Immune Suppression Treatment for Sickle Cell Disease

Recruiting at 5 trial locations

Overseen By Jaap Jan Boelens, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Disqualifiers: HIV, Active hepatitis B or C, 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

24 Participants Needed

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?

Research shows that high-dose dexamethasone can shorten hospital stays and reduce the need for blood transfusions in children with sickle cell disease experiencing acute chest syndrome, a common complication. ^{1 2 3 4 5}

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. ^{6 7 8 9 10}

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. ^{11 12 13 14 15}

Research Team

Maria Cancio, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

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.

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.

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
• Cyclophosphamide
• Dexamethasone
• Fludarabine
• Rituximab
• Tacrolimus

Trial Overview The 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

Group I: Participants with Sickle Cell Disease or β-Thalassemia Experimental Treatment 8 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

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

High-dose dexamethasone (DXM) treatment was found to be effective in achieving a favorable response in both splenectomized and non-splenectomized Mexican mestizo patients with idiopathic thrombocytopenic purpura (ITP), with 9 out of 19 patients responding positively after six treatment cycles.

However, the duration of the favorable response was short, with only four patients maintaining their response after six months, suggesting that additional treatment strategies may be necessary for longer-term remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High doses of dexamethasone in adult patients with idiopathic thrombocytopenic purpura. Gutiérrez-Espíndola, GR., Morales-Polanco, MR., Guerrero-Rivera, S., et al.[2019]

In a study of eight patients with Diamond-Blackfan anemia who did not respond to standard prednisone doses, very high doses of methylprednisolone (up to 100 mg/kg per day) led to sustained remission in three patients for over 21 months.

While the treatment showed efficacy, it also resulted in significant toxic effects, including elevated liver enzymes and episodes of bacteremia, highlighting the need for careful monitoring during high-dose glucocorticoid therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose intravenous methylprednisolone therapy for patients with Diamond-Blackfan anemia refractory to conventional doses of prednisone. Bernini, JC., Carrillo, JM., Buchanan, GR.[2019]

In a randomized trial involving 38 children with sickle cell disease and acute chest syndrome, intravenous dexamethasone significantly reduced the average hospital stay from 80 hours to 47 hours, indicating its efficacy in managing this condition.

Dexamethasone treatment also decreased the need for blood transfusions and reduced the duration of oxygen and analgesic therapy, with no significant side effects observed, suggesting it is a safe and effective option for treating acute chest syndrome in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. Bernini, JC., Rogers, ZR., Sandler, ES., et al.[2022]

In a study of seven children aged 5 to 16 with refractory chronic idiopathic thrombocytopenic purpura (ITP), pulsed high-dose oral dexamethasone therapy showed partial responses in 43% of patients after the first treatment cycle, but only 29% achieved complete responses by the end of the sixth cycle.

The long-term effectiveness was limited, as only one patient (14%) maintained a partial response one year after completing the therapy, indicating that this treatment may not be consistently effective in children with chronic ITP compared to adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura. Chen, JS., Wu, JM., Chen, YJ., et al.[2019]

In a study involving seven patients with autoimmune haemolytic anaemia (AIHA), pulsed high-dose dexamethasone (HDD) was well tolerated and effectively improved symptoms of haemolysis in all participants.

The treatment regimen, adapted from successful protocols for autoimmune thrombocytopenic purpura, involved administering 40 mg of dexamethasone for 4 days at the start of each 28-day cycle, demonstrating its potential as a viable option for managing AIHA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulsed high-dose dexamethasone in chronic autoimmune haemolytic anaemia of warm type. Meyer, O., Stahl, D., Beckhove, P., et al.[2019]

Dexamethasone (DEX) is more effective than prednisone (PRED) in reducing the risk of serious events in children with acute lymphoblastic leukemia (ALL), including central nervous system relapse, based on a meta-analysis of eight studies.

However, DEX is associated with a higher risk of severe side effects, such as increased mortality during induction therapy and neuro-psychiatric issues, raising concerns about its overall safety despite its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Teuffel, O., Kuster, SP., Hunger, SP., et al.[2018]

In a randomized trial involving over 1000 children with standard-risk acute lymphoblastic leukemia (ALL), dexamethasone was found to significantly reduce the risk of central nervous system relapses compared to prednisone, with a 6-year relapse rate of 3.7% versus 7.1%.

The study also showed that dexamethasone improved event-free survival rates at 6 years (85%) compared to prednisone (77%), indicating that dexamethasone may be a more effective treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Bostrom, BC., Sensel, MR., Sather, HN., et al.[2021]

Dexamethasone (DXM) is significantly more effective than prednisolone (PDN) in treating acute lymphoblastic leukemia (ALL), showing better cytotoxicity in vitro and leading to lower rates of central nervous system relapses and improved event-free survival in children.

