Stem Cell Transplant 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, Pregnancy, Leukemic transformation, 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

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to improve stem cell transplants for individuals with myelofibrosis, a bone marrow disorder, by using a JAK inhibitor to reduce complications such as graft versus host disease. The study tests a treatment plan that includes medications like cyclophosphamide, fludarabine, and melphalan, alongside stem cell infusion. It involves two groups to evaluate the effectiveness of the JAK inhibitor when administered before, during, and after the transplant. Suitable candidates have primary or secondary myelofibrosis and qualify for stem cell transplant. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must be willing to take a JAK inhibitor for at least 8 weeks before the transplant and continue it for 9-12 months after, as tolerated.

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

Research has shown that JAK inhibitors, used to treat myelofibrosis, can reduce symptoms, shrink the spleen, and improve survival rates. Most patients tolerate them well, but some may not respond to the drug or experience disease progression over time.

Studies on melphalan, a chemotherapy drug, have found it safe in high doses for preparing the body for stem cell transplants, though it can cause side effects like nausea or infections.

Fludarabine, another chemotherapy drug used in transplants, is effective but may lead to risks such as infections or low blood cell counts.

Cyclophosphamide helps prevent graft-versus-host disease, where donor cells attack the recipient's body, after transplants. It generally works well but can cause side effects like infections or low blood cell counts.

Overall, these treatments are safe for many patients, but side effects can occur. Participants should discuss any concerns with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for myelofibrosis focus on managing symptoms with drugs like ruxolitinib, a JAK inhibitor, and supportive therapies. However, researchers are excited about the stem cell transplant protocol because it aims to address the root cause of the disease by replacing unhealthy bone marrow with healthy stem cells. This treatment is distinct because it combines a JAK inhibitor with a specific conditioning regimen using melphalan and fludarabine, followed by graft-versus-host disease (GVHD) prophylaxis. This approach could potentially lead to longer-lasting remission and better overall outcomes compared to current symptom-focused therapies.

What evidence suggests that this trial's treatments could be effective for myelofibrosis?

In this trial, participants will receive different treatment regimens. Research has shown that JAK inhibitors, included in both cohorts, can reduce symptoms and spleen size in patients with myelofibrosis (MF) and may also extend patient survival. Melphalan, used in the conditioning phase, improved blood cell counts in about 67% of MF patients. Fludarabine, also part of the conditioning regimen, proved effective for MF patients receiving stem cell transplants, leading to good long-term outcomes. Cyclophosphamide, used for GVHD prophylaxis, aids in the successful acceptance of the transplant and has demonstrated promising survival rates. Overall, these treatments offer hope for effectively managing MF. ^{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 adults over 18 with primary or secondary myelofibrosis who may benefit from a stem cell transplant. They should have been on a JAK inhibitor for at least 8 weeks, have good organ function, and not be pregnant or HIV positive. Ideal candidates don't have severe liver disease, uncontrolled infections, or previous allogeneic transplants.

Inclusion Criteria

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

ABO matched donors preferred over minor ABO mismatched and major ABO mismatch donors

Ability to understand and sign a written informed consent document

Exclusion Criteria

Pregnant or trying to conceive

Platelets < 100 (caution for platelets > 50)

I have a donor who is a perfect or near-perfect match for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

JAK Inhibitor Therapy

Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation.

8 weeks

Conditioning and Transplant

Patients receive melphalan, fludarabine, and undergo total-body irradiation followed by peripheral blood stem cell infusion.

6 days

GVHD Prophylaxis

Patients receive cyclophosphamide, tacrolimus, mycophenolate mofetil, and G-CSF for GVHD prophylaxis.

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-ups between day 80-100, at 1 year, and then up to 5 years.

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• JAK Inhibitor
• Melphalan
• Tacrolimus

Trial Overview

The study tests if taking a JAK inhibitor before undergoing reduced intensity haploidentical transplantation can lower graft failure in myelofibrosis patients. It includes pre-treatment with drugs like Cyclophosphamide and Fludarabine followed by stem cell transplantation.

