Ruxolitinib for Bone Marrow Failure

Recruiting in Bethesda (>99 mi)

Overseen By Emma M Groarke, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Must not be taking: Chemotherapy, Immunomodulatory, others

Disqualifiers: Fanconi anemia, MDS/MPN, others

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

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

Compensation: Varies

Number of Visits: 5

Duration: 6 months

145 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Immune bone marrow failure is a condition that occurs when a person s immune system attacks the cells of the bone marrow. This can lead to diseases including different types of anemias and blood cancers. Some of these diseases can be deadly. Better treatments are needed. Objective: To test a drug (ruxolitinib) in people with different types of immune bone marrow failure. Eligibility: Adults aged 18 and older with an immune bone marrow failure. Design: Participants will be screened. They will have a physical exam. They will give samples of blood and saliva. They will have a bone marrow biopsy: A large needle will be inserted into a small cut to remove a sample of the soft tissue inside the bone. Some participants may have a skin biopsy: A small piece of skin will be removed. Some may have a computed tomography (CT) scan: They will lie on a table that slides into a donut-shaped machine that uses X-rays to make pictures of the inside of the body. Ruxolitinib is a tablet taken by mouth. Participants will take the drug twice a day for up to 6 months. Participants will have blood tests every week while they are taking the drug. These tests can be done by the participant s own physician and the results sent to the researchers. Participants will have clinic visits after taking the drug for 3 months and 6 months and then after 1, 2, and 3 years. The blood tests and bone marrow biopsy will be repeated. Participants who improve while taking the drugs may go on to an extension phase of the study.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you are on certain treatments like erythropoiesis-stimulating agents, hypomethylating agents, chemotherapy, or immunomodulatory therapy, you must not have taken them within 8 weeks prior to joining the study.

What evidence supports the effectiveness of the drug Ruxolitinib for bone marrow failure?

Ruxolitinib, a drug that blocks certain proteins (JAK1/2) involved in inflammation, has shown benefits in treating myelofibrosis, a condition related to bone marrow failure, by reducing spleen size and improving symptoms. However, it does not significantly affect the underlying bone marrow issues and can cause low blood cell counts. ^{1 2 3 4 5}

What safety data exists for Ruxolitinib in humans?

Ruxolitinib is generally well tolerated in humans, but some common side effects include anemia (low red blood cell count), thrombocytopenia (low platelet count), and lymphopenia (low white blood cell count). Rare side effects include skin reactions and neurological symptoms like dizziness and headache. These side effects are usually manageable with dosage adjustments. ^{5 6 7 8 9}

How is the drug Ruxolitinib unique for treating bone marrow failure?

Ruxolitinib is unique because it is an oral medication that specifically inhibits Janus Kinase (JAK) 1 and 2, which are involved in abnormal signaling pathways in bone marrow diseases. This mechanism helps reduce symptoms and improve blood cell counts, offering a novel approach compared to other treatments that may not target these pathways directly. ^{3 9 10 11 12}

Research Team

Emma M Groarke, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

Adults over 18 with immune bone marrow failure, willing to consent and use contraception if of childbearing potential. Excluded are those with certain genetic disorders, recent cancer treatments, uncontrolled infections or severe organ dysfunction, current pregnancy or breastfeeding, inability to swallow pills, or a history of acute thrombosis within the last 6 months.

Inclusion Criteria

For females of childbearing potential, willingness to use accepted methods of contraception

Ability to understand and sign a written informed consent document

I am 18 years old or older.

Exclusion Criteria

I am currently receiving treatment for cancer.

I have recently been treated with specific medications.

I do not have any severe illnesses that prevent me from daily activities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive ruxolitinib twice a day for up to 6 months

6 months

Weekly blood tests, clinic visits at 3 and 6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Clinic visits at 1, 2, and 3 years

Extension

Participants who improve may continue treatment in an extension phase

Treatment Details

Interventions

• Ruxolitinib

Trial Overview The trial is testing Ruxolitinib tablets taken twice daily for up to six months in patients with various types of immune bone marrow failure. It includes regular blood tests and clinic visits at specified intervals including after treatment completion to monitor effects.

Participant Groups

Group I: Subjects with hypoplastic MDS Experimental Treatment 1 Intervention

Subjects are defined as patients with a diagnosis of hMDS clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.

Group II: Subjects with TLGL Experimental Treatment 1 Intervention

Subjects are defined as patients with a diagnosis of TLGL clinically confirmed by a licensed physician or advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.

