Stem Cell Transplant for Severe Aplastic Anemia
Palo Alto (17 mi)Overseen byRichard W Childs, M.D.
Age: Any Age
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?Background:
Severe aplastic anemia (SAA), and myelodysplastic syndrome (MDS), and paroxysmal nocturnal hemoglobinuria
(PNH) cause serious blood problems. Stem cell transplants using bone marrow or blood plus chemotherapy can help. Researchers want to see if using peripheral blood stem cells (PBSCs) rather than bone marrow cells works too. PBSCs are easier to collect and have more cells that help transplants.
Objectives:
To see how safely and effectively SAA, MDS and PNH are treated using peripheral blood hematopoietic stem cells from a family member plus chemotherapy.
Eligibility:
Recipients ages 4-60 with SAA, MDS or PNH and their relative donors ages 4-75
Design:
Recipients will have:
* Blood, urine, heart, and lung tests
* Scans
* Bone marrow sample
Recipients will need a caregiver for several months. They may make fertility plans and a power of attorney.
Donors will have blood and tissue tests, then injections to boost stem cells for 5-7 days.
Donors will have blood collected from a tube in an arm or leg vein. A machine will separate stem cells and maybe white blood cells. The rest of the blood will be returned into the other arm or leg.
In the hospital for about 1 month, recipients will have:
* Central line inserted in the neck or chest
* Medicines for side effects
* Chemotherapy over 8 days and radiation 1 time
* Stem cell transplant over 4 hours
Up to 6 months after transplant, recipients will stay near NIH for weekly physical exams and blood tests.
At day 180, recipients will go home. They will have tests at their doctor s office and NIH several times over 5 years.
Is the drug Cyclophosphamide a promising treatment for severe aplastic anemia?Yes, Cyclophosphamide is a promising treatment for severe aplastic anemia. Studies show high survival rates and successful recovery in many patients, even without bone marrow transplantation. It has been effective in restoring normal blood cell production and preventing relapses.13689
What data supports the idea that Stem Cell Transplant for Severe Aplastic Anemia is an effective treatment?The available research shows that Stem Cell Transplant for Severe Aplastic Anemia is effective, especially when using post-transplantation cyclophosphamide (PTCy). In one study, 85% of patients survived two years after receiving this treatment, and all surviving patients no longer needed blood transfusions. Another study found that using high-dose cyclophosphamide without a transplant led to complete recovery in 7 out of 10 patients, with no relapses over a long follow-up period. These results suggest that this treatment can be more effective than traditional immunosuppressive therapies, which often have incomplete recoveries and higher chances of relapse.36789
What safety data exists for stem cell transplant in severe aplastic anemia?Safety data for stem cell transplant in severe aplastic anemia includes studies on high-dose cyclophosphamide (Cytoxan) used for conditioning patients. Animal studies have shown dose-limiting toxicities, with cardiac toxicity being a concern at higher doses. In humans, patients with severe aplastic anemia conditioned with cyclophosphamide followed by allogeneic marrow transplantation have a long-term survival rate of about 80% if done before transfusion. A study on 67 patients treated with high-dose cyclophosphamide reported a 10-year overall survival rate of 88% for treatment-naive patients, indicating it is a highly effective therapy. However, patients with refractory SAA had lower survival rates. The treatment is associated with risks such as pancytopenia and gastrointestinal toxicity, but it allows for successful engraftment and recovery.12456
Do I need to stop my current medications for the trial?The trial protocol does not specify if you need to stop taking your current medications. However, since the trial involves chemotherapy and a stem cell transplant, it's possible that some medications may need to be adjusted. Please consult with the trial coordinators for specific guidance.
Eligibility Criteria
This trial is for people aged 4-55 with severe aplastic anemia, myelodysplastic syndrome (MDS), or paroxysmal nocturnal hemoglobinuria (PNH) who haven't responded to standard treatments. They need a family member donor aged 4-75. Participants must understand the study and consent; minors will need guardian consent. Exclusions include certain heart, liver, kidney issues, active infections not responding to treatment, HIV positive individuals, pregnant women or those not using birth control.Inclusion Criteria
I have been diagnosed with severe aplastic anemia.
I don't have antibodies against the donor's tissue markers.
My PNH does not respond to eculizumab/ravulizumab or I can't access this treatment.
My severe aplastic anemia has turned into MDS.
I have a severe bone marrow condition and standard treatments haven't worked for me.
I have a family member who can donate stem cells and is a partial HLA match.
I am between the ages of 4 and 55.
Exclusion Criteria
I have an infection that isn't getting better with treatment.
