Ruxolitinib for Large Granular Lymphocytic Leukemia

Recruiting at 2 trial locations

Overseen By Lily Yang

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Jonathan Brammer

Must not be taking: Antimicrobials, Immunosuppressants

Disqualifiers: Active infection, HIV, Hepatitis, 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: 12 months

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests ruxolitinib, a drug designed to shrink tumors in patients with T-cell large granular lymphocyte leukemia by blocking enzymes that promote cancer cell growth. The goal is to determine if ruxolitinib can effectively halt the progression of this specific leukemia type. Individuals diagnosed with T-LGLL who experience severe anemia or frequent infections might be suitable candidates. Participants must have tried at least one other treatment without success and be able to swallow pills. As a Phase 2 trial, this research measures ruxolitinib's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Do I have to stop taking my current medications for the trial?

Yes, you must stop taking your current medications for at least 14 days or 5 half-lives, whichever is longer, before starting the trial. However, if you are on stable, chronic prednisone (10 mg or less) for rheumatologic/autoimmune conditions, you may continue it.

Is there any evidence suggesting that ruxolitinib is likely to be safe for humans?

Research has shown that ruxolitinib is generally well-tolerated. In studies involving patients with large granular lymphocyte leukemia, most responded well to the treatment. Evidence suggests it is safe, even for those at high risk.

While some side effects might occur, they are usually manageable. Since this trial is in Phase 2, earlier phases have already tested ruxolitinib, demonstrating some safety in humans. However, as with any treatment, individual experiences may vary. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Ruxolitinib is unique because it targets the JAK-STAT pathway, which is crucial for the survival and proliferation of abnormal large granular lymphocytes in Large Granular Lymphocytic Leukemia. Unlike standard treatments that often involve immunosuppressive therapy or chemotherapy, ruxolitinib specifically inhibits the JAK1 and JAK2 enzymes, offering a more targeted approach. Researchers are excited about ruxolitinib because it has the potential to provide a more effective and less toxic treatment option, potentially improving outcomes and quality of life for patients with this rare condition.

What evidence suggests that ruxolitinib might be an effective treatment for large granular lymphocytic leukemia?

Research has shown that ruxolitinib, the treatment under study in this trial, can help treat T-cell large granular lymphocyte leukemia. Studies have found that patients using ruxolitinib experienced longer periods without cancer progression. Ruxolitinib blocks certain enzymes that cancer cells need to grow, potentially reducing tumor size. It may also address bone marrow issues common in leukemia. Overall, these findings suggest that ruxolitinib could be a promising treatment option for this condition. ^{1 2 3 6 7}

Who Is on the Research Team?

Jonathan E. Brammer, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults with T-cell large granular lymphocyte leukemia (T-LGLL) who have tried at least one treatment without success and are not currently on therapy. They must have symptoms like low hemoglobin, need regular blood transfusions, or suffer from frequent infections due to low neutrophil counts. Their liver and kidney functions should be near normal, they can't be pregnant, and must agree to use birth control.

Inclusion Criteria

I have symptoms of anemia with low hemoglobin levels.

I have low white blood cell counts and get infections often.

I can perform daily activities with minimal assistance.

Exclusion Criteria

My kidney function is severely reduced.

I have not had a heart attack or unstable chest pain in the last 2 months.

Platelet count < 50,000/uL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ruxolitinib orally twice daily on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants who achieve a response (CR or PR) may receive an additional 12 months of ruxolitinib, for a maximum of 24 months.

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Ruxolitinib

Trial Overview The trial is testing Ruxolitinib's effectiveness in shrinking tumors for patients with T-LGLL. It's a phase II study where the drug aims to inhibit enzymes that cancer cells need to grow.

How Is the Trial Designed?

Group I: Treatment (ruxolitinib) Experimental Treatment 1 Intervention

Patients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days for 12 months in the absence of disease progression or unacceptable toxicity. Patients who achieve a response (CR or PR) may receive an additional 12 months of ruxolitinib, for a maximum of 24 months.

