Pre-Transplant JAK Inhibitor for Myelofibrosis

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if taking a JAK inhibitor, a medication that blocks certain enzymes to slow abnormal cell growth, before a stem cell transplant can improve treatment outcomes for people with myelofibrosis. Myelofibrosis, a rare bone marrow disorder, can cause severe symptoms like spleen enlargement and fatigue. The trial tests whether starting the JAK inhibitor ruxolitinib before the transplant can reduce these symptoms and lead to better overall results. Suitable participants have myelofibrosis and are preparing for a stem cell transplant with a matched donor. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, potentially improving outcomes before wider use.

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.

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

Research has shown that ruxolitinib, a type of medication, is generally well-tolerated by people with myelofibrosis, a bone marrow disorder. Studies have identified anemia (a low red blood cell count) and thrombocytopenia (a low platelet count) as the most common side effects. These side effects did not worsen with long-term use. One study found that, even after nearly three years, 78% of patients using ruxolitinib were still alive, indicating a favorable safety profile. A blood test is recommended before starting the medication to monitor any potential changes in blood cell levels. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for myelofibrosis?

Researchers are excited about using ruxolitinib before allogeneic hematopoietic stem cell transplantation to treat myelofibrosis because it targets a specific pathway involved in the disease. Unlike traditional treatments that primarily focus on managing symptoms, ruxolitinib inhibits the JAK2 enzyme, which plays a crucial role in the abnormal blood cell production seen in myelofibrosis. By addressing the root cause, this approach offers the potential for more effective disease management and improved patient outcomes. Additionally, combining ruxolitinib with stem cell transplantation may enhance the overall effectiveness of the transplant, offering a promising new strategy for patients.

What evidence suggests that this treatment might be an effective treatment for myelofibrosis?

Research shows that using a medication called ruxolitinib before a stem cell transplant can help people with myelofibrosis. In this trial, participants will receive ruxolitinib before undergoing a stem cell transplant. Studies have found that patients taking ruxolitinib had better survival rates, with one study reporting a 61% survival rate two years after treatment. Another study found that using ruxolitinib before and after the transplant lowered the risk of graft-versus-host disease, where donor cells attack the patient's body, and improved transplant success. Additionally, ruxolitinib has reduced spleen size and improved physical abilities in patients before the transplant. These findings suggest that ruxolitinib could make the transplant process easier and more successful for people with myelofibrosis. ^{6 7 8 9 10}

Who Is on the Research Team?

Rachel B. Salit

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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

My kidney function, measured by creatinine clearance, is good.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/OA-25-00020

Phase II Study of Peri- and Post-Transplant Ruxolitinib for ... With a median follow-up of 27 months (range 1-64), 1-year GRFS was 71%. Overall survival (OS), progression-free survival, and cumulative ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11482566/

Improved Outcomes in Myelofibrosis after Allogeneic Stem ... Our data show that outcomes for patients transplanted in a more recent era have improved notably, with a 3-year PFS of 57.7% for the entire ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01790295

Ruxolitinib Prior to Transplant in Patients With Myelofibrosis This study plans to evaluate whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size, improve physical performance levels ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5030817/

Outcomes of Allogeneic Hematopoietic Cell Transplantation in ... Overall survival (OS) at two years was 61% (95%CI, 49–71). This was 91% (95% CI, 69–98) for those who experienced clinical improvement, and 32% (95% CI, 8–59) ...

5. ajmc.com ajmc.com/view/in-myelofibrosis-ruxolitinib-before-and-after-allo-hsct-may-improve-success-rate

In Myelofibrosis, Ruxolitinib Before and After Allo-HSCT ... Ruxolitinib given to patients with myelofibrosis before and after stem cell transplant cuts the risk of graft-vs-host disease and may boost the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4380721/

Efficacy, safety, and survival with ruxolitinib in patients with ... Ruxolitinib continued to be generally well tolerated; there was no pattern of worsening grade ≥3 anemia or thrombocytopenia with longer-term ruxolitinib ...

7. jhoonline.biomedcentral.com jhoonline.biomedcentral.com/articles/10.1186/s13045-023-01471-z

Ten years of treatment with ruxolitinib for myelofibrosis Cytopenias, in particular anemia and thrombocytopenia, are the most frequent adverse events (AEs) with ruxolitinib in patients with MF (Table 1) ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12490404/

Long-term safety and effectiveness of ruxolitinib in patients ... At Week 144 (Day 1008), the Kaplan – Meier estimated overall survival rate was 78% in the ruxolitinib arm, 61% in the intent-to-treat control ...

9. hcp.jakafi.com hcp.jakafi.com/myelofibrosis/safety

Safety Profile in Intermediate or High-Risk Myelofibrosis (MF) Jakafi® (ruxolitinib) adverse reactions · The most frequently observed adverse reactions were thrombocytopenia and anemia · Perform a pretreatment CBC, and ...

10. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.6573

Efficacy and safety of ruxolitinib in patients with lower risk ... By week 48, 26 (65.0%) patients achieved a ≥ 50% decrease in palpable spleen length. 32 (80.0%) patients achieved a ≥ 50% reduction from ...