Ruxolitinib for Bone Marrow Failure

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether ruxolitinib (also known as Jakafi, Jakavi, or Opzelura) can treat immune bone marrow failure, a condition where the immune system mistakenly attacks bone marrow cells. This condition can lead to serious blood disorders, such as certain anemias and blood cancers. The trial will test ruxolitinib on different groups with various forms of this condition to evaluate its effectiveness. Individuals diagnosed with immune bone marrow failure who have not responded to other treatments might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, the research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that ruxolitinib is generally safe for treating various conditions, including certain blood disorders and immune system issues. Studies identify anemia (a decrease in red blood cells) and fever as the most common side effects. Anemia occurs in about 29.1% of patients, while fever affects about 15.8%. Other side effects may include low platelet levels, which can lead to easy bruising or bleeding.

The FDA has already approved ruxolitinib for other uses, indicating a good understanding of its safety. However, like any medication, it requires careful monitoring. Regular blood tests track changes and manage side effects. This ongoing assessment is crucial to ensure the treatment remains safe and effective for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for bone marrow failure?

Unlike the standard treatments for bone marrow failure, which often include immunosuppressive therapies and bone marrow transplants, Ruxolitinib targets the JAK-STAT signaling pathway. This pathway is crucial for regulating immune function and cell growth, making Ruxolitinib potentially more effective in addressing the underlying issues of bone marrow failure. Researchers are excited because this new mechanism of action could offer hope for patients who do not respond well to current therapies, and it may provide a less invasive option compared to a transplant.

What evidence suggests that ruxolitinib might be an effective treatment for immune bone marrow failure?

Research shows that ruxolitinib, which participants in this trial may receive, may help treat immune-related bone marrow failure. In studies on severe aplastic anemia (SAA), ruxolitinib improved blood cell counts and reduced overly active immune cells. For moderate aplastic anemia (MAA), it boosted blood components like white and red blood cells. In patients with hypoplastic myelodysplastic syndrome (hMDS), some reports indicate that ruxolitinib improved symptoms when other treatments failed. It also showed promise in treating T-cell large granular lymphocyte leukemia (TLGL) by shrinking tumors and improving survival rates. For pure red cell aplasia (PRCA), early findings suggest ruxolitinib can be effective, especially in cases related to TLGL leukemia. ^{2 3 5 6 7}

Who Is on the Research Team?

Emma M Groarke, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Are You a Good Fit for This Trial?

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

Ability to understand and sign a written informed consent document

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

I have T-LGL leukemia with low blood counts.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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, 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]

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 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 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 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]

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]

Citations

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Efficacy of combined low-dose ruxolitinib and cyclosporine ... Using low-dose RUX or CsA monotherapy as controls, we found that RUX and CsA combined therapy significantly improved WBC, NEU, RBC, and PLT 2 weeks after BMF ...

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Trial in Progress: A Phase I/II Study of the JAK1/2 Inhibitor ... Use of ruxolitinib in pre-clinical data in a murine model of immune BMF achieved effective count recovery, suppressed activated T-cells, ...

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Ten years of experience with ruxolitinib since approval for ... This review covers ruxolitinib efficacy and safety data from clinical trials and real-world settings in the decade since ruxolitinib was ...

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Clinical Review - Ruxolitinib (Jakavi) - NCBI - NIH The most commonly reported TEAEs in the ruxolitinib group (ruxolitinib versus BAT) were anemia (29.1% versus 12.7%), pyrexia (15.8% versus 9.5%), increase in ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497122013076

Efficacy of JAK1/2 inhibition in murine immune bone ... Ruxolitinib prophylaxis prevents and ruxolitinib therapy treats murine immune aplastic anemia. •. Ruxolitinib inhibits T-cell infiltration ...

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf

JAKAFI (Ruxolitinib) Label - accessdata.fda.gov Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed ...

7. canjhealthtechnol.ca canjhealthtechnol.ca/index.php/cjht/article/download/SR0688r/1144?inline=1

Ruxolitinib (Jakavi) In the REACH 2 trial, as of the secondary analysis, the percentage of patients reporting at least 1 treatment-emergent adverse event (TEAE) was 99.3% in the ...