Ruxolitinib for Lung Dysfunction Post Stem Cell Transplant

(HSCT Trial)

Recruiting at 1 trial location

Overseen By Evelyn Nguyen, MS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Children's Hospital Medical Center, Cincinnati

Must be taking: Flovent, Montelukast, Steroids, Ruxolitinib

Disqualifiers: Uncontrolled infection, Pregnancy, Recent GVHD treatment, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

40 Participants Needed

Trial Summary

What is the purpose of this trial?

Hematopoietic stem cell transplant (HSCT) is an effective but toxic therapy, and lung injury affects as many as 25% of children receiving HSCT. Improved transplant techniques and major improvements in survival mean that HSCT is being more widely used, and more mismatched grafts are being used. Bronchiolitis obliterans (BO) is a major limitation of pediatric HSCT success as BO is commonly diagnosed late in children, when lung injury is irreversible, leading to long term morbidity or even death. Currently, there are major gaps in our knowledge regarding incidence, etiology and optimal treatment of BO following HSCT, and important diagnostic limitations specific to children. Diagnosis of BO is usually based on performance of pulmonary function tests, which is usually impossible in ill children under 10. Even older children who feel unwell or un-cooperative may be unable to produce interpretable data. These deficiencies in diagnosis mean that BO is commonly diagnosed late, meaning fibrosis has occurred and lesions are irreversible. The hypothesis for this interventional trial is that early treatment with standard Flovent/montelukast and steroids plus ruxolitinib will reverse lung injury and reduce the frequency of chronic pulmonary impairment or florid BO.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are taking investigational agents for GVHD, you must stop them at least 30 days before starting the trial treatment.

What data supports the effectiveness of the drug Ruxolitinib for lung dysfunction after stem cell transplant?

Ruxolitinib has shown effectiveness in reducing symptoms and improving outcomes in patients with myelofibrosis undergoing stem cell transplants, and it has been used successfully to treat lung issues in transplant patients when reintroduced after discontinuation. This suggests it may help with lung dysfunction post-transplant by reducing inflammation and improving overall transplant outcomes. ^{1 2 3 4 5}

Is Ruxolitinib generally safe for humans?

Ruxolitinib has been used in various conditions and is generally considered safe, but it can cause side effects like anemia (low red blood cell count) and thrombocytopenia (low platelet count), which are usually manageable. There have been reports of infections and breathing problems when stopping the drug, so careful monitoring is important. ^{2 4 6 7 8}

How is the drug Ruxolitinib unique for treating lung dysfunction after stem cell transplant?

Ruxolitinib is unique because it is an oral medication that inhibits the Janus kinase (JAK) pathway, which is involved in immune function and inflammation. This mechanism may help manage lung dysfunction after stem cell transplant, although it is primarily used for conditions like myelofibrosis and can increase the risk of infections. ^{2 9 10 11 12}

Research Team

Kasiani Myers, MD

Principal Investigator

Children's Hospital Medical Center, Cincinnati

Eligibility Criteria

This trial is for people aged 5 to 60 who've had a bone marrow transplant and are showing early signs of lung problems. They need good blood, kidney, and liver function. It's not for those allergic to the study drug, pregnant or breastfeeding individuals without birth control, or anyone treated with other experimental drugs for graft-versus-host disease in the last month.

Inclusion Criteria

I am between 5 and 60 years old and have had a stem cell transplant with early lung issues.

My kidneys are working well enough (CrCl ≥ 30 mL/min).

My blood tests for immune cells, clotting, and platelets are within normal ranges.

Exclusion Criteria

I currently have a lung infection that is not under control.

I am not pregnant, breastfeeding, or at risk of becoming pregnant or fathering a child, or I can use effective birth control.

Known hypersensitivity to any constituent of the study medication

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive early treatment with Flovent/montelukast, steroids, and ruxolitinib to reverse lung injury

24 weeks

Regular visits for monitoring lung function

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ruxolitinib

Trial Overview The trial tests if adding Ruxolitinib to standard treatments like Flovent/montelukast and steroids can reverse early lung damage after a stem cell transplant. The goal is to prevent chronic lung issues or severe Bronchiolitis Obliterans by treating it sooner.

Participant Groups

Group I: Ruxolitinib Treatment Experimental Treatment 1 Intervention

Ruxolitinib is already approved in United States, European Union for the following indications:

Approved in United States as Jakafi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Vitiligo

Approved in European Union as Jakavi for:

• Intermediate or high-risk myelofibrosis
• Polycythemia vera
• Steroid-refractory acute graft-versus-host disease
• Chronic graft-versus-host disease
• Non-segmental vitiligo

Who Is Running the Clinical Trial?

Children's Hospital Medical Center, Cincinnati

Lead Sponsor

Trials

844

Recruited

6,566,000+

Findings from Research

In a study of 14 patients with myelofibrosis who received allogeneic hematopoietic cell transplantation after treatment with ruxolitinib, 71.4% experienced relief from myelofibrosis-related symptoms, and 64% had a significant reduction in spleen size.

Ruxolitinib treatment prior to transplantation was associated with a high engraftment rate of 93% and may improve outcomes by reducing inflammatory cytokines, potentially lowering the risk of graft failure and acute graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. Jaekel, N., Behre, G., Behning, A., et al.[2021]

Ruxolitinib, an oral JAK1/2 inhibitor, is effective in reducing spleen size and symptom burden in patients with intermediate and high-risk myelofibrosis, making it a valuable treatment option before hematopoietic stem cell transplantation (HSCT).