I have a family member who is a near-perfect match for a stem cell donation.
I have been diagnosed with Fanconi's anemia.
My heart's pumping ability is significantly reduced.
I do not have any major illnesses or organ failures that would prevent me from surviving a transplant.
I am eligible for a stem cell transplant from a fully matched donor.
I need some help with my daily activities.
I am not pregnant and willing to use birth control or abstain for a year.
My kidney function is reduced, with a creatinine clearance rate below 50.
Treatment Details
The trial tests if peripheral blood stem cells from a relative plus chemotherapy can treat SAA, MDS and PNH effectively and safely. Patients undergo extensive testing before receiving chemo and radiation followed by the stem cell transplant in hospital for about a month with follow-up visits over five years.
1Treatment groups
Experimental Treatment
Group I: Treatment ArmExperimental Treatment2 Interventions
G-CSF mobilized peripheral stem cells and post haplo-identical transplantation cyclophosphamide
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:
National Institutes of Health Clinical CenterBethesda, MD
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Who is running the clinical trial?
National Heart, Lung, and Blood Institute (NHLBI)Lead Sponsor
References
High-dose therapy and bone marrow transplantation. [2018]Toxicity to the bone marrow is a frequent limiting factor in the use of high doses of chemotherapeutic agents. Bone marrow transplantation overcomes the marrow toxicity problem, but it is not protective to other organs. Extensive animal studies have been carried out in the mouse, the rat, rhesus monkeys, and dogs to delineate the dose-limiting toxicity of cyclophosphamide (Cytoxan) (CY) therapy. Studies in the dog have shown 100 mg/kg of CY to be lethal with supportive care alone. Dogs given this dose followed by stored autologous marrow recovered after a period of profound pancytopenia and severe gastrointestinal toxicity. This dose of CY also permitted allogeneic engraftment in the dog. Monkeys given up to 200 mg/kg of CY have uneventful hematopoietic recovery, but doses of 240 mg/kg were generally fatal even when stored autologous marrow was infused. Cardiac toxicity was the limiting factor. CY 180 mg/kg was not lethal and permitted successful allogeneic marrow engraftment. CY is successfully used for conditioning leukemia or aplastic anemia patients for bone marrow transplantation. Patients with severe aplastic anemia are conditioned with CY 50 mg/kg on each of four days followed by allogeneic marrow transplantation. Patients undergoing transplantation before transfusion have a long-term survival rate of about 80%. Patients with genetic disorders of the marrow generally have a normocellular or hypercellular marrow, and the preparative regimen must include destruction of the abnormal marrow as well as immunosuppression sufficient to permit engraftment. Patients with thalassemia are treated with dimethylbusulfan 5 mg/kg or busulfan 14 mg/kg followed by CY 50 mg/kg on each of four days. Approximately 100 thalassemia patients have been treated, with a survival rate of approximately 75%. For patients with leukemia, radiotherapy is generally added to the CY conditioning regimen. In the early Seattle studies, 1,000 rad total body irradiation was combined with CY 60 mg/kg on each of two days. There were many early deaths, but some long-term survivors are alive and well 5 to 13 years later. Current regimens involve fractionated total body irradiation and various post-grafting immunosuppressive regimens designed to prevent graft-v-host disease. Complications and problems of current regimens are discussed, and future goals for marrow transplantation are presented.
Effects of in vitro purging with 4-hydroperoxycyclophosphamide on the hematopoietic and microenvironmental elements of human bone marrow. [2021]We describe the effects of 4-hydroperoxycyclophosphamide (4-HC) on the hematopoietic and stromal elements of human bone marrow. Marrow cells were exposed to 4-HC and then assayed for mixed (CFU-Mix), erythroid (BFU-E), granulomonocytic (CFU-GM), and marrow fibroblast (CFU-F) colony-forming cells and studied in the long-term marrow culture (LTMC) system. The inhibition of colony formation by 4-HC was dose and cell-concentration dependent. The cell most sensitive to 4-HC was CFU-Mix (ID50 31 mumol/L) followed by BFU-E (ID50 41 mumol/L), CFU-GM (ID50 89 mumol/L), and CFU-F (ID50 235 mumol/L). In LTMC, a dose-related inhibition of CFU-GM production was noted. Marrows treated with 300 mumol/L 4-HC were completely depleted of CFU-GM but were able to generate these progenitors in LTMC. Marrow stromal progenitors giving rise to stromal layers in LTMC, although less sensitive to 4-HC cytotoxicity, were damaged by 4-HC also in a dose-related manner. Marrows treated with 4-HC up to 300 mumol/L, gave rise to stromal layers composed of fibroblasts, endothelial cells, adipocytes, and macrophages. Cocultivation experiments with freshly isolated autologous hematopoietic cells showed that stromal layers derived from 4-HC-treated marrows were capable of sustaining the long-term production of CFU-GM as well as controls.
