Stem Cell Transplant Prep Regimen for Immune Deficiency Disorders

Recruiting at 2 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Disqualifiers: HIV, Pregnancy, Infections, 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

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method to prepare patients with immune system disorders for stem cell transplants. It examines whether a combination of four drugs—Alemtuzumab (also known as Campath, Lemtrada, or MabCampath), Fludarabine, Melphalan, and Thiotepa—can help the body accept donor stem cells more effectively, with fewer side effects. The treatment aims to reduce the risk of the body rejecting the new cells. Suitable candidates for this trial include those with an immune deficiency disorder who have a matching stem cell donor. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that alemtuzumab, fludarabine, melphalan, and thiotepa each present specific safety concerns. Alemtuzumab can cause serious side effects, including immune system issues, infusion reactions, and rare but serious heart and blood vessel problems. Some patients have required surgery for thyroid issues.

Fludarabine may lead to infections and, in some cases, can be fatal. Common side effects include fever, chills, nausea, and fatigue. It also poses a potential risk for pregnant individuals.

Melphalan is known to suppress bone marrow, reducing blood cell production. Reports have linked its use to leukemia in other conditions.

Thiotepa can harm an unborn baby and may cause genetic changes. While generally safe under controlled conditions, patients should avoid vaccines during treatment.

These drugs have demonstrated effectiveness but carry potential serious side effects. They require strict medical supervision. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment regimen for immune deficiency disorders because it combines several powerful drugs—Alemtuzumab, Fludarabine, Melphalan, and Thiotepa—in a unique way to prepare patients for stem cell transplants. Unlike traditional therapies that might focus on just one or two drugs, this combination aims to better suppress the immune system, reducing the risk of transplant rejection. Alemtuzumab, in particular, is notable for targeting and depleting specific immune cells, potentially leading to more successful transplants and improved patient outcomes. This approach could offer a more comprehensive preparation process, enhancing the effectiveness of the stem cell transplant overall.

What evidence suggests that this trial's treatments could be effective for immune deficiency disorders?

In this trial, participants will receive a preparative regimen that includes alemtuzumab, fludarabine, melphalan, and thiotepa. Research has shown that alemtuzumab effectively reduces disease activity over several years, with only 13% of patients experiencing worsening conditions compared to 21% with another treatment. When administered in the right dose, fludarabine can improve patient outcomes without adding extra risks. Melphalan achieves high response rates, with over half of the patients attaining a very good response or better. Thiotepa-based conditioning has demonstrated strong survival rates, with some studies reporting 86% survival over three years. Together, these treatments aim to improve transplant success by reducing rejection risks and helping donor cells integrate better. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

This trial is for people under 28 with certain immune disorders like DiGeorge Syndrome and Wiskott-Aldrich Syndrome. They must have normal organ function, a performance status of at least 40%, and a matched donor for cell transplant. People with HIV, uncontrolled infections, or who are pregnant/breastfeeding can't join.

Inclusion Criteria

Your blood creatinine levels are within a certain range.

Your liver enzymes are not more than 5 times the normal upper limit.

Your heart is pumping normally, with a strong enough force.

Exclusion Criteria

Pregnant or breastfeeding

I have not had an uncontrolled viral infection in the week before starting alemtuzumab.

I haven't had severe fungal or bacterial infections in the last month.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Participants undergo a reduced intensity immunosuppressive preparative regimen to establish engraftment of donor hematopoietic cells

4-6 weeks

Hematopoietic Stem Cell Transplantation

Participants receive hematopoietic stem cell transplantation to optimize donor cell engraftment

1 week

Follow-up

Participants are monitored for safety and effectiveness after transplantation

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Fludarabine
• Melphalan
• Thiotepa

Trial Overview

The study tests whether a mix of drugs (alemtuzumab, fludarabine, thiotepa, melphalan) before a cell transplant can help the body accept new immune cells with manageable side effects in patients with immune deficiencies.

How Is the Trial Designed?

