Stem Cell Transplant for Myelofibrosis
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Fred Hutchinson Cancer Research Center
Must be taking: JAK inhibitors
Disqualifiers: HIV, Pregnancy, Leukemic transformation, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This initial cohort of this phase II trial studied the outcomes of using a JAK inhibitor prior to reduced intensity haploidentical (Haplo) transplantation for the treatment of primary or secondary myelofibrosis (MF). The primary risk of using Haplo HCT in patients with MF is graft failure. In the first cohort, all patients engrafted. There were no instances of graft failure. However, a large number of patients did have graft versus host disease as a complication of their transplant. JAK inhibitors have since been approved for the indication of graft versus host disease treatment. And we are also using them for graft versus host disease prevention in a study of MF patients with sibling and unrelated donors. Therefore, we are opening a new cohort of the current study using the JAK inhibitor prior to, during and after Haplo transplant. Our goal is to decrease graft versus host disease in patients receiving a Haplo MF transplant without increasing the risk of graft failure.
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.
What data supports the effectiveness of the treatment for myelofibrosis?
Research shows that using fludarabine and melphalan as part of a reduced-intensity conditioning regimen for stem cell transplants can effectively control myelofibrosis, although it may lead to higher non-relapse mortality compared to other regimens. Both fludarabine-melphalan and fludarabine-busulfan regimens have been used successfully, with similar overall survival rates.12345
Is the combination of melphalan and fludarabine safe for use in stem cell transplants?
How is the stem cell transplant treatment for myelofibrosis using Cyclophosphamide, Fludarabine, and Melphalan different from other treatments?
This treatment is unique because it combines Cyclophosphamide, Fludarabine, and Melphalan as a conditioning regimen for stem cell transplants, which is a curative approach for myelofibrosis. The combination of these drugs is used to prepare the body for the transplant by suppressing the immune system and creating space in the bone marrow for new stem cells, offering a potentially more effective disease control compared to other regimens.2341011
Eligibility Criteria
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
See 14 more
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.
See 9 more
Trial Timeline
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
Treatment Details
Interventions
- Cyclophosphamide (Reduced Intensity Conditioning)
- Fludarabine (Reduced Intensity Conditioning)
- JAK Inhibitor (JAK Inhibitor)
- Melphalan (Reduced Intensity Conditioning)
- Tacrolimus (Immunosuppressant)
Trial OverviewThe 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.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: Cohort II (JAK inhibitor, conditioning, GVHD prophylaxis)Experimental Treatment16 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 Treatment16 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Fred Hutch/University of Washington Cancer ConsortiumSeattle, WA
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Who Is Running the Clinical Trial?
Fred Hutchinson Cancer Research CenterLead Sponsor
Fred Hutchinson Cancer CenterLead Sponsor
References
Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis. [2021]The aim of this study is to compare clinical outcomes of patients who underwent allogeneic stem cell transplantation (HCT) for myelofibrosis with reduced intensity conditioning (RIC) using either Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/ carmustine Melphalan (FBM) or Fludarabine Melphalan (FluMel) regimens. Sixty-one patients were identified who underwent HCT with one of these RIC regimens. Overall survival (OS) was not different in the 3 groups. However, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FluMel than BuFlu, in both CD3 and CD33 fractions. For instance, 100% donor chimerism in CD33 fraction was present in 100% patients in FBM cohort, 90% in FluMel cohort while 44% in BuFlu cohort at day +100. Acute graft-versus host disease, grade 2-4 and grade 3-4, was not statistically different in the 3 groups (BuFlu 47 and 35%, FBM 68 and 27%, FluMel 68 and 46%; p = 0.31 and 0.45). Relapses and non-relapse mortality was also not statistically significantly different. Our study shows similar OS with these 3 RIC regimens in myelofibrosis; although donor chimerism at day +30 and day +100 was better in patients who received FBM and FluMel.
Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis. [2018]Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens.
Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis. [2023]Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P
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. [2021]As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM).
Are new conditioning regimens for transplants in acute myelogenous leukemia better? [2019]Pretransplant conditioning regimens designed to decrease leukemia relapse and increase leukemia-free survival in allotransplants in acute myelogenous leukemia (AML) were developed recently. We review studies of new regimens containing drugs like busulfan, cytarabine, melphalan or etoposide as well as novel radiation schemes. Results are compared to those achieved with cyclophosphamide and total body radiation. Some new regimens seem inferior. Others seem to decrease relapse but do not improve leukemia-free survival because of increased deaths from causes other than leukemia. In a third group of new regimens reporting improved antileukemia efficacy and increased leukemia-free survival, results are not convincingly superior to cyclophosphamide and total body radiation. This failure to detect major improvements with new conditioning regimens may indicate the relative insensitivity of current clinical trial designs to detect improvement or the absence of an effective dose-response relationship in AML.
Current and Novel Alkylators in Multiple Myeloma. [2023]A large number of novel treatments for myeloma have been developed and approved; however, alkylating drugs continue to be part of standard regimens. Additionally, novel alkylators are currently being developed. We performed a non-systematized literary search for relevant papers and communications at large conferences, as well as exploiting the authors' knowledge of the field, to review the history, current use and novel concepts around the traditional alkylators cyclophosphamide, bendamustine and melphalan and current data on the newly developed pro-drug melflufen. Even in the era of targeted treatment and personalized medicine, alkylating drugs continue to be part of the standard-of-care in myeloma, and new alkylators are coming to the market.