Complete remission in severe aplastic anemia after high-dose cyclophosphamide without bone marrow transplantation. [2021]Severe aplastic anemia (SAA) can be successfully treated with allogeneic bone marrow transplantation (BMT) or immunosuppressive therapy. However, the majority of patients with SAA are not eligible for BMT because they lack an HLA-identical sibling. Conventional immunosuppressive therapy also has major limitations; many of its remissions are incomplete and relapse or secondary clonal disease is common. Cyclophosphamide is a potent immunosuppressive agent that is used in all BMT conditioning regimens for patients with SAA. Preliminary evidence suggested that high-dose cyclophosphamide, even without BMT, may be beneficial to patients with SAA. Therefore, 10 patients with SAA and lacking an HLA-identical sibling were treated with high-dose cyclophosphamide (45 mg/kg/d) for 4 consecutive days with or without cyclosporine. A complete response (hemoglobin level, > 13 g/dL; absolute neutrophil count, > 1.5 x 10(9)/L, and platelet count > 125 x 10(9)/L) was achieved in 7 of the 10 patients. One of the complete responders died from the acquired immunodeficiency syndrome 44 months after treatment with high-dose cyclophosphamide. The 6 remaining patients are alive and in continuous complete remission, with a median follow-up of 10.8 years (range, 7.3 to 17.8 years). The median time to last platelet transfusion and time to 0.5 x 10(9) neutrophils/L were 85 and 95 days, respectively. None of the complete responders has relapsed or developed a clonal disease. These results suggest that high-dose cyclophosphamide, even without BMT, may be more effective than conventional immunosuppressive therapy in restoring normal hematopoiesis and preventing relapse or secondary clonal disorders. Hence, further studies confirming the efficacy of this approach in SAA are indicated.
A phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood hematopoietic progenitor cells. [2013]Fourteen patients with stage II-IV breast cancer were enrolled in a phase II study of cyclophosphamide followed by PIXY321 as a means of mobilizing peripheral blood progenitor cells (PBPC). All 14 women tolerated PIXY321 well, with the predominant toxicities being erythema at the injection site, fever, and arthralgias. A median of two aphereses yielded a mean of 1.3 x 10(8) mononuclear cells/kg, 8.9 x 10(4) colony-forming units-granulocyte/macrophage (CFU-GM)/kg, and 4.5 x 10(6) CD34+ cells/kg. All 14 patients underwent high-dose chemotherapy with PBPC support, the median day to ANC >500 cells/microliter was 10.6, and the median day to platelets >20,000 cells/microliter was 13. The day of 90th percentile platelet recovery was 15. When compared to PBPCs mobilized by cyclophosphamide followed by GM-CSF, the use of PIXY321 may confer an advantage of enhanced platelet recovery.
Advances in mobilization for the optimization of autologous stem cell transplantation. [2021]In autologous stem cell transplantation, mobilized peripheral blood has replaced the bone marrow as the preferred source of hematopoietic stem cells (HSCs). Because HSCs normally exist in the blood in very low numbers, the use of agents to "mobilize" HSCs from the marrow niche to the peripheral blood is essential for successful transplantation. Until recently, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor were the only approved agents by the US Food and Drug Administration for use as peripheral blood stem cell (PBSC)-mobilizing agents in the United States, but G-CSF has become the gold standard. Unfortunately, some patients fail to mobilize sufficient numbers of PBSCs for transplantation in response to G-CSF with or without chemotherapy. Recently, a new agent, plerixafor (AMD3100) added to G-CSF has been approved to enhance PBSC mobilization. This review will discuss the current methodologies to improve hematopoietic stem cell mobilization.
High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. [2021]Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder that can be treated with bone marrow transplantation, immunosuppressive therapy, and high-dose cyclophosphamide. Here, we report long-term follow-up on 67 SAA patients (44 treatment-naive and 23 refractory) treated with high-dose cyclophosphamide. At 10 years, the overall actuarial survival was 88%, the response rate was 71% with the majority being complete, and the actuarial event-free survival was 58% in 44 treatment-naive SAA patients. Patients with refractory SAA fared less well after high-dose cyclophosphamide therapy; at 10 years, overall actuarial survival, response, and actuarial event-free survival rates were 62%, 48%, and 27%, respectively. High-dose cyclophosphamide is highly effective therapy for severe aplastic anemia. Large randomized controlled trials will be necessary to establish how results of high-dose cyclophosphamide compare with either bone marrow transplantation or standard immunosuppressive regimens, such as antithymocyte globulin and cyclosporine.