Group III: Subjects with SAA Experimental Treatment 1 Intervention

Subjects are defined as patients with a diagnosis of SAA clinically confirmed by a licensed physician oran advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.

Group IV: Subjects with PRCA Experimental Treatment 1 Intervention

Subjects are defined as patients with a diagnosis of PRCA clinically confirmed by a licensed physician or advanced practitioners who meet the inclusion and exclusion criteria and can provide informed consent.

Group V: Subjects with MAA Experimental Treatment 1 Intervention

Subjects are defined as patients with a diagnosis of MAA clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.

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?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Findings from Research

Ruxolitinib, a JAK1/2 inhibitor, provides rapid and significant relief for myelofibrosis patients by reducing spleen size and improving symptoms, but it does not address the underlying bone marrow fibrosis or mutant allele burden, and patients may develop resistance over time.

Other JAK inhibitors like fedratinib, pacritinib, and momelotinib show promise for patients who do not respond well to ruxolitinib, and novel treatments targeting anemia are also being explored, indicating a growing landscape of options for managing myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis. Bose, P.[2023]

Momelotinib, a JAK inhibitor, shows promise in treating myelofibrosis by improving anemia, spleen size, and symptoms, with overall survival (OS) and leukemia-free survival (LFS) rates comparable to ruxolitinib in JAKi-naïve patients.

Achieving transfusion independence (TI) is linked to better survival outcomes, highlighting momelotinib's effectiveness in promoting erythropoiesis and its potential role in treatment strategies for myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. Mesa, R., Harrison, C., Oh, ST., et al.[2022]

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]

Ruxolitinib is an effective oral treatment for myelofibrosis, leading to significant reductions in spleen size and symptom burden for most patients, and may improve survival rates regardless of JAK2 V617F mutation status.

The main side effects of ruxolitinib include thrombocytopenia (low platelet count) and anemia, and its metabolism can be affected by other medications that inhibit the CYP3A4 enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib. Becker, H., Engelhardt, M., von Bubnoff, N., et al.[2021]

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 JAK-2 inhibitor used for treating myeloproliferative neoplasms, is generally associated with very rare skin toxicity, but an unusual case of erythematous skin eruption with necrotic centers was observed in a patient with primary myelofibrosis.

This case highlights the need for increased awareness of potential skin side effects from ruxolitinib, especially as JAK-2 inhibitors may be used more widely in dermatological treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. Dasanu, CA.[2021]

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]

Ruxolitinib is an effective JAK2 inhibitor used to treat myelofibrosis and polycythemia vera, but it carries risks of immunosuppression and increased chances of skin cancer.

An 80-year-old woman treated with ruxolitinib experienced unusual neurological symptoms, including weakness and hypoesthesia in her right arm and leg, highlighting the need for monitoring neurological side effects in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpected Neurological Symptoms of Ruxolitinib: A Case Report. Furia, F., Canevini, MP., Federici, AB., et al.[2023]

Ruxolitinib is an effective treatment for patients with polycythaemia vera (PV) who do not respond well to hydroxyurea, showing superior results in reducing hematocrit and spleen size after 32 weeks in the phase III RESPONSE trial.

The drug is generally well tolerated, with manageable side effects like mild to moderate anemia and thrombocytopenia, making it a valuable option for PV patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib: A Review in Polycythaemia Vera. McKeage, K.[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 currently the only approved treatment for myelofibrosis, but patients who stop taking it face poor outcomes, highlighting a significant need for alternative therapies.

New JAK inhibitors like fedratinib and momelotinib are being revisited, and combination therapies, such as adding azacitidine to ruxolitinib, show promise in improving treatment responses and managing side effects like cytopenias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Concepts of Treatment for Patients with Myelofibrosis. Bose, P., Alfayez, M., Verstovsek, S.[2023]

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

Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis. [2023]

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

Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. [2022]

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

Peritransplantation Use of Ruxolitinib in Myelofibrosis. [2021]

4. Germany pubmed.ncbi.nlm.nih.gov

Ruxolitinib. [2021]

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

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

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

Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. [2021]

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

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

8. Canada pubmed.ncbi.nlm.nih.gov

Unexpected Neurological Symptoms of Ruxolitinib: A Case Report. [2023]

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

Ruxolitinib: A Review in Polycythaemia Vera. [2021]

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

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

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

New Concepts of Treatment for Patients with Myelofibrosis. [2023]

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

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