Immune Suppression Treatment for Sickle Cell Disease
Recruiting in Palo Alto (17 mi)
+5 other locations
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Memorial Sloan Kettering Cancer Center
Disqualifiers: HIV, Active hepatitis B or C, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?
Hematopoietic Cell Transplantation/HCT involves receiving healthy blood-forming cells (stem cells) from a donor to replace the diseased or damaged cells in participants' bone marrow. The researchers think giving participants treatment with fludarabine and dexamethasone, drugs that lower the activity of the body's immune system (immune suppression), before standard conditioning therapy and HCT may help prevent serious side effects, including graft failure and GvHD. In this study, depending on how participants' body responds to the fludarabine and dexamethasone, the study doctor may decide participants should receive another drug, called cyclophosphamide, instead of fludarabine. In addition, depending on the results of participants' routine blood tests, participants may receive the drugs bortezomib and rituximab, which also help with immune suppression.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study doctor to get a clear answer based on your specific situation.
What data supports the effectiveness of the drug dexamethasone for sickle cell disease?
Is dexamethasone generally safe for use in humans?
Dexamethasone has been shown to be effective in treating childhood acute lymphoblastic leukemia, but it is associated with higher risks of certain side effects like neuro-psychiatric issues and muscle weakness. It can also increase liver toxicity when used with methotrexate in children with brain tumors.678910
How does the drug combination of Cyclophosphamide and Dexamethasone for sickle cell disease differ from other treatments?
This drug combination is unique because Cyclophosphamide is an immunosuppressant that selectively targets T cells, which can help manage immune-related complications, while Dexamethasone is a steroid that reduces inflammation. This approach may offer a novel way to address the immune system's role in sickle cell disease, which is not typically the focus of standard treatments.1112131415
Eligibility Criteria
This trial is for people aged 12-35 with sickle cell disease or β-thalassemia who need a stem cell transplant. They must have had certain complications like stroke, organ damage, or frequent pain episodes and agree to use contraception. Excluded are those over age 50, with recent strokes, uncontrolled infections, liver issues, HIV/hepatitis B/C, pregnancy, obesity (BMI >40), prior transplants or other cancers.Inclusion Criteria
ALT or AST ≤ 3 times institutional upper limit of normal.
I have had 2 or more episodes of prolonged erections in the last 2 years.
I am mostly active and can care for myself.
See 24 more
Exclusion Criteria
HIV positive
I have had a bone marrow transplant from a donor.
I have not had a stroke or brain surgery in the last 6 months.
See 9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Pre-Transplant Immune Suppression
Participants receive immune suppression treatment with fludarabine and dexamethasone, and possibly cyclophosphamide, bortezomib, and rituximab based on response and blood tests
4-6 weeks
Hematopoietic Cell Transplantation (HCT)
Participants undergo hematopoietic cell transplantation to replace diseased or damaged cells
1 week
Follow-up
Participants are monitored for safety and effectiveness after transplantation, focusing on treatment-related mortality and graft failure
1 year
Treatment Details
Interventions
- Bortezomib (Proteasome Inhibitor)
- Cyclophosphamide (Alkylating agents)
- Dexamethasone (Corticosteroid)
- Fludarabine (Antimetabolites)
- Rituximab (Monoclonal Antibodies)
- Tacrolimus (Immunosuppressant)
Trial OverviewThe study tests if immune suppression drugs like fludarabine and dexamethasone before standard therapy can prevent graft failure and GvHD in patients receiving stem cell transplants. Other drugs may be added based on blood test results to improve immune suppression.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Participants with Sickle Cell Disease or β-ThalassemiaExperimental Treatment8 Interventions
Participants will have severe sickle cell disease or transfusion-dependent β-thalassemia.