In vitro and in vivo activity of melflufen (J1)in lymphoma. [2019]Melphalan has been used in the treatment of various hematologic malignancies for almost 60 years. Today it is part of standard therapy for multiple myeloma and also as part of myeloablative regimens in association with autologous allogenic stem cell transplantation. Melflufen (melphalan flufenamide ethyl ester, previously called J1) is an optimized derivative of melphalan providing targeted delivery of active metabolites to cells expressing aminopeptidases. The activity of melflufen has compared favorably with that of melphalan in a series of in vitro and in vivo experiments performed preferentially on different solid tumor models and multiple myeloma. Melflufen is currently being evaluated in a clinical phase I/II trial in relapsed or relapsed and refractory multiple myeloma.
Acute left ventricular failure following melphalan and fludarabine conditioning. [2013]Cardiotoxicity has rarely been reported as a complication of melphalan or fludarabine administration as single agents. Recently, melphalan and fludarabine have been used in combination as non-myeloablative conditioning chemotherapy prior to allogeneic stem cell transplantation. We have observed the development of severe left ventricular failure in three of 21 patients treated with this combination. Cardiotoxicity in this context has not previously been reported and has implications for the assessment, monitoring and treatment of patients undergoing pre-transplant conditioning with melphalan and fludarabine.
In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells. [2023]The alkylating agent melphalan prolongs survival in patients with multiple myeloma; however, it is associated with toxicities and development of drug-resistance. Here, we evaluated the efficacy of melphalan-flufenamide (mel-flufen), a novel dipeptide prodrug of melphalan in multiple myeloma.
Transplantation Outcomes of Myelofibrosis with Busulfan and Fludarabine Myeloablative Conditioning. [2023]Outcomes of myelofibrosis (MF) with allogeneic stem cell transplantation (allo-SCT) have improved over the past decade, related in part to advances in supportive treatments and conditioning regimens. Several factors are known to predict transplantation outcomes. However, most studies lack homogeneity in conditioning regimens used, limiting their ability to assess prognostic factors on transplantation outcomes. We aimed to identify the risk factors that predict transplantation outcomes in patients with MF who underwent matched or mismatched allo-SCT using a uniform myeloablative conditioning regimen consisting of busulfan and fludarabine with tacrolimus and methotrexate-based graft-versus-host disease prophylaxis. This single-center study included patients with MF who underwent allo-SCT with a matched unrelated donor (MUD), matched related donor (MRD), or mismatched unrelated donor (MMUD) and received busulfan and fludarabine conditioning with methotrexate/tacrolimus-based GVHD prophylaxis. Sixty-five patients with MF met the study criteria and were included in our analysis. At a median follow-up of 35.6 months, the 3-year cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and overall survival (OS) for all study patients were 27%, 20%, and 65%, respectively. In a multivariable analysis for CIR, prior use of JAK inhibitors was significantly associated with a decreased risk of relapse (hazard ratio [HR], .33; 95% confidence interval [CI], .11 to .99; P = .048). For NRM, Hematopoietic Cell Transplantation Comorbidity Index (≥3 versus 12 months versus ≤12 months: NRM: HR, 7.20; 95% CI, .96 to 53.94; P = .055; OS: HR, 2.60; 95% CI, .95 to 7.14; P = .06). In a homogenous cohort of MF patients uniformly treated with busulfan/fludarabine myeloablative conditioning and methotrexate-based GVHD prophylaxis, we show that donor choice and HCT-CI are the 2 strongest predictors for improved survival after allo-SCT.
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. [2020]Acute myeloid leukemia with myelodysplastic changes and monosomy 7 is a rare form of pediatric leukemia associated with very poor disease-free survival. The refractoriness of the disease is due to the protection offered by the bone marrow niche, making leukemic stem cells impervious to whatever chemotherapy or myeloablative regimen is chosen. Using a mobilizing agent for haematopoietic stem cells, Plerixafor, could sensitise leukemic cells to the myeloablative therapy. This approach was not previously used in a pediatric population, and in adult populations, was used in combination with busulphan with no difference in overall survival. We describe the case of a 4-year-old boy affected by refractory acute myeloid leukemia with myelodysplastic changes and monosomy 7. The child had never achieved a remission. We proposed a combined time-scheduled scheme of therapy with plerixafor and melphalan. Combining pharmacokinetics of plerixafor with pharmacokinetics and rapid and elevated myeloablative potential of melphalan in high dosage (200 mg/m²), we succeeded in mobilizing more than 85% of stem blasts immediately before infusion of Melphalan. The count of residual blasts after 8 h from melphalan infusion was only 1.3 cells/μL. The child achieved an engraftment at day +32 with full donor chimerism. Sixteen months after haematopoietic stem cell transplantation (HSCT), he is well and in complete remission. Our case suggests that the use of plerixafor before a conditioning therapy with melphalan could induce remission in acute myeloid leukemia refractory to the usual conditioning therapy in pediatric patients. This work adds strength to the body of knowledge regarding the "personalized" conditioning regimen for high-risk leukemic patients.