How Is the Trial Designed?

Group I: Cohort II (JAK inhibitor, conditioning, GVHD prophylaxis) Experimental Treatment 16 Interventions

JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. Additionally, patients receive a JAK inhibitor following transplantation beginning day 5 through 9-12 months after transplant. CONDITIONING: Patients receive melphalan IV over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo TBI on day -1 or day -1 and day 0. TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0. GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then PO for about 6 months, mycophenolate mofetil PO BID or TID beginning day 5 for 6 weeks, and G-CSF SC beginning day 7 until neutrophil recovery is \> 1,500/mm\^3. All patients undergo MRI, CT, bone marrow biopsy and aspiration and blood sample collection throughout the trial. Patients also undergo ECHO or MUGA on the trial.

Group II: Cohort I (JAK inhibitor, conditioning, GVHD prophylaxis) Experimental Treatment 16 Interventions

JAK INHIBITOR THERAPY: Patients receive a JAK inhibitor at least 8 weeks prior to the start of HCT conditioning through day -4 before transplantation. CONDITIONING: Patients receive melphalan IV over 1 hour on day -5, fludarabine IV over 30-60 minutes on days -5 to -2, and undergo TBI on day -1 or day -1 and day 0. TRANSPLANT: Patients receive peripheral blood stem cell infusion on day 0. GVHD PROPHYLAXIS: Patients then receive cyclophosphamide IV over 3 hours on days 3-4, tacrolimus IV beginning day 5 then PO for about 6 months, mycophenolate mofetil PO BID or TID beginning day 5 for 6 weeks, and G-CSF SC beginning day 7 until neutrophil recovery is \> 1,500/mm\^3. All patients undergo MRI, CT, bone marrow biopsy and aspiration and blood sample collection throughout the trial. Patients also undergo ECHO or MUGA on the trial.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

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+

Published Research Related to This Trial

In a study of 21 patients undergoing non-myeloablative conditioning chemotherapy with melphalan and fludarabine before allogeneic stem cell transplantation, three patients developed severe left ventricular failure, indicating a potential risk of cardiotoxicity with this treatment combination.

This finding is significant as cardiotoxicity from melphalan and fludarabine has not been previously reported, highlighting the need for careful assessment and monitoring of cardiac health in patients receiving this pre-transplant regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute left ventricular failure following melphalan and fludarabine conditioning. Ritchie, DS., Seymour, JF., Roberts, AW., et al.[2013]

In a study of 160 patients with myelofibrosis undergoing reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation, the fludarabine-melphalan (FM) regimen resulted in a higher incidence of acute graft-versus-host disease (62%) compared to the fludarabine-busulfan (FB) regimen (31%).

While both RIC regimens showed similar overall survival rates (52% for FM and 59% for FB), the FM regimen was associated with a significantly lower relapse rate, indicating it may provide better disease control despite a higher risk of nonrelapse mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis. Robin, M., Porcher, R., Wolschke, C., et al.[2018]

In a study of 872 adults with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (allo-HCT), the conditioning regimen of fludarabine/busulfan was associated with better overall survival and lower rates of early non-relapse mortality and acute graft-versus-host disease (GvHD) compared to fludarabine/melphalan in the reduced-intensity conditioning (RIC) group.

In the myeloablative conditioning (MAC) group, fludarabine/busulfan also showed lower rates of acute GvHD and improved graft-versus-host disease-free relapse-free survival (GRFS) compared to busulfan/cyclophosphamide, indicating it may be the preferred conditioning regimen for patients with myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis. Murthy, GSG., Kim, S., Estrada-Merly, N., et al.[2023]

In a study of 65 patients with myelofibrosis undergoing allogeneic stem cell transplantation (allo-SCT) with a uniform conditioning regimen, donor type and the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) were identified as the strongest predictors of survival outcomes.

