Fludarabine RIC for Bone Marrow Failure Syndrome
Recruiting in Palo Alto (17 mi)
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase < 1
Recruiting
Sponsor: Children's Hospital of Philadelphia
Disqualifiers: Uncontrolled infections, Myelodysplastic syndrome, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This is a pilot study to determine whether fludarabine-based reduced intensity conditioning (RIC) regimens facilitate successful donor engraftment of patients with acquired aplastic anemia (AA) and Inherited bone marrow failure (iBMF) syndromes undergoing Matched related donor bone marrow transplant (MRD-BMT).
Do I need to stop my current medications for the trial?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.
What data supports the effectiveness of the drug Fludarabine for bone marrow failure syndrome?
Research shows that Fludarabine, when used as part of a conditioning regimen for bone marrow transplantation, has been effective in patients with Fanconi's anemia, a condition related to bone marrow failure. It has been shown to help with successful engraftment (the process where transplanted cells start to grow and make healthy blood cells) and reduce rejection without increasing toxicity.
12345Is Fludarabine generally safe for humans?
Fludarabine is generally safe at recommended doses, but it can cause myelosuppression (a decrease in bone marrow activity) and, at high doses, severe neurotoxicity (nerve damage). It has been used safely in bone marrow transplants for conditions like Fanconi's anemia, but it can also damage certain cells and increase immune responses, which may lead to complications.
13467How is the drug Fludarabine RIC unique for treating Bone Marrow Failure Syndrome?
Fludarabine RIC is unique because it uses fludarabine, a less toxic conditioning agent, which can reduce complications and improve engraftment in bone marrow transplants, especially for patients with conditions like Fanconi's anemia who are sensitive to traditional treatments.
12489Eligibility Criteria
This trial is for young people (ages 0-22) with bone marrow failure syndromes like aplastic anemia or inherited conditions causing low blood counts. They need a fully matched related bone marrow donor, good organ function, and no uncontrolled infections. Pregnant females or those without a suitable donor are excluded.Inclusion Criteria
I am 22 or younger with a rare disorder affecting my bone marrow.
I have a relative who is a perfect match for my transplant needs.
I have severe aplastic anemia confirmed by specific tests and blood counts.
+7 more
Exclusion Criteria
I do not have any untreated serious infections.
I have been diagnosed with Myelodysplastic syndrome.
I do not have a fully matched family donor for a transplant.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Conditioning
Participants receive fludarabine-based reduced intensity conditioning (RIC) regimens to facilitate donor engraftment
1-2 weeks
Transplantation
Participants undergo matched related donor bone marrow transplantation
1 day
Post-Transplant Monitoring
Participants are monitored for neutrophil engraftment and graft failure
Up to 1 year
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests if fludarabine-based reduced intensity conditioning helps patients with acquired aplastic anemia or inherited bone marrow failures successfully accept transplants from matched donors.
3Treatment groups
Experimental Treatment
Group I: Inherited Bone Marrow Failure Syndrome no Trilineage AplasiaExperimental Treatment1 Intervention
Patients with inherited bone marrow failure (iBMF) syndromes without trilineage aplasia includes those with diagnoses of Severe Congenital Neutropenia, Diamond-Blackfan Anemia, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with thymoglobulin, busulfan and fludarabine.
Group II: Inherited Bone Marrow Failure Syndrome + Trilineage AplasiaExperimental Treatment1 Intervention
Patients with inherited bone marrow failure (iBMF) syndromes with trilineage aplasia includes those with diagnoses of Fanconi Anemia, Dyskeratosis Congenita, and related conditions. Patients will receive a matched related donor bone marrow transplant following conditioning with fludarabine, cyclophosphamide, thymoglobulin.
Group III: Acquired Aplastic Anemia (AA)Experimental Treatment1 Intervention
Patients with severe or very severe acquired aplastic anemia (AA). Patients will receive a matched related donor bone marrow transplant following reduced intensity conditioning (RIC) including thymoglobulin (ATG), fludarabine and dose-reduced cyclophosphamide.
Fludarabine is already approved in European Union, United States, Canada for the following indications:
🇪🇺 Approved in European Union as Fludara for:
- Chronic lymphocytic leukemia
- Mantle-cell lymphoma
- Non-Hodgkin's lymphoma
🇺🇸 Approved in United States as Fludara for:
- Chronic lymphocytic leukemia
- Non-Hodgkin's lymphoma
- Stem Cell Transplant Conditioning
🇨🇦 Approved in Canada as Fludara for:
- Chronic lymphocytic leukemia
- Non-Hodgkin's lymphoma
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Children's Hospital of PhiladelphiaPhiladelphia, PA
Loading ...
Who Is Running the Clinical Trial?
