Pre-Transplant JAK Inhibitor for Myelofibrosis

Recruiting in Seattle (>99 mi)

Overseen By Rachel B. Salit

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must be taking: JAK inhibitors

Disqualifiers: HIV, Uncontrolled infections, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

61 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well giving a JAK inhibitor before a donor stem cell transplant works in treating patients with myelofibrosis that developed without another condition (primary) or evolved from other bone marrow disorders (secondary). JAK inhibitors are a class of drugs that may stop the growth of abnormal cells by blocking an enzyme needed for cell growth. Giving a JAK inhibitor such as ruxolitinib before a donor stem cell transplant may help reduce symptoms of myelofibrosis such as inflammation and enlargement of the spleen, improve the patient's general physical condition, and prevent complications from occurring after the transplant. Infusing healthy stem cells from a donor into the patient may help the patient's bone marrow work normally and make stem cells, red blood cells, white blood cells, and platelets. Giving a JAK inhibitor before a donor stem cell transplant may help improve transplant outcomes in patients with myelofibrosis.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, it does require that participants have been on the JAK inhibitor ruxolitinib for at least 8 weeks before the transplant and continue it until 4 days before the transplant.

What data supports the effectiveness of the treatment Allogeneic Hematopoietic Stem Cell Transplantation with Ruxolitinib for Myelofibrosis?

Research shows that using ruxolitinib (a drug that reduces inflammation and spleen size) before stem cell transplantation can improve outcomes for myelofibrosis patients. It helps reduce symptoms and may improve survival rates, especially when a matched sibling donor is available for the transplant. ^{1 2 3 4 5}

Is the pre-transplant use of JAK inhibitors like Ruxolitinib safe for myelofibrosis patients?

Ruxolitinib, a JAK inhibitor, is generally used to reduce symptoms in myelofibrosis patients, but its safety around the time of stem cell transplantation is not fully understood. Some patients experience side effects like cytokine storm (a severe immune reaction) when stopping the drug, and there is limited data on long-term safety. More studies are needed to better understand its safety and optimal use in this setting. ^{1 2 3 5 6}

How does the drug ruxolitinib differ from other treatments for myelofibrosis?

Ruxolitinib is unique because it is a JAK1/2 inhibitor that helps reduce symptoms like splenomegaly (enlarged spleen) and improves overall condition before a stem cell transplant, which is the only curative option for myelofibrosis. Its use in the period around transplantation may improve outcomes by reducing inflammation and symptoms, although its long-term effects and optimal use in this setting are still being studied. ^{1 2 3 5 7}

Research Team

Rachel B. Salit

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for patients with primary or secondary myelofibrosis, a type of bone marrow cancer. Participants should have certain risk levels by DIPSS scores, good physical function (Karnofsky >= 70), adequate kidney and liver function, no severe lung issues, and not be on supplemental oxygen. They must understand the study and consent to participate. Pregnant or breastfeeding individuals, those with HIV or uncontrolled infections, prior transplants are excluded.

Inclusion Criteria

My condition is considered intermediate-1, intermediate-2, or high-risk.

Meeting criteria for 1st phase as above, at time of initiation of JAK inhibitor, including ability to understand and willingness to sign a written informed consent; patients arriving to our institution for transplant and not enrolled in Part 1 may still be enrolled in Part 2 if Part 1 criteria met; these patients will have Part 1 endpoints transcribed from medical records

I have been diagnosed with primary or secondary myelofibrosis according to specific medical guidelines.

Exclusion Criteria

I don't have a closely matched donor for a transplant.

I have had a fungal infection in the past 6 months without seeing an infectious disease specialist.

I am HIV positive.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

JAK Inhibitor Treatment

Participants receive ruxolitinib orally twice daily from at least 8 weeks prior to the start of conditioning through day -4 before transplantation, with a taper schedule reducing the dose every 2-3 days beginning after day -4.

8 weeks

Conditioning

Patients are assigned to either myeloablative or reduced-intensity conditioning regimens before transplant.