Group I: Preparative Experimental Treatment 1 Intervention

Alemtuzumab is already approved in United States, European Union for the following indications:

Approved in United States as Campath for:

• Chronic lymphocytic leukemia
• Multiple sclerosis

Approved in European Union as Lemtrada for:

• Multiple sclerosis

Approved in European Union as Campath for:

• Chronic lymphocytic leukemia

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Published Research Related to This Trial

In a study of 127 patients undergoing allogeneic hematopoietic cell transplantation, reducing the dose of alemtuzumab to 10 mg for graft-versus-host disease (GVHD) prophylaxis was feasible and did not significantly increase the risk of severe aGVHD compared to higher doses.

The study found that while there were no significant differences in the incidence of severe aGVHD across different alemtuzumab doses, the 20 mg dose showed a significant difference in the incidence of aGVHD grade II-IV compared to the 40 mg dose, suggesting that lower doses may be effective in preventing GVHD while minimizing potential side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel GVHD-prophylaxis with low-dose alemtuzumab in allogeneic sibling or unrelated donor hematopoetic cell transplantation: the feasibility of deescalation. Bertz, H., Spyridonidis, A., Wäsch, R., et al.[2017]

A new conditioning strategy for bone marrow transplantation (BMT) in 16 patients resulted in stable donor engraftment in 14 out of 16 recipients, with neutrophils and platelets engrafting within a median of 13 and 24 days, respectively.

The regimen showed a low incidence of acute graft-versus-host disease (GVHD), with no cases of chronic GVHD, making it a promising option for treating nonmalignant diseases despite some early infections observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. Shenoy, S., Grossman, WJ., DiPersio, J., et al.[2005]

Azathioprine (AZA) can cause rare but severe allergic reactions, as demonstrated in two cases of systemic scleroderma with polymyositis, one resulting in Stevens-Johnson syndrome and the other in systemic papular erythema.

The drug-induced lymphocyte stimulation test (DLST) proved to be an effective diagnostic tool for identifying AZA allergy, showing significantly elevated stimulation indices in the allergic patients compared to healthy volunteers, indicating a strong immune response to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug eruption caused by azathioprine: value of using the drug-induced lymphocytes stimulation test for diagnosis. Mori, H., Yamanaka, K., Kaketa, M., et al.[2019]

In a study of 17 pediatric patients undergoing matched unrelated hematopoietic stem cell transplantation (HSCT) with Campath-1H, the incidence of grade I-II acute graft versus host disease (GVHD) was only 29.4%, and no cases of chronic GVHD were observed, suggesting effective reduction of GVHD risk.

Despite a 35.3% relapse rate of primary disease, the overall survival rates were high at 100% at 100 days and 94% at one year, indicating that Campath-1H does not significantly increase the risk of life-threatening infections or relapse compared to conventional regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pretransplant conditioning with Campath-1H (alemtuzumab) in pediatric matched unrelated hematopoietic stem cell transplants: an institutional experience. Nageswara Rao, AA., Kumar, R., Altaf, S., et al.[2017]

In a study of 50 patients with severe aplastic anemia undergoing hematopoietic stem cell transplantation (HSCT) using an alemtuzumab-based conditioning regimen, the overall survival rates were high at 95% for matched sibling donors and 83% for unrelated donors over 2 years.

The regimen resulted in a low incidence of acute graft-versus-host disease (GVHD) at 13.5% and chronic GVHD at only 4%, indicating that this treatment approach is both effective and safe, particularly for younger patients and those with fewer comorbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Marsh, JC., Gupta, V., Lim, Z., et al.[2021]

Azathioprine can cause severe myelosuppression in patients with the NUDT15 minor variant, highlighting the importance of genetic testing before treatment.

Recognizing typical symptoms associated with this adverse reaction is crucial for timely intervention and patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Azathioprine-induced severe myelosuppression accompanied by massive hair loss and painful oral ulcer in an autoimmune hepatitis patient with NUDT15 minor variant: A case report. Takeuchi, Y., Noritake, H., Matsumoto, M., et al.[2021]

The study involved 25 patients with hematologic malignancies undergoing nonmyeloablative transplantation using a regimen that included Campath-1H, which aimed to reduce the risk of graft-versus-host disease (GVHD).

