Reduced Intensity BMT + Cyclophosphamide for Primary Immunodeficiency & Bone Marrow Failure

Overseen By Heather J Symons, MD, MHS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Disqualifiers: HIV, Hepatitis B/C, Pregnancy, 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

27 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness and safety of a new approach to bone marrow transplant for individuals with specific genetic disorders affecting the immune system or bone marrow. It employs a less intense method to prepare the body for the transplant, testing whether this improves donor cell acceptance. Participants may receive different combinations of treatments, such as alemtuzumab (an immunotherapy), cyclophosphamide (a chemotherapy drug), and fludarabine (a chemotherapy drug), based on their condition. This trial may suit individuals with conditions like Severe Combined Immunodeficiency (SCID) or Fanconi anemia who experience frequent infections or low blood cell counts. As a Phase 2 trial, it focuses on assessing the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant research.

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 trial coordinators or your doctor.

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

Research shows that the treatments under study—alemtuzumab, cyclophosphamide, fludarabine, melphalan, and low-dose total body irradiation—have been used in other medical contexts with varying safety levels.

Alemtuzumab has been researched for conditions like multiple sclerosis, where regular blood tests are crucial for managing risks. Cyclophosphamide is commonly used in cancer treatments but can significantly lower blood cell counts, especially in patients with prior treatments.

Fludarabine is often used in bone marrow transplants and generally does not lead to transplant failure or serious illnesses afterward. Melphalan can greatly reduce bone marrow activity, potentially causing infections or bleeding, so bone marrow recovery is important before its continued use.

Low-dose total body irradiation prepares patients for transplants and is usually safer than higher doses, but it still carries a higher risk of secondary cancers compared to the general population.

In this trial, these treatments are combined. While safety information exists for each treatment individually, the trial will carefully monitor the safety of the combination. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care, which typically involves intensive chemotherapy and radiation, this reduced-intensity bone marrow transplantation protocol aims to minimize side effects while maintaining effectiveness. Researchers are excited about this approach because it combines lower doses of chemotherapy agents like Cyclophosphamide and Melphalan with total body irradiation, making the treatment potentially safer for patients with primary immunodeficiency and bone marrow failure. Additionally, the use of post-transplantation Cyclophosphamide and immunosuppressants like Tacrolimus and Mycophenolic acid mofetil helps in reducing the risk of graft-versus-host disease, a common complication in bone marrow transplants. This treatment could offer a more tolerable and effective option for patients who are particularly vulnerable to the harsh effects of traditional treatments.

What evidence suggests that this trial's treatments could be effective?

Research has shown that treatments using alemtuzumab and fludarabine are promising for similar conditions. In this trial, participants in various treatment arms will receive different combinations of these drugs. Alemtuzumab has achieved high success rates, with up to 86% of patients surviving certain immune disorders. Fludarabine, when combined with other treatments, has effectively helped patients receive donor bone marrow in cases of bone marrow failure. Studies on melphalan suggest it is safe and effective when combined with other drugs. Low-dose total body irradiation has been useful in slowing disease progression and maintaining remission. Cyclophosphamide, especially when used with stem cell transplants, has shown a high survival rate, with 92% of patients surviving according to related studies. Together, these treatments provide a strong basis for addressing the conditions targeted in this trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Heather J Symons, MD, MHS

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for patients with primary immune deficiencies, immune dysregulatory syndromes, or inherited bone marrow failure. They must have a confirmed diagnosis and an available donor that matches their human leukocyte antigens (HLA) to varying degrees. Participants need proper organ function and agree to contraception if of childbearing potential.

Inclusion Criteria

I have a diagnosed inherited bone marrow failure disorder.

I have been diagnosed with a specific immune deficiency condition.

Available donor as follows: Cohort A - Fully HLA matched sibling or other first-degree family member, Cohort B - Fully HLA matched unrelated 10/10 donor using high-resolution DNA-based typing at the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1, Cohort C - Mismatched unrelated donor at 8 or 9/10 alleles, using high-resolution typing as above, HLA-haploidentical family members of any degree who match at least one allele of each of the following genetic loci: HLA-A, -B, -C, DRB1, and DQB1. A minimum match of 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype, The patient and/or legal guardian must sign informed consent for BMT, Patients with adequate organ function as measured by: Cardiac: Left ventricular ejection fraction (LVEF) at rest must be ≥ 35%. For patients aged <13 years, shortening fraction (SF) > 25% by echocardiogram or LVEF by multigated acquisition scan (MUGA) may be used, Hepatic: Bilirubin ≤ 3.0 mg/dL; and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase (ALP) < 5 x upper limit of normal (ULN), Renal: Serum creatinine within normal range for age, or if serum creatinine outside normal range for age, then renal function (creatinine clearance or glomerular filtration rate (GFR)) > 40 mL/min/1.73m2, Pulmonary: forced expiratory volume-one second (FEV1), forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO) > 50% predicted (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation > 92% on room air, Karnofsky or Lansky performance status ≥70%, Females and males of childbearing potential must agree to practice 2 effective methods of contraception at the same time, or agree to abstinence

Exclusion Criteria

- Your blood test shows a bad reaction to other people's white blood cells. - You have had a transplant of someone else's stem cells. - You have an uncontrolled infection caused by bacteria, viruses, or fungi. - You have a specific type of anemia or genetic condition affecting your blood. - You have tested positive for HIV. - You have active Hepatitis B or C. - You are pregnant or breastfeeding. - You have an ongoing or recent history of cancer.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment Evaluation

Documentation of detailed history, physical examination, and standard evaluation of cardiac, pulmonary, liver, and renal function. Disease evaluation and pre-BMT blood drawn for correlative labs.