8 days

Transplant

Patients undergo allogeneic hematopoietic stem cell transplant or umbilical cord blood transplant on day 0.

1 day

GVHD Prophylaxis

Patients receive GVHD prophylaxis with tacrolimus, methotrexate, or mycophenolate mofetil depending on the type of transplant.

Up to 180 days

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-ups at 6 months, 1 year, and then yearly for 4 years.

5 years

Treatment Details

Interventions

• Allogeneic Hematopoietic Stem Cell Transplantation
• Ruxolitinib

Trial Overview The trial tests if taking a JAK inhibitor drug called ruxolitinib before receiving stem cells from a donor can improve outcomes for myelofibrosis patients. The treatment aims to reduce symptoms like spleen enlargement and help the new stem cells work better in producing healthy blood cells after transplant.

Participant Groups

Group I: Treatment (ruxolitinib, transplant) Experimental Treatment 12 Interventions

Patients receive a ruxolitinib and undergo myeloablative or reduced-intensity conditioning followed by transplant and GVHD prophylaxis; see detailed description.

Allogeneic Hematopoietic Stem Cell Transplantation is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in United States as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in Canada as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Approved in Japan as Allogeneic Hematopoietic Stem Cell Transplantation for:

• Primary immunodeficiency disorders
• Immune dysregulatory disorders
• Hemophagocytic lymphohistiocytosis
• Bone marrow failure syndromes
• Hemoglobinopathies

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

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, a JAK 1/2 inhibitor, has shown benefits in treating myelofibrosis by reducing spleen size and improving symptoms, but its use around the time of hematopoietic stem cell transplantation (HCT) poses challenges such as unpredictable responses and potential cytokine storms upon discontinuation.

There is a need for more research to establish the best timing and protocols for using JAK inhibitors like ruxolitinib in HCT settings to improve patient outcomes, including engraftment and survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How we manage JAK inhibition in allogeneic transplantation for myelofibrosis. Ballinger, TJ., Savani, BN., Gupta, V., et al.[2015]

Allogeneic hematopoietic stem-cell transplantation (HSCT) is still the only curative treatment for myelofibrosis, and its use has increased due to better patient selection and advancements in donor matching and supportive care.

The approval of the JAK inhibitor ruxolitinib has raised important questions about its role in the transplant setting, particularly regarding its use before transplantation and how it may affect patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic stem-cell transplantation for myelofibrosis. Lavi, N., Rowe, JM., Zuckerman, T.[2021]

In a phase 2 trial involving 76 myelofibrosis patients, a short course of ruxolitinib before transplantation led to a high transplantation rate of 92%, with 31% achieving a partial response prior to the procedure.

One-year disease-free survival (DFS) after transplantation was 55%, with significantly better outcomes for patients receiving HLA-matched sibling donor transplants (83% DFS) compared to those with unrelated donors (40% for HLA-matched and 34% for mismatched).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups. Robin, M., Porcher, R., Orvain, C., et al.[2022]

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, 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]

Allogeneic stem cell transplantation (allo-SCT) is currently the only curative treatment for myelofibrosis (MF), but many patients are ineligible due to age and poor health.

Ruxolitinib, the first JAK inhibitor approved for advanced MF, improves symptoms and spleen size but does not significantly alter the disease's progression, highlighting the need for further research on its effects during the peritransplant period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era? Tamari, R., Mughal, TI., Rondelli, D., et al.[2021]

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. England pubmed.ncbi.nlm.nih.gov

How we manage JAK inhibition in allogeneic transplantation for myelofibrosis. [2015]

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

Allogeneic stem-cell transplantation for myelofibrosis. [2021]

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

Ruxolitinib before allogeneic hematopoietic transplantation in patients with myelofibrosis on behalf SFGM-TC and FIM groups. [2022]

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

Peritransplantation Use of Ruxolitinib in Myelofibrosis. [2021]

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

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era? [2021]