheresis in Poor-Mobilizer Patients Rescued by Plerixafor. Valentini, CG., Pellegrino, C., Putzulu, R., et al.[2023]

A study involving normal volunteers showed that combining rhIL-3 with rhG-CSF for progenitor cell mobilization is safe and well-tolerated, with adverse effects similar to those of the individual treatments.

The sequential administration of rhIL-3 followed by rhG-CSF significantly increased the number of circulating CD34+ cells, which are important for stem cell collection, making it an effective protocol for enhancing stem cell mobilization.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant human interleukin-3 (rhIL-3) enhances the mobilization of peripheral blood progenitor cells by recombinant human granulocyte colony-stimulating factor (rhG-CSF) in normal volunteers. Huhn, RD., Yurkow, EJ., Tushinski, R., et al.[2017]

In a study involving 15 patients with multiple myeloma and non-Hodgkin's lymphoma, the combination of G-CSF and the CXCR4 antagonist AMD3100 significantly increased the number of primitive blood progenitor cells (PBPC), enhancing their potential for bone marrow reconstitution.

Patients receiving PBPC mobilized with G-CSF and AMD3100 experienced faster recovery of leukocytes and platelets after transplantation, with 91% achieving complete hematologic reconstitution within 35 days, indicating improved efficacy of this mobilization strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A combination of granulocyte-colony-stimulating factor (G-CSF) and plerixafor mobilizes more primitive peripheral blood progenitor cells than G-CSF alone: results of a European phase II study. Fruehauf, S., Veldwijk, MR., Seeger, T., et al.[2021]

References

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

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim. [2022]

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

Development and validation of a predictive model to guide the use of plerixafor in pediatric population. [2022]

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

Results of a Prospective Randomized, Open-Label, Noninferiority Study of Tbo-Filgrastim (Granix) versus Filgrastim (Neupogen) in Combination with Plerixafor for Autologous Stem Cell Mobilization in Patients with Multiple Myeloma and Non-Hodgkin Lymphoma. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Salvage treatment with plerixafor in poor mobilizing allogeneic stem cell donors: results of a prospective phase II-trial. [2022]

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

Safety and Biosimilarity of ior&#174;LeukoCIM Compared to Neupogen&#174; Based on Toxicity, Pharmacodynamic, and Pharmacokinetic Studies in the Sprague-Dawley Rat. [2018]

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

Towards a comprehensive safety understanding of granulocyte-colony stimulating factor biosimilars in treating chemotherapy associated febrile neutropenia: Trends from decades of data. [2020]

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

Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Day -1 CD34+ Cells and Platelet Count Predict the Number of Apheresis in Poor-Mobilizer Patients Rescued by Plerixafor. [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Recombinant human interleukin-3 (rhIL-3) enhances the mobilization of peripheral blood progenitor cells by recombinant human granulocyte colony-stimulating factor (rhG-CSF) in normal volunteers. [2017]

10. England pubmed.ncbi.nlm.nih.gov

A combination of granulocyte-colony-stimulating factor (G-CSF) and plerixafor mobilizes more primitive peripheral blood progenitor cells than G-CSF alone: results of a European phase II study. [2021]