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:
Memorial Sloan Kettering Suffolk - Commack (Consent only)Commack, NY
Memorial Sloan Kettering at Basking Ridge (Consent only)Basking Ridge, NJ
Memorial Sloan Kettering Bergen (Consent only)Montvale, NJ
Memorial Sloan Kettering Westchester (Consent only)Harrison, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Memorial Sloan Kettering Cancer CenterLead Sponsor
References
High doses of dexamethasone in adult patients with idiopathic thrombocytopenic purpura. [2019]High-dose dexamethasone (DXM) has been used in treatment of patients with idiopathic thrombocytopenic purpura (ITP) who are refractory to other treatments such as prednisone and splenectomy; nevertheless, different studies show variable success rates, this postulated as possibly being due to racial differences. The objective of this study was to determine DXM effectiveness at high doses in Mexican mestizo adult patients diagnosed with ITP with and without splenectomy.
High-dose intravenous methylprednisolone therapy for patients with Diamond-Blackfan anemia refractory to conventional doses of prednisone. [2019]To assess the efficacy and toxicity of very high doses of glucocorticoids in patients with congenital pure red cell aplasia (Diamond-Blackfan anemia) who did not respond to standard doses of prednisone.
Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. [2022]Acute chest syndrome (ACS) in patients with sickle cell disease (SCD) has historically been managed with oxygen, antibiotics, and blood transfusions. Recently high-dose corticosteroid therapy was shown to reduce the duration of hospitalization in children with SCD and vaso-occlusive crisis. Therefore, we chose to assess the use of glucocorticoids in ACS. We conducted a randomized, double-blind placebo-controlled trial to evaluate the efficacy and toxicity of intravenous dexamethasone (0.3 mg/kg every 12 hours x 4 doses) in children with SCD hospitalized with mild to moderately severe ACS. Forty-three evaluable episodes of ACS occurred in 38 children (median age, 6.7 years). Twenty-two patients received dexamethasone and 21 patients received placebo. There were no statistically significant differences in demographic, clinical, or laboratory characteristics between the two groups. Mean hospital stay was shorter in the dexamethasone-treated group (47 hours v 80 hours; P = .005). Dexamethasone therapy prevented clinical deterioration and reduced the need for blood transfusions (P
Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura. [2019]The effectiveness of pulsed high-dose oral dexamethasone therapy in children with refractory chronic idiopathic thrombocytopenic purpura (ITP) is evaluated.
Pulsed high-dose dexamethasone in chronic autoimmune haemolytic anaemia of warm type. [2019]The management of patients with autoimmune haemolytic anaemia of warm type (AIHA) is often problematic. Recently, pulsed high-dose dexamethasone (HDD) has been shown to be effective in the treatment of autoimmune thrombocytopenic purpura (AITP). In this study we treated seven patients with AIHA with HDD. The regimen recommended for treatment of refractory AITP (40 mg dexamethasone for 4 d at the beginning of each 28 d cycle) was employed in almost all cases. Prior to dexamethasone administration, haemolysis was decompensated in all seven patients. HDD was well tolerated and led to an improvement of haemolysis in all cases.
Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. [2018]This systematic review and meta-analysis compared the efficacy and toxicity of dexamethasone (DEX) versus prednisone (PRED) for induction therapy in childhood acute lymphoblastic leukemia (ALL). We searched biomedical literature databases and conference proceedings for randomized controlled trials comparing DEX and PRED during induction therapy for childhood ALL. A total of eight studies were eligible for inclusion in this meta-analysis. DEX, in comparison with PRED, reduced events (that is, death from any cause, refractory or relapsed leukemia, or second malignancy; risk ratio (RR) 0.80; 95% confidence interval (CI), 0.68-0.94) and central nervous system relapse (RR 0.53; 95% CI, 0.44-0.65), but did not alter bone marrow relapse (RR 0.90; 95% CI, 0.69-1.18) or overall mortality (RR 0.91; 95% CI, 0.76-1.09). Patients receiving DEX had a higher risk of mortality during induction (RR 2.31; 95% CI, 1.46-3.66), neuro-psychiatric adverse events (RR 4.55; 95% CI, 2.45-8.46) and myopathy (RR 7.05; 95% CI, 3.00-16.58). There was no statistically significant difference in the risk of osteonecrosis, sepsis, fungal infection, diabetes or pancreatitis. DEX in induction therapy for children with ALL is more efficacious than PRED. However, DEX is also associated with more toxicity, and currently it remains unclear whether short-term superiority of DEX will also result in better overall survival.
Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. [2021]Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse.
Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia? [2019]Corticosteroids are essential and one of the mainstays in the treatment of acute lymphoblastic leukemia (ALL). In vitro assays show that dexamethasone(DXM) is five to six times more cytotoxic to leukemic lymphoblasts than prednisolone (PDN) [1], and the use of DXM as an alternative drug for PDN is an important issue in the treatment of childhood ALL. The current randomized comparisons in childhood ALL indicated a statistically significant and clinically important decrease in rate of isolated central nervous system (CNS) relapses and an increase in event-free survival (EFS) with DXM. However, the data were limited in adult ALL. Recently, Labar et al. [2] reported their first investigation in comparison of the antileukemic activity and toxicity between DXM and PDN for adult patients with ALL and lymphoblastic lymphoma (LBL) through a randomized clinical trial (the ALL-4 trial of the EORTC Leukemia Group), and the author concluded that DXM as a steroid therapy for adult patients with ALL/LBL did not show any benefit compared with PDN, which did not support the experience from several other pediatric studies. In Labar’s observation, about 70% of adult patients were high risk (HR) ALL. Most of the patients in pediatric trials were standard risk (SR) ALL. In our study, we also evaluate the role of DXM compared with PDN during induction or subsequent phases of therapy in adult ALL with emphasis on SR group.
Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. [2022]To summarise and review the best available evidence on the poorer outcome of adverse drug reactions (ADRs) induced by oral dexamethasone in adolescents with Acute Lymphoblastic Leukaemia (ALL) than in children with ALL.
Dexamethasone increases hepatotoxicity of MTX in children with brain tumors. [2013]In the treatment of children with brain tumors, dexamethasone and methotrexate are often utilized simultaneously. As previously shown, dexamethasone can reduce the efficacy of methotrexate in vitro (Anticancer Res. 14: 1585-8). Consequently, DEX has been avoided during high dose methotrexate infusions in a pilot study.
The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. [2018]Cyclophosphamide is an alkylating agent belonging to the group of oxazaphosporines. As cyclophosphamide is in clinical use for more than 40 years, there is a lot of experience using this drug for the treatment of cancer and as an immunosuppressive agent for the treatment of autoimmune and immune-mediated diseases. Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer. However, cyclophosphamide can also increase the number of myeloid-derived suppressor cells. Combination of cyclophosphamide with other immunomodulatory agents could be a promising approach to treat different forms of advanced cancer.
[Restorative effect of traxanox on the suppression of antibody production in BALB/c mice]. [2019]The number of spleen-rosette forming cells (RFC) and thymus-RFC was assayed on day 4 after immunization with 5 X 10(8) sheep red blood cells (SRBC) in BALB/c mice. The number was decreased significantly by oral administration of cyclophosphamide (20 mg/kg) on days--1 and 0. The decrease in spleen-RFC and thymus-RFC by the pretreatment with cyclophosphamide was significantly restored or had a tendency to be restored by traxanox at doses of 3 and 30 mg/kg (p.o.). In addition, traxanox (30 mg/kg, p.o.) protected the reduced number of RFC in mice treated with cyclophosphamide (3 mg/kg, p.o.). Traxanox (30 mg/kg, p.o.) restored the decreased number of spleen-RFC and thymus-RFC in mice pretreated with dexamethasone (0.1 mg/kg, p.o.), and protected the decrease in the RFC in mice treated with prednisolone (10 mg/kg, p.o.). Also, phagocytosis of SRBC by the spleen adherent cells obtained from mice treated with dexamethasone (0.1 mg/kg, p.o.) was inhibited markedly in comparison with that by the spleen adherent cells of untreated mice. The transfer of the spleen adherent cells treated with dexamethasone into syngeneic recipient mice had no effect on the number of spleen hemolytic plaque forming cells (HPFC). On the other hand, the inhibition of phagocytosis of SRBC by spleen adherent cells of mice pretreated with dexamethasone was restored by the addition of traxanox (10 and 30 microM). The transfer of the spleen adherent cells treated with traxanox resulted in an increase in HPFC number. Traxanox (30 mg/kg, p.o.) protected the decrease in spleen-RFC and thymus-RFC in mice treated with indomethacin 1 mg/kg, p.o.) or acetylsalicylic acid (300 mg/kg, p.o.). Traxanox (3-30 mg/kg, p.o.) restored the decreased number of HPFC, spleen-RFC and thymus-RFC in mice pretreated with carrageenan (0.03 mg). The suppression of phagocytosis of SRBC by spleen adherent cells was restored by the treatment with traxanox (3 and 30 microM). The transfer of the spleen adherent cells treated with traxanox also resulted in an increase in HPFC count. These results strongly suggest that traxanox restores the artificially suppressed immune responses via macrophages.
