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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new preparation method for stem cell transplants in individuals with severe sickle cell disease or transfusion-dependent β-thalassemia. The focus is on using drugs like fludarabine and dexamethasone to reduce immune system activity and prevent serious complications after receiving healthy donor cells. If necessary, additional drugs such as cyclophosphamide (an immune suppression drug), bortezomib, and rituximab may be used based on the participant's response. Individuals who have experienced multiple pain crises or severe anemia affecting daily life may be suitable for this trial. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group of participants.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have shown that cyclophosphamide improves outcomes for patients with sickle cell disease undergoing stem cell transplants. Research indicates it helps prevent severe graft-versus-host disease, where donor cells attack the patient's body, and enhances transplant success. One study reported a 94.1% survival rate two years post-procedure.

Dexamethasone, however, has been associated with side effects. In patients with sickle cell disease, it may increase the risk of blood clots. Despite this, it can reduce the need for blood transfusions and shorten hospital stays, though it might lead to more frequent rehospitalizations.

Both drugs have advantages and disadvantages, but they are part of an approach aimed at improving transplant success. Participants considering this trial should weigh these factors and discuss them with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Most treatments for sickle cell disease, like hydroxyurea or blood transfusions, focus on managing symptoms and preventing complications. But Cyclophosphamide and Dexamethasone work differently by suppressing the immune system, which can help reduce the harmful effects of sickled cells in the blood. Researchers are excited about these treatments because they target the underlying immune response, potentially offering a new way to manage severe cases of sickle cell disease and transfusion-dependent β-thalassemia. This approach might not only improve symptoms but also decrease the need for frequent blood transfusions, which is a significant advantage over current options.

What evidence suggests that this trial's treatments could be effective for sickle cell disease?

This trial will evaluate cyclophosphamide and dexamethasone for patients with sickle cell disease. Studies have shown that cyclophosphamide can significantly improve outcomes for patients undergoing stem cell transplants for this condition. Notably, over 90% of these transplants result in favorable long-term outcomes, with 88% of patients not experiencing a recurrence of their disease. This success largely stems from cyclophosphamide's ability to prevent severe complications like graft-versus-host disease (GvHD) and enhance the transplant's success rate. Research also indicates that dexamethasone can reduce the need for blood transfusions, though it may increase the risk of blood clots. Overall, combining these treatments aims to make stem cell transplants for sickle cell disease more effective and safer. ^{6 7 8 9 10}

Who Is on the Research Team?

Maria Cancio, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

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.

Hepatic iron content ≥ 3 mg Fe/g liver dry weight

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5727815/

Cyclophosphamide improves engraftment in patients with ... Posttransplant cyclophosphamide prevents severe GVHD, increases engraftment, and improves the success rate for haploidentical HSCT. Abstract.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7118612/

Haploidentical bone marrow transplant with posttransplant ... The development of haploidentical HCT (haplo-HCT) with high doses of posttransplant cyclophosphamide (PTCy) has allowed for curative long-term potential.

3. sciencedirect.com sciencedirect.com/science/article/pii/S1319016424000999

The effectiveness of hematopoietic stem cell ... Several studies have shown that HSCT, when performed on children with sickle cell disease (SCD), has favorable long-term outcomes, with over 90 % of transplants ...

4. astctjournal.org astctjournal.org/article/S1083-8791(17)30799-1/fulltext

Outcomes of Unrelated Donor Stem Cell Transplantion with ... This preparative regimen along with the use of post-transplant cyclophosphamide offers a promising approach for unrelated donor transplants in patients with SCD ...

5. hopkinsmedicine.org hopkinsmedicine.org/news/newsroom/news-releases/2023/12/a-cure-for-sickle-cell-disease

A Cure for Sickle Cell Disease Of the 42 participants, 95% were still alive two years after transplant, and 88% have not seen their sickle cell disease return and are ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11684491/

Successful Management of Severe and Refractory ... In this paper, we presented a case of sickle cell anemia who developed severe AIHA that failed to maintain response to multiple treatment lines.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11960486/

Clinical Outcomes Among Patients With Sickle Cell ... The purpose of this study is to synthesize evidence on disease-specific outcomes in patients with sickle cell disease (SCD) or transfusion-dependent beta- ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S2666636725014472

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell ... This systematic review and meta-analysis present strong evidence for the safety and efficacy of allo-HSCT in SCD treatment, with an OS of 94% ...

9. astctjournal.org astctjournal.org/article/S1083-8791(20)30012-4/fulltext

Hematopoietic Stem Cell Transplantation for Severe ... Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results ...

10. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2152265025025492

A Case of Hemoglobin SC Disease and Multiple Myeloma ... She began treatment with lenalidomide, bortezomib, dexamethasone, and daratumumab. Her course was complicated by recurrent sickle cell crises, hepatotoxicity, ...