Ruxolitinib for Large Granular Lymphocytic Leukemia

Recruiting at 2 trial locations

Overseen By Lily Yang

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Jonathan Brammer

Must not be taking: Antimicrobials, Immunosuppressants

Disqualifiers: Active infection, HIV, Hepatitis, others

No Placebo Group

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial tests if ruxolitinib can shrink tumors in patients with a specific type of leukemia called T-cell large granular lymphocyte leukemia. Ruxolitinib works by blocking enzymes that cancer cells need to grow. The goal is to see if this medication can help these patients when other treatments might not work. Ruxolitinib is an oral medication used to treat myelofibrosis and polycythemia vera, but its effects in these conditions are uncertain.

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.

What data supports the idea that Ruxolitinib for Large Granular Lymphocytic Leukemia is an effective treatment?

The available research does not provide specific data on the effectiveness of Ruxolitinib for Large Granular Lymphocytic Leukemia. Instead, it highlights other treatments like methotrexate, cyclosporine, and cyclophosphamide, which show response rates of 40-65%. These treatments are commonly used and have shown effectiveness in managing the condition. There is mention of JAK-3 inhibitors, which are similar to Ruxolitinib, as promising in relapse settings, but no specific data on Ruxolitinib itself is provided. ^{1 2 3 4 5}

What safety data is available for Ruxolitinib?

Ruxolitinib, a JAK1/JAK2 inhibitor, has been associated with several adverse events based on data from the WHO pharmacovigilance database. These include infectious events (especially viral, fungal, and mycobacterial infections), musculoskeletal disorders, embolism and thrombosis, and malignant skin neoplasms. A case of fatal JC virus meningitis has also been reported. However, no significant increase in major cardiovascular events was found. Ruxolitinib has been used in various conditions, including myelofibrosis, polycythemia vera, graft-versus-host disease, and acute lymphoblastic leukemia, with varying efficacy and safety profiles. ^{6 7 8 9 10}

Is the drug Ruxolitinib a promising treatment for Large Granular Lymphocytic Leukemia?

Ruxolitinib shows promise as a treatment because it effectively targets specific pathways involved in certain types of leukemia, leading to remission in some cases. It has been successful in treating other blood-related conditions, suggesting it could be beneficial for Large Granular Lymphocytic Leukemia as well. ^{7 8 9 11 12}

Research Team

Jonathan E. Brammer, MD

Principal Investigator

Ohio State University Comprehensive Cancer Center

Eligibility Criteria

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.

Platelet count < 50,000/uL

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

Trial Timeline

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

Treatment Details

Interventions

• Ruxolitinib (Janus Kinase (JAK) Inhibitor)

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.

Participant Groups

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.

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+

Findings from Research

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]

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]

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 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 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]

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, 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]

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 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 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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Diagnosis of large granular lymphocytic leukemia in a patient previously treated for acute myeloblastic leukemia. [2021]

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

Clinical features and treatment outcomes in large granular lymphocytic leukemia (LGLL). [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Large Granular Lymphocytic Leukemia: From Immunopathogenesis to Treatment of Refractory Disease. [2021]

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

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

5. Portugal pubmed.ncbi.nlm.nih.gov

Rheumatoid arthritis and associated large granular lymphocytic leukemia--successful treatment with rituximab. [2018]

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

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. [2023]

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

Ruxolitinib for the treatment of graft-versus-host disease. [2021]

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

Efficacy of ruxolitinib in acute lymphoblastic leukemia: A systematic review. [2022]

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

A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML). [2021]

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

Fatal ruxolitinib-related JC virus meningitis. [2021]

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

Targeting JAK1/2 and mTOR in murine xenograft models of Ph-like acute lymphoblastic leukemia. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review. [2023]