Reduced Intensity BMT + Cyclophosphamide for Primary Immunodeficiency & Bone Marrow Failure
Recruiting in Palo Alto (17 mi)
Overseen byHeather J Symons, MD, MHS
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Disqualifiers: HIV, Hepatitis B/C, Pregnancy, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?
This is a Phase II prospective trial to assess the rates of donor engraftment using reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) and post-transplant cyclophosphamide (PTCy) for patients with primary immune deficiencies (PID), immune dysregulatory syndromes (IDS), and inherited bone marrow failure syndromes (IBMFS).
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.
What data supports the effectiveness of the treatment Alemtuzumab (Campath) in combination with other therapies for primary immunodeficiency and bone marrow failure?
Alemtuzumab (Campath) is effective in killing lymphocytes, which helps in managing conditions like chronic lymphocyte leukemia and autoimmune diseases. Additionally, a combination of Fludarabine, Melphalan, and Total Body Irradiation has shown improved survival and disease control in patients undergoing reduced-intensity conditioning for transplantation.12345
Is the treatment with Alemtuzumab and other drugs generally safe for humans?
What makes the Reduced Intensity BMT + Cyclophosphamide treatment unique for primary immunodeficiency and bone marrow failure?
This treatment is unique because it combines reduced-intensity conditioning with drugs like Alemtuzumab, which helps prevent graft-versus-host disease by targeting specific immune cells, and includes low-dose total body irradiation to enhance disease control while minimizing toxicity. This approach aims to improve outcomes by balancing effective treatment with reduced side effects compared to more intensive regimens.12348
Eligibility Criteria
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
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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.
Trial Timeline
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
Treatment Details
Interventions
- Alemtuzumab (Monoclonal Antibodies)
- Cyclophosphamide (Alkylating agents)
- Fludarabine (Antimetabolites)
- Low Dose Total Body Irradiation (Radiation)
- Melphalan (Alkylating agents)
- Mycophenolate Mofetil (Immunosuppressants)
- Tacrolimus (Immunosuppressants)
Trial OverviewThe 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.
Participant Groups
2Treatment groups
Experimental Treatment
Group I: PID/IDSExperimental Treatment7 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: 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 II: IBMFSExperimental Treatment6 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.) 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).
Alemtuzumab is already approved in United States, European Union, 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Johns Hopkins UniversityBaltimore, MD
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Who Is Running the Clinical Trial?
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsLead Sponsor
References
CAMPATH: from concept to clinic. [2018]Lymphocyte depletion has a long history in the area of therapeutic immunosuppression. CAMPATH-1H (alemtuzumab) was generated in an attempt to replace anti-lymphocyte globulins in the transplant arena. Its efficacy in killing lymphocytes has established it as a licensed drug for the management of chronic lymphocyte leukaemia. Short-term therapy with alemtuzumab has demonstrated long-term benefit in a number of autoimmune conditions. This drug has the potential to facilitate recruitment of tolerance processes so enabling drug minimization in transplantation, autoimmune and hypersensitivity diseases.
Acute renal failure and disseminated intravascular coagulation following an idiosyncratic reaction to Alemtuzumab (Campath 1H) or fludarabine. [2017]Alemtuzumab (Campath 1H) is a recombinant DNA derived humanized monoclonal antibody which targets CD