Patients who had previously used JAK inhibitors showed a significantly decreased risk of relapse after transplantation, highlighting the potential benefit of this treatment prior to allo-SCT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplantation Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning. Joseph, J., Srour, SA., Milton, DR., et al.[2023]

In a study of 61 patients undergoing allogeneic stem cell transplantation for myelofibrosis, overall survival rates were similar across three reduced intensity conditioning regimens: Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/carmustine Melphalan (FBM), and Fludarabine Melphalan (FluMel).

Patients receiving FBM or FluMel showed significantly higher rates of 100% donor chimerism at both day +30 and day +100 compared to those receiving BuFlu, indicating better engraftment with these regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis. Jain, T., Kunze, KL., Temkit, M., et al.[2021]

Melflufen, a derivative of melphalan, demonstrated significantly higher potency against lymphoma cells compared to melphalan, with IC50 values showing up to 49-fold superiority in cell lines and an average of 108-fold in primary cultures.

In preclinical studies, melflufen showed effective cytotoxicity with minimal side effects in a xenograft model, indicating its potential as a safer and more effective treatment option for relapsed or refractory multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo activity of melflufen (J1)in lymphoma. Delforoush, M., Strese, S., Wickström, M., et al.[2019]

Alkylating drugs like cyclophosphamide, bendamustine, and melphalan remain essential components of standard treatment regimens for myeloma, even with the emergence of novel therapies.

Newly developed alkylators, such as the pro-drug melflufen, are being introduced, indicating ongoing innovation in the treatment landscape for myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current and Novel Alkylators in Multiple Myeloma. Schjesvold, F., Oriol, A.[2023]

Melphalan-flufenamide (mel-flufen) shows greater efficacy than traditional melphalan, achieving higher intracellular concentrations and lower cytotoxicity levels (IC50) in multiple myeloma cells, including those resistant to melphalan and bortezomib.

Preclinical studies indicate that mel-flufen not only inhibits tumor growth more effectively than melphalan in animal models but also enhances the effects of other treatments like lenalidomide and bortezomib, suggesting it could improve outcomes for multiple myeloma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. Chauhan, D., Ray, A., Viktorsson, K., et al.[2023]

The reduced-intensity stem-cell transplantation (RIST) regimen using fludarabine and melphalan resulted in a lower nonrelapse mortality (NRM) rate of 8% compared to 17% in the conventional stem cell transplantation (CST) group, indicating a safer option for patients.

Both RIST and CST regimens showed similar overall survival rates of 43%, suggesting that RIST can be as effective as CST while also reducing the incidence of graft-versus-host disease (GVHD) and nonrelapse mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen. Imataki, O., Ohnishi, H., Ohbayashi, Y., et al.[2021]

A 4-year-old boy with refractory acute myeloid leukemia and monosomy 7 achieved complete remission after a novel treatment combining the mobilizing agent plerixafor with high-dose melphalan, demonstrating the potential of this approach in pediatric patients.

The treatment successfully mobilized over 85% of stem blasts before melphalan infusion, leading to significant reduction in residual blasts and successful engraftment, suggesting that personalized conditioning regimens can improve outcomes for high-risk leukemia cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Remission of a Refractory Acute Myeloid Leukemia with Myelodysplastic- and Monosomy 7-Related Changes after a Combined Conditioning Regimen of Plerixafor, Cytarabine and Melphalan in a 4-Year-Old Boy: A Case Report and Review of Literature. Grasso, AG., Granzotto, M., Zanon, D., et al.[2020]

Recent studies on pretransplant conditioning regimens for acute myelogenous leukemia (AML) show mixed results, with some new regimens reducing leukemia relapse but not improving overall leukemia-free survival due to increased mortality from non-leukemia causes.

A subset of new regimens demonstrated improved antileukemia efficacy and leukemia-free survival, but their benefits were not significantly better than traditional treatments like cyclophosphamide and total body radiation, suggesting potential limitations in current clinical trial designs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Are new conditioning regimens for transplants in acute myelogenous leukemia better? Aurer, I., Gale, RP.[2019]

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This platform protocol will evaluate the safety and efficacy of post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GVHD) prophylaxis ...