[Antitumor and immunodepressive action of dexamethasone on a leukemia L-1210 model]. [2013]The effect of single administration of dexamethason in doses of 10, 20, 50 and 100 mg/kg on the spleen content of lymphomic colonies, normal colony-forming units and antibody-forming cells was studied in experiments on CBA and DBA/2 mice with transplanted leukemia L-1210. It has bear dependence on the dosage, the immunodepressant action of the drug being more pronounced in CBA mice as compared to DBA/2 mice with leukemia L-1210. The immunodepressant activity of dexamethason is approximately equal to the antineoplasic one. Single administration of the drug has practically no effect on hemopoiesis.
Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. [2020]Cyclophosphamide is an alkylating agent used to treat malignancies and immune-mediated inflammatory non-malignant processes such as lupus nephritis and immune-mediated neuropathies. It has been studied as a treatment for multiple sclerosis (MS) for the past 30 years and is used by physicians in selected cases of progressive or worsening MS. Review of published reports suggests that it is efficacious in cases of worsening MS that have an inflammatory component as evidenced by relapses and/or gadolinium (Gd)-enhancing lesions on magnetic resonance imaging (MRI) or in patients in earlier stages of disease where inflammation predominates over degenerative processes in the central nervous system (CNS). There is no evidence of efficacy in primary progressive MS or later stages of secondary progressive MS. Although a general immunosuppressant that affects both T- and B-cell function, cyclophosphamide has selective immune effects in MS by suppressing IL-12 and Th1-type responses and enhancing Th2/Th3 responses (IL-4, IL-10, TGF-beta; eosinophils in peripheral blood). Side effects include nausea, alopecia, infertility, bladder toxicity and risk of malignancy. The most commonly used regimens involve every 4- to 8-week outpatient i.v. pulse therapy given with or without corticosteroids and are usually well-tolerated by patients. Cyclophosphamide is currently used in patients whose disease is not controlled by beta-interferon or glatiramer acetate and those with rapidly worsening MS.
Cyclosporin A inhibits thymus-dependent but not thymus-independent immune responses induced by dextran B512. [2019]We have compared previous studies of the immune response to dextran (Dx) B512 in thymus-deficient nu/nu and thymectomized, lethally irradiated, and bone marrow-reconstituted mice with those obtained with cyclosporin A (CyA) as a T-cell-inhibiting drug. Our data show that only immune responses to TD forms of Dx B512 are susceptible to suppression by CyA, whereas anti-alpha 1-6 and anti-DNP antibodies induced by high molecular weight dextran and DNP-native Dx, respectively, were not inhibited. Similar results were obtained when polyclonal responses were studied. The polyclonal response induced by another dextran preparation, the polyanion dextran sulphate (DxS), was inhibited by CyA to the same extent as polyclonal T-cell activation by T-cell mitogens.