1-2 weeks

Preparative Regimen

Administration of Alemtuzumab, Fludarabine, Melphalan, and Total Body Irradiation to prepare for bone marrow transplantation.

2 weeks

Bone Marrow Transplantation

Bone marrow harvested and infused. Post-transplantation Cyclophosphamide administered to prevent GVHD.

1 week

Post-BMT Evaluation

Patients followed during the initial post-BMT period and after discharge to the referring physician.

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including disease-free survival and overall survival assessments.

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Alemtuzumab
• Cyclophosphamide
• Fludarabine
• Low Dose Total Body Irradiation
• Melphalan
• Mycophenolate Mofetil
• Tacrolimus

Trial Overview The study tests reduced intensity conditioning hematopoietic stem cell transplant with post-transplant cyclophosphamide in patients with specific immune and bone marrow conditions. It aims to see how well donors' cells are accepted by the recipients' bodies using this method.

How Is the Trial Designed?

Group I: Short Telomere Syndrome Experimental Treatment 6 Interventions

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25-50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Starting dose for haplo/MMUD= 50 mg/kg; starting dose for HLA matched= 25 mg/kg Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

Group II: PID/IDS/IBMFS Experimental Treatment 7 Interventions

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. Melphalan 70 mg/m2/day IV infusion over 30-60 minutes on days -3 and -2. (Or may be given as a single infusion of 140 mg/m2/day on day -2.) Total body irradiation (PID/IDS): 200 cGy will be administered in a single fraction on day -1. Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 50mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on day 5, at least 24 hours after completion of posttransplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

Group III: Fanconi Anemia or DNA-dsb repair Experimental Treatment 6 Interventions

Alemtuzumab IV infusion over 2 hours on days -14, -13, and -12. Day -14 3 mg followed by 10 mg. Day -13 15 mg (or 10 mg if \<10 kg). Day -12 20 mg (or 10 mg if \<10 kg). Fludarabine 30 mg/m2/day IV infusion over 2 hours on days -6 to -2. TBI 200 cGY day -1 Bone Marrow will be harvested and infused on day 0. Post-transplantation Cyclophosphamide 25 mg/kg will be given on D+3 post-transplant (within 60-72 hr of marrow infusion) and on D+4 post-transplant. Tacrolimus begins on day 5, at least 24 hours after completion of post transplantation Cy at 0.015mg/kg IBW/dose IV over 4 hours every 12 hours. Mycophenolic acid mofetil (MMF) begins on day 5 at a dose of 15 mg/kg PO TID (based upon actual body weight) with the maximum total daily dose not to exceed 3 grams (1 g PO TID).

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Maryland Stem Cell Research Fund

Collaborator

Trials

1

Recruited

1+

Published Research Related to This Trial

The addition of total body irradiation (TBI) and a reduction in melphalan dosage in the FluMelTBI-75 regimen led to improved overall survival (OS) and progression-free survival (PFS) compared to the standard FluMel regimen, based on a phase II trial involving 94 patients.

FluMelTBI-75 was better tolerated, showing a significant reduction in stomatitis and improved disease control for patients not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-Intensity Conditioning with Fludarabine, Melphalan, and Total Body Irradiation for Allogeneic Hematopoietic Cell Transplantation: The Effect of Increasing Melphalan Dose on Underlying Disease and Toxicity. Chen, GL., Hahn, T., Wilding, GE., et al.[2022]

In a study of 507 acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, those receiving a higher dose of melphalan (120-140 mg/m2) had a significantly better overall survival rate (48.9%) compared to those on a lower dose (40.3%).

The survival benefit from higher-dose melphalan was linked to reduced tumor-related mortality, particularly in younger patients and those not in complete remission, suggesting that this treatment approach may be especially effective for physically fit individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of melphalan dose and total body irradiation use in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation with reduced-intensity conditioning. Harada, K., Yanada, M., Machida, S., et al.[2020]

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]

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]

In a study of 113 patients with chronic lymphoproliferative disorders treated with alemtuzumab, 22% experienced symptomatic reactivation of cytomegalovirus (CMV), but most responded well to antiviral therapy.

Low serum albumin levels were identified as a significant risk factor for developing symptomatic CMV reactivation, highlighting the need for monitoring this parameter in patients undergoing alemtuzumab treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low serum albumin level is associated with cytomegalovirus reactivation in patients with chronic lymphoproliferative diseases treated with alemtuzumab (Campath-1H)-based therapies. Borthakur, G., Lin, E., Faderl, S., et 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]

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]

The FEAM conditioning regimen, which includes fotemustine, etoposide, cytarabine, and melphalan, was found to be feasible and safe for 84 patients with relapsed/refractory lymphoma, showing manageable toxicity levels and acceptable engraftment times.

Engraftment occurred at a median of 11 days for neutrophils and 13 days for platelets, with only 2.4% transplant-related mortality, indicating that FEAM may be a viable alternative to the traditional BEAM regimen, although further long-term studies are necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. Musso, M., Scalone, R., Marcacci, G., et al.[2014]

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