High-dose Cyclophosphamide is Effective Therapy for Pediatric Severe Aplastic Anemia. [2019]Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression.
A Case Series of Post-Transplantation Cyclophosphamide in Unrelated Donor Hematopoietic Cell Transplantation for Aplastic Anemia. [2021]Patients with severe aplastic anemia (SAA) who fail immunosuppressive therapy have a dismal prognosis. Hematopoietic stem cell transplantation (HSCT) from an unrelated donor (URD) is one of the most effective treatment options. Two institutions have independently adopted a post-transplantation cyclophosphamide (PTCy) approach for patients with SAA undergoing HSCT from a URD. Thirteen patients were included, 11 of whom had been treated with immunosuppressive therapy. Eight patients had a mismatched URD. All patients were conditioned with fludarabine, cyclophosphamide, and total body irradiation, in various dosage combinations. PTCy was given at a dose of 100 mg/kg. Two patients died, and overall survival was 85% at 2 years. All patients engrafted, but 1 patient developed secondary graft failure. Of the 11 patients alive after 2 years, 9 had complete donor chimerism. All surviving patients were transfusion-independent. Ten patients (77%) had cytomegalovirus reactivation, and 2 patients had more than 1 reactivation. No Epstein-Barr virus reactivation or post-transplantation lymphoproliferative disease was observed. Four patients had mild hemorrhagic cystitis. In summary, our findings show that PTCy is a promising treatment for patients with SAA undergoing URD HSCT.
Alternative Transplantation With Post-Transplantation Cyclophosphamide in Aplastic Anemia: A Retrospective Report From the BMF-WG of Hunan Province, China. [2023]Although the possibility of first-line hematopoietic cell transplantation (HCT) from alternative donors in severe aplastic anemia (SAA) patients has been suggested recently, transplantation strategies are still being investigated. We established a novel post-transplantation cyclophosphamide-based HCT protocol for patients with SAA in prior studies. We explores the effectiveness and safety of this HCT approach either as first-line or as salvage treatment in SAA patients. Outcomes of 71 consecutive young patients, who received HCT from unrelated or haploidentical donors, were retrospectively analyzed. According to their treatment before transplantation, the patients were classified into treatment-naive (TN) and relapsed or refractory (R/R) patients. The R/R patients were designated as such when a patient did not respond to previous immunosuppressive therapy or relapsed. We administered an antithymocyte globulin (ATG)-free, total body irradiation (TBI)-free conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine, all in an intravenous formula. We used a thorough post-transplantation prophylaxis regimen for GVHD, including post-transplantation cyclophosphamide (PTCy) and short-term methotrexate and long-term cyclosporine A. The median age of the cohort was 16 (95% confidence interval, 12-20) years at transplantation. Most patients (61 of 71) received HCT from haploidentical donors, and the others received HCT from unrelated donors. TN patients (n = 38) were younger and had a shorter time-to-transplant and lower HCT-specific comorbidity index than patients with R/R diseases (n = 33). The frequencies of graft failure, grade II-IV acute graft-versus-host disease (GVHD), and moderate-severe chronic GVHD were similar, at 5.3% versus 6.5% (P = .057), 8.3% versus 0% (P = .109), and 5.7% versus 0% (P = .199) between R/R and TN patients. With a median 42-month follow-up, the frequencies of overall survival (OS) and event-free survival (EFS) were higher in the TN group than in the R/R group (100% versus 84.8% [P = .013] and 86.8% versus 75.8% [P = .255], respectively). All patients who achieved successful engraftment showed full donor chimerism. Four patients, all in the R/R group, suffered from donor-type aplasia; of these, 2 died, 1 was salvaged with another transplantation, and the final one was still receiving transfusion at the last follow-up. Currently, 93.9% (62 of 66) of the patients are alive more than 12 months after transplantation; of these 93.5% (58 of 62) no longer receive immunosuppression, including 91.7% (33 of 34) of the TN group and 89.3% (25 of 28) in the R/R group. This novel TBI-free and ATG-free HCT protocol using a reduced-intensity conditioning regimen followed by modified PTCy achieved promising engraftment, minimal GVHD risk, and encouraging OS and EFS. Our study suggests that unrelated or haploidentical HCT with PTCy can be used as a first-line treatment for young patients with SAA. Nevertheless, further efforts are needed to explore possibilities for older patients and patients with a poor performance status.