Children's Hospital of PhiladelphiaLead Sponsor
References
Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. [2021]Fludarabine is a nonmyeloablative immunosuppressant increasingly used as a component of alternative conditioning regimens before allogeneic bone marrow transplantation. It is expected to reduce conditioning-related toxicity and proinflammatory activation of the host tissues. However, in our in vitro study, we provide evidence that 2-fluoroadenine 9-beta-D-arabinofuranoside (F-Ara) as the active metabolized form of fludarabine damages human microvascular endothelial cells (HMECs) and dermal and alveolar epithelial cell lines after 48 hours of culture when it is used in pharmacologically relevant concentrations (range, 10 microg/mL-1 microg/mL). In addition, flow cytometric analyses revealed a significant up-regulation of intercellular adhesion molecule 1 and major histocompatibility complex (MHC) class I molecules by F-Ara, suggesting a proinflammatory activation of HMECs. Cytotoxicity assays demonstrated that target HMECs pretreated with F-Ara (10 microg/mL) showed increased lysis by allogeneic MHC class I-restricted cytotoxic T lymphocytes from healthy human donors. We conclude that, beside its immunosuppressive activities, F-Ara can be harmful for target tissues of transplantation-related complications and can even stimulate allogeneic immune responses. We identified the pharmaceutical compound defibrotide as protective against F-Ara- induced apoptosis and alloactivation, importantly, without affecting the antileukemic effect of F-Ara. This observation argues for a potential clinical usage of defibrotide in pretransplantation conditioning.
Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia. [2005]A fludarabine-based protocol (fludarabine (25 mg/m(2)/day x 6 days), cyclophosphamide (10 mg/kg/day x 2 days) and ATG (ATGAM 10 mg/kg/day x 4 days)) was used in four multiply transfused Fanconi's anemia (FA) patients aged 5-15 years to reduce rejection during allogeneic bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mini methotrexate. The graft source was G-CSF-stimulated bone marrow or peripheral blood stem cells (PBSC) in two patients each. All patients engrafted with median time to ANC>500/mm(3) being 14 days (range: 12-17) and unsupported platelet count >20 ,000/mm(3) being 13 days (range: 11-18). One patient had secondary graft rejection on day 56 and expired on day 69 due to fungal pneumonia. One patient who developed acute myeloid leukemia on day 56 underwent successful induction with cytosine and daunorubicin followed by peripheral blood stem cell (PBSC) rescue on day 70 and is presently in remission with complete donor chimerism and grade I GVHD. At a median follow-up of 13 months (range: 4-21), three patients (75%) are well with complete donor chimerism. Addition of fludarabine to the conditioning regimen for BMT in FA can provide additional immunosuppression for engraftment without increasing toxicity.
Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. [2018]Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine's metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4(+) and CD8(+) cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients.
A fludarabine-based protocol for bone marrow transplantation in Fanconi's anemia. [2013]Allogeneic bone marrow transplantation (BMT) is an effective therapy for Fanconi's anemia (FA). However, mortality and transplant-related complications are usually high due to increased sensitivity to the alkylating agents and radiation commonly used for pre-transplant conditioning. Fludarabine monophosphate is a purine analogue that has been proven effective as a conditioning agent for chronic lymphocytic leukemia patients. We report a child with FA in leukemic transformation with thrombocytopenia and 20% myeloblasts who underwent successful BMT following conditioning with fludarabine/ATG/cyclophosphamide. The regimen was well tolerated, no transplant-related complications were observed, and engraftment was rapid. The child is currently 10 months post-BMT, in excellent clinical condition with a normal blood count, 100% chimerism and no sign of graft-versus-host disease (GVHD). We suggest that this fludarabine-based regimen may be effective in the conditioning of standard, as well as transforming, FA patients for BMT.
[Conditioning regimen containing fludarabine instead of cyclophosphamide for haploidentical hematopoietic stem cell transplantation]. [2013]To explore the feasibility and safety of conditioning regimen containing fludarabine (Flud) for haploidentical hematopoietic stem cell transplantation (HSCT).
Phase I study of fludarabine (2-fluoro-ara-AMP). [2019]Fludarabine phosphate is a derivative of adenosine arabinoside. The compound is an antimetabolite which resists deamination by the addition of a phosphate moiety. A phase I trial was conducted and showed the safe dose to good-risk patients to be 20 mg/m2 in 125 ml of 5% dextrose given over 30 min every 12 hr for 6 doses. The cycle can be repeated every 21 days. The major side-effect is myelosuppression, which can be severe at higher doses.
Protection against fludarabine neurotoxicity in leukemic mice by the nucleoside transport inhibitor nitrobenzylthioinosine. [2019]Fludarabine phosphate (F-ara-AMP, Fludara) is rapidly converted in the circulation to fludarabine (F-ara-A) and is among the most effective single agents in the treatment of chronic lymphocytic leukemia. Although current treatment protocols are well tolerated, severe neurotoxicity was a consequence of high-dose F-ara-AMP regimens used in early phase I trials against adult acute leukemia. The present study showed that in mice implanted with leukemia L1210, fatal neurotoxicity, which initially manifested as hind-limb paralysis, was a consequence of high-dose F-ara-AMP treatment. However, the incidence of neurotoxicity was reduced by the coadministration of NBMPR-P, the 5'-phosphate of nitrobenzylthioinosine, a potent inhibitor of the es equilibrative nucleoside transport (NT) system. NBTGR-P, the 5'-phosphate of nitrobenzylthioguanosine (also a potent NT inhibitor) similarly prevented F-ara-AMP neurotoxicity in this experimental system. Treatment with F-ara-AMP/NBMPR-P combinations was more effective with respect to the fractional yield of "cured" mice than were the same treatment regimens without NBMPR-P.
Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. [2015]Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are 2 widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (allo-SCT).
Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience. [2023]Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine-total body irradiation (TBI) with fludarabine among patients with hematologic diseases.