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?

Jonathan Brammer

Lead Sponsor

Trials

2

Recruited

60+

John Reneau

Lead Sponsor

Trials

4

Recruited

90+

Ohio State University Comprehensive Cancer Center

Lead Sponsor

Trials

350

Recruited

295,000+

Published Research Related to This Trial

A study analyzing 126,815 safety reports found that the JAK inhibitors ruxolitinib, tofacitinib, and baricitinib are associated with increased risks of infectious adverse events, particularly viral, fungal, and mycobacterial infections.

Tofacitinib specifically showed a significant association with gastrointestinal perforation events, while no significant increase in major cardiovascular events was observed, indicating a need for careful monitoring of these risks in patients using JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. Hoisnard, L., Lebrun-Vignes, B., Maury, S., et al.[2023]

In a phase I clinical trial involving 20 patients with chronic myelomonocytic leukemia (CMML), ruxolitinib was found to be safe, with no dose-limiting toxicities and only one case of grade 3 thrombocytopenia, indicating a favorable safety profile for this treatment.

Ruxolitinib demonstrated promising efficacy, with a total response rate of 35% and significant improvements in symptoms and spleen size, particularly benefiting patients with disease-related symptoms, suggesting it warrants further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML). Padron, E., Dezern, A., Andrade-Campos, M., et al.[2021]

A 67-year-old woman with rheumatoid arthritis developed neutropenia and recurrent infections, leading to a diagnosis of large granular lymphocytic (LGL) leukemia, highlighting the potential link between autoimmune diseases and this type of leukemia.

The treatment involved an anti-TNF therapy and rituximab, suggesting that these therapies may be effective in managing LGL leukemia in patients with underlying autoimmune conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis and associated large granular lymphocytic leukemia--successful treatment with rituximab. Raposo, A., Cerqueira, M., Costa, J., et al.[2018]

A patient developed T-cell large granular lymphocytic (LGL) leukemia two years after successfully achieving remission from acute myeloblastic leukemia, indicating a potential risk of secondary malignancies following treatment for acute leukemia.

This case highlights the importance of long-term monitoring for patients who have undergone treatment for acute myeloblastic leukemia, as they may be at risk for developing other lymphoproliferative disorders like LGL leukemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnosis of large granular lymphocytic leukemia in a patient previously treated for acute myeloblastic leukemia. Bozdag, SC., Namdaroglu, S., Kayikci, O., et al.[2021]

Large Granular Lymphocyte Leukemia (LGLL) is a rare disorder that often requires treatment due to severe anemia or neutropenia in about 50% of cases, highlighting the need for effective management strategies.

Current treatments with immunosuppressive agents have a cumulative response rate of approximately 60%, but refractory cases necessitate further research into targeted therapies to improve outcomes for patients with severe symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease. Zawit, M., Bahaj, W., Gurnari, C., et al.[2021]

Large granular lymphocytic leukemia (LGLL) has a favorable prognosis with a median overall survival of over 10 years, but its management is complicated due to limited prospective studies and a lack of established treatment guidelines.

For asymptomatic patients, a 'watch and wait' approach is recommended, while immunomodulators like methotrexate and cyclophosphamide show response rates of 50-65%, and newer therapies targeting the JAK/STAT pathway are promising for relapsed cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Large granular lymphocytic leukemia. Current diagnostic and therapeutic approaches and novel treatment options. Matutes, E.[2017]

A 72-year-old man with myelofibrosis developed symptoms of meningitis, including fever and cognitive impairment, just 14 days after starting treatment with ruxolitinib, suggesting a potential link between the drug and JC virus meningitis.

The diagnosis was supported by positive JC virus PCR in the cerebrospinal fluid (CSF) and MRI findings, indicating that ruxolitinib may increase the risk of serious viral infections like JC virus meningitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fatal ruxolitinib-related JC virus meningitis. Ballesta, B., González, H., Martín, V., et al.[2021]

In a study of 8 pediatric B-ALL cases, the JAK inhibitor ruxolitinib significantly reduced peripheral and splenic blast counts, especially in samples with JAK-activating mutations, indicating its potential efficacy in treating high-risk Ph-like acute lymphoblastic leukemia.