The impact of ruxolitinib on HSCT outcomes is not well understood, and there is significant variability in how it is used in patients transitioning to HSCT, highlighting the need for more research to guide treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peritransplantation Use of Ruxolitinib in Myelofibrosis. Ibrahim, U., Petrone, GEM., Mascarenhas, J., et al.[2021]

In a study of 551 myelofibrosis patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT), those who were pretreated with the JAK1/2 inhibitor ruxolitinib (RUX) showed a higher leukocyte engraftment rate (94%) compared to those who did not respond to RUX (85%).

Patients with ongoing spleen response at the time of transplantation after RUX treatment had a significantly lower risk of relapse (8.1% vs. 19.1%) and better 2-year event-free survival (68.9% vs. 53.7%), indicating that RUX pretreatment can be beneficial without negatively impacting transplantation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT. Kröger, N., Sbianchi, G., Sirait, T., et al.[2022]

Ruxolitinib, a drug used to treat steroid-refractory acute graft-versus-host disease in allogeneic hematopoietic cell transplantation (HCT) recipients, can lead to acute hypoxemic respiratory failure upon discontinuation, as observed in three patients within three months of stopping the medication.

Reinitiating ruxolitinib along with systemic corticosteroids resulted in rapid clinical improvement for these patients, highlighting the need for careful management of ruxolitinib dosing and discontinuation to avoid serious respiratory complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients. Anandappa, AJ., Hobbs, GS., Dey, BR., et al.[2021]

In a study of 8 patients with acute or chronic graft versus host disease (GVHD) who were unresponsive to standard treatments, ruxolitinib demonstrated a high overall response rate of 85%, with 50% achieving complete response.

Ruxolitinib was well-tolerated, indicating it could be a promising rescue therapy for patients suffering from refractory GVHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. Sarmiento Maldonado, M., Ramírez Villanueva, P., Bertín Cortes-Monroy, P., et al.[2022]

Ruxolitinib, a treatment for myelofibrosis, has been associated with a case of EBV reactivation leading to a severe lymphoproliferative disorder in a 57-year-old female patient, highlighting a potential risk of opportunistic infections.

This case emphasizes the need for close monitoring of patients on Ruxolitinib for signs of viral reactivations and opportunistic infections, as they may pose serious health risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib. Pálmason, R., Lindén, O., Richter, J.[2022]

In a phase 3 study involving 222 patients with polycythemia vera, ruxolitinib significantly outperformed standard therapy, achieving hematocrit control in 60% of patients and a 35% reduction in spleen volume in 38% of patients, compared to only 20% and 1% respectively in the standard therapy group.

Ruxolitinib also led to a higher rate of complete hematologic remission (24% vs. 9%) and a greater reduction in total symptom scores (49% vs. 5%), while maintaining a manageable safety profile with low rates of severe anemia and thrombocytopenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. Vannucchi, AM., Kiladjian, JJ., Griesshammer, M., et al.[2022]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

Ruxolitinib, a new treatment for myelofibrosis, has been linked to an increased risk of opportunistic infections, including Pneumocystis jiroveci pneumonitis.

Given this risk, it is recommended that clinicians consider prophylactic measures against Pneumocystis infections for patients undergoing ruxolitinib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. Lee, SC., Feenstra, J., Georghiou, PR.[2022]

Patients treated with ruxolitinib, a JAK inhibitor for myelofibrosis and polycythemia vera, have a significantly increased risk of developing Mycobacterium tuberculosis (MTB) and atypical mycobacterial infections (AMI), with reporting odds ratios of 9.2 and 8.3, respectively.

Out of the reported cases, 13.2% of patients with MTB and 34.8% with AMI died, highlighting the importance of screening for latent MTB before starting ruxolitinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mycobacterial Infections With Ruxolitinib: A Retrospective Pharmacovigilance Review. Anand, K., Burns, EA., Ensor, J., et al.[2021]

Ruxolitinib, a selective JAK1 and JAK2 inhibitor, has shown significant efficacy in treating myelofibrosis, with phase II and III trials demonstrating substantial reductions in spleen size and improvements in symptoms and quality of life for patients.

In phase III studies, ruxolitinib recipients achieved a spleen volume reduction of ≥35% at week 24 compared to placebo (41.9% vs. 0.7%) and best available therapy (31.9% vs. 0%), while also showing longer overall survival, although it requires close monitoring due to potential serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of myelofibrosis: its clinical potential. Ostojic, A., Vrhovac, R., Verstovsek, S.[2021]

Ruxolitinib is commonly used for managing myelofibrosis symptoms, but many patients experience treatment failure after 2-3 years, highlighting the need for alternative therapies like fedratinib.

Fedratinib has shown efficacy in reducing spleen volume and symptoms in patients with myelofibrosis, and ongoing trials are focused on understanding its long-term effects and managing potential gastrointestinal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. England, JT., Gupta, V.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib. [2021]

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

Peritransplantation Use of Ruxolitinib in Myelofibrosis. [2021]

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

Impact of prior JAK-inhibitor therapy with ruxolitinib on outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis: a study of the CMWP of EBMT. [2022]

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

Hypoxemic Respiratory Failure Following Ruxolitinib Discontinuation in Allogeneic Hematopoietic Cell Transplantation Recipients. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Compassionate use of ruxolitinib in acute and chronic graft versus host disease refractory both to corticosteroids and extracorporeal photopheresis. [2022]

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

Case-report: EBV driven lymphoproliferative disorder associated with Ruxolitinib. [2022]

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

Ruxolitinib versus standard therapy for the treatment of polycythemia vera. [2022]

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

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy. [2022]

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

Mycobacterial Infections With Ruxolitinib: A Retrospective Pharmacovigilance Review. [2021]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of myelofibrosis: its clinical potential. [2021]

12. England pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. [2022]