While the regimen showed a low nonrelapse mortality rate of 12% and successful engraftment in most patients, acute GVHD occurred in 40% of cases, indicating that GVHD remains a significant challenge in this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A study of a reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation for patients with hematologic malignancies using Campath-1H as part of a graft-versus-host disease strategy. Shore, T., Harpel, J., Schuster, MW., et al.[2017]

In a study of 38 pediatric patients treated with high-dose thiotepa, nearly 80% experienced a consistent pattern of skin reactions, including diffuse erythema, desquamation, and hyperpigmentation, particularly in intertriginous and occluded areas.

Recognizing these common cutaneous effects of thiotepa can enhance patient care, although the study's limitations include reliance on chart data and the absence of dermatologist follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous effects of thiotepa in pediatric patients receiving high-dose chemotherapy with autologous stem cell transplantation. Rosman, IS., Lloyd, BM., Hayashi, RJ., et al.[2013]

Azathioprine has been shown to have a moderate therapeutic effect in severe atopic dermatitis, supported by high-quality evidence from 43 reviewed studies.

While azathioprine also demonstrated efficacy in other dermatological conditions like parthenium dermatitis and bullous pemphigoid, the safety of its off-label use remains uncertain due to limited data, highlighting the need for further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Off-label use of azathioprine in dermatology: a systematic review. Schram, ME., Borgonjen, RJ., Bik, CM., et al.[2022]

CAMPATH-1H (alemtuzumab) is effective in depleting lymphocytes and is licensed for treating chronic lymphocyte leukemia, showcasing its efficacy in managing blood cancers.

Short-term use of alemtuzumab has shown long-term benefits in various autoimmune conditions, suggesting it may help in reducing the need for ongoing immunosuppressive drugs in transplantation and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAMPATH: from concept to clinic. Waldmann, H., Hale, G.[2018]

In a phase II pilot study involving 24 patients with chronic lymphocytic leukemia (CLL) who had previously undergone chemotherapy, alemtuzumab demonstrated significant efficacy, with 33% of patients achieving a major response and a median survival time of 35.8 months.

Despite its effectiveness, the treatment was associated with a high incidence of opportunistic infections due to low lymphocyte counts, suggesting that future studies should implement mandatory antimicrobial prophylaxis to enhance patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. Rai, KR., Freter, CE., Mercier, RJ., et al.[2017]

A patient with proliferative lupus nephritis experienced severe bone marrow inhibition after 15 days of azathioprine (AZA) therapy, despite having no common mutations in the TPMT gene, which is typically associated with thiopurine metabolism.

This case highlights that severe myelosuppression can occur in patients on AZA even in the absence of known TPMT mutations, indicating the need for careful monitoring of blood cell counts during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bone marrow inhibition induced by azathioprine in a patient without mutation in the thiopurine S-methyltransferase pathogenic site: A case report. Zhou, XS., Lu, YY., Gao, YF., et al.[2021]

Alemtuzumab (Campath 1H), a monoclonal antibody targeting CD52 on B and T cells, is increasingly used as a conditioning agent for bone marrow transplantation, but it can have serious side effects.

In a case study of a 37-year-old woman, acute renal failure and disseminated intravascular coagulation (DIC) occurred after receiving Campath, leading to the abortion of her transplant and ongoing dialysis, highlighting the need for caution and further investigation into its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. Osborne, WL., Lennard, AL.[2017]

A population pharmacokinetic model for alemtuzumab was developed using data from 206 pediatric patients, revealing that body weight significantly affects the drug's clearance and distribution, which can lead to variable drug exposure.

The study suggests that the current standard dosing method may not be optimal for all children, and individualized dosing based on this model could improve treatment outcomes and reduce toxicity associated with alemtuzumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. Admiraal, R., Jol-van der Zijde, CM., Furtado Silva, JM., et al.[2023]

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13% of patients who took LEMTRADA experienced confirmed disability progression compared with 21% of those who took Rebif.

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Our results demonstrate that reductions in disease activity and cerebral atrophy with alemtuzumab continue over 5 years. ARR remained low over 5 years, and most ...

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With regards to safety, Lemtrada has rare but serious side effects, including disorders of the heart, blood vessels and immune system and measures have been put ...

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A special safety concern of alemtuzumab revolves around its association with the development of secondary autoimmune diseases, such as thyroid diseases, immune ...