A recent trial indicated that DXM did not provide additional benefits over PDN in adult ALL patients, particularly those at high risk, suggesting that the effectiveness of DXM may vary significantly between pediatric and adult populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia? Zheng, C., Liu, X., Wu, J., et al.[2019]

Adolescents with Acute Lymphoblastic Leukaemia (ALL) experience more severe adverse drug reactions (ADRs) from oral dexamethasone compared to younger children, with higher incidences of issues like hyperglycemia, infections, and thrombosis, based on a review of 11 studies.

The increased severity of ADRs in adolescents may be linked to age-related differences in how dexamethasone is processed in the body and the effects of puberty, highlighting the need for healthcare professionals to closely monitor this age group during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. Hu, L., Kim Emily, AN., Juh Allen, YE.[2022]

In a study comparing 33 children treated with methotrexate and dexamethasone to 24 children treated with methotrexate alone, no serious brain edema or differences in bone marrow toxicity or mucositis were observed, indicating that the combination is not more harmful in those respects.

However, liver enzyme levels were significantly higher in the group receiving dexamethasone, suggesting increased hepatotoxicity, which supports the recommendation to eliminate dexamethasone from high-dose methotrexate treatment protocols for children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dexamethasone increases hepatotoxicity of MTX in children with brain tumors. Wolff, JE., Hauch, H., Kühl, J., et al.[2013]

Cyclophosphamide, a well-established drug for over 40 years, has both antitumor and immunosuppressive properties, making it useful in cancer treatment and autoimmune diseases.

Low-dose cyclophosphamide selectively suppresses regulatory T cells, which can help counteract immunosuppression in cancer, suggesting that combining it with other immunomodulatory agents may enhance treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Ahlmann, M., Hempel, G.[2018]

Oral administration of traxanox significantly restored the number of spleen and thymus rosette forming cells (RFC) that were decreased by cyclophosphamide and other immunosuppressive treatments in BALB/c mice, indicating its potential as an immune response enhancer.

Traxanox not only protected against the reduction of immune cells caused by various drugs but also improved phagocytosis and increased hemolytic plaque forming cells (HPFC), suggesting it may help restore immune function suppressed by medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Restorative effect of traxanox on the suppression of antibody production in BALB/c mice]. Hisadome, M., Goto, K., Kadobe, Y., et al.[2019]

Dexamethasone exhibits dose-dependent immunosuppressive effects in mice with transplanted leukemia, with a stronger effect observed in CBA mice compared to DBA/2 mice.

The immunosuppressive activity of dexamethasone is comparable to its anti-cancer effects, while a single dose does not significantly impact blood cell production (hemopoiesis).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Antitumor and immunodepressive action of dexamethasone on a leukemia L-1210 model]. Berezina, TA., Uteshev, BS., Babichev, VS.[2013]

Cyclophosphamide is effective for treating worsening multiple sclerosis (MS) with inflammatory components, particularly in earlier stages of the disease, but shows no efficacy in primary progressive MS or late-stage secondary progressive MS.

While it has immunosuppressive effects, cyclophosphamide selectively alters immune responses in MS, enhancing certain protective responses while having potential side effects like nausea and risk of malignancy; it is typically administered as outpatient therapy every 4 to 8 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. Weiner, HL., Cohen, JA.[2020]

In a study comparing immune responses in different mouse models, it was found that cyclosporin A (CyA) effectively suppresses immune responses to thymus-dependent (TD) forms of dextran (Dx) B512, but not to other forms of dextran or DNP-native Dx.

The research indicates that while CyA inhibits T-cell activation in response to certain dextran preparations, it does not affect all types of dextran-induced antibody responses, suggesting a selective mechanism of action for CyA in modulating immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporin A inhibits thymus-dependent but not thymus-independent immune responses induced by dextran B512. Fernandez, C., Palacios, R., Möller, G.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

High doses of dexamethasone in adult patients with idiopathic thrombocytopenic purpura. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

High-dose intravenous methylprednisolone therapy for patients with Diamond-Blackfan anemia refractory to conventional doses of prednisone. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Beneficial effect of intravenous dexamethasone in children with mild to moderately severe acute chest syndrome complicating sickle cell disease. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Pulsed high-dose dexamethasone therapy in children with chronic idiopathic thrombocytopenic purpura. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Pulsed high-dose dexamethasone in chronic autoimmune haemolytic anaemia of warm type. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

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]

8. United States pubmed.ncbi.nlm.nih.gov

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia? [2019]

9. Australia pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

Dexamethasone increases hepatotoxicity of MTX in children with brain tumors. [2013]

11. Germany pubmed.ncbi.nlm.nih.gov

The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. [2018]

12. Japan pubmed.ncbi.nlm.nih.gov

[Restorative effect of traxanox on the suppression of antibody production in BALB/c mice]. [2019]

13. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Antitumor and immunodepressive action of dexamethasone on a leukemia L-1210 model]. [2013]

14. England pubmed.ncbi.nlm.nih.gov

Treatment of multiple sclerosis with cyclophosphamide: critical review of clinical and immunologic effects. [2020]

15. England pubmed.ncbi.nlm.nih.gov

Cyclosporin A inhibits thymus-dependent but not thymus-independent immune responses induced by dextran B512. [2019]