The mTOR inhibitor rapamycin effectively controlled leukemia burden in all samples and significantly prolonged survival in xenograft models, suggesting it could be a valuable treatment option for this aggressive leukemia subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. Maude, SL., Tasian, SK., Vincent, T., et al.[2022]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, was approved by the FDA for treating steroid-refractory acute graft-versus-host disease (GVHD) based on promising results from the Phase II REACH1 trial.

The drug shows potential not only for treating SR acute GVHD but also for preventing GVHD and possibly serving as a first-line therapy, highlighting its versatility in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of graft-versus-host disease. Ali, H., Salhotra, A., Modi, B., et al.[2021]

Ruxolitinib is a well-absorbed tyrosine kinase inhibitor with 95% bioavailability, primarily metabolized in the liver, and its pharmacokinetics can vary based on factors like gender and body weight.

The drug's effectiveness can be influenced by liver and renal function, necessitating dose adjustments, and while model-informed precision dosing could enhance treatment personalization, more research is needed before it can be routinely implemented.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. Appeldoorn, TYJ., Munnink, THO., Morsink, LM., et al.[2023]

In a study of 204 patients with large granular lymphocytic leukemia (LGLL) followed for a median of 36 months, initial treatment responses to methotrexate, cyclosporine, and cyclophosphamide were similar, ranging from 40-50%.

Patients with STAT3 mutations had a higher need for therapy but also experienced better overall survival, while methotrexate provided the most durable responses among the treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). Sanikommu, SR., Clemente, MJ., Chomczynski, P., et al.[2022]

Ruxolitinib, a Janus kinase inhibitor, showed promising efficacy in treating Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL), with 7 out of 12 patients achieving complete remission and 2 achieving partial remission after treatment.

The study highlights the potential of targeting the JAK-STAT signaling pathway in Ph-like ALL patients, particularly those with specific gene fusions affecting JAK2 and EPOR, suggesting that ruxolitinib could be a valuable addition to standard therapy for this high-risk leukemia subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. Kołodrubiec, J., Kozłowska, M., Irga-Jaworska, N., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38639192/

Efficacy of ruxolitinib in the treatment of relapsed/refractory ... This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia.

2. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/10.1111/bjh.19476

Efficacy of ruxolitinib in the treatment of relapsed/refractory ... Outcomes of large granular lymphocytic leukaemia patients treated with ruxolitinib. (A) Progression-free survival. (B) Overall survival ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05592015

NCT05592015 | Ruxolitinib for the Treatment of T-Cell ... This phase II trial tests whether ruxolitinib works to shrink tumors in patients with T-cell large granular lymphocyte leukemia. Ruxolitinib may stop the growth ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497123047870

Ruxolitinib Promotes Clinical Responses in Large Granular ... Ruxolitinib may interrupt JAK/STAT-dependent paracrine inflammatory signals that promote bone marrow suppression.

5. ovid.com ovid.com/journals/bjha/pdf/10.1111/bjh.19476~efficacy-of-ruxolitinib-in-the-treatment-of

Efficacy of ruxolitinib in the treatment of relapsed/refractory ... FIGURE 3 Outcomes of large granular lymphocytic leukaemia patients treated with ruxolitinib. ... A phase II clinical trial evaluating ruxolitinib ...

6. ash.confex.com ash.confex.com/ash/2023/webprogram/Paper190752.html

Evaluation of Safety and Efficacy of Ruxolitinib in Patients ... Ruxolitinib was well-tolerated in this high risk population, and was associated with positive responses in the majority of patients.

7. sciencedirect.com sciencedirect.com/science/article/pii/S0006497124015672

A modern view of LGL leukemia The efficacy of ruxolitinib was recently confirmed in a prospective phase 2 clinical trial. ... A phase 1/2 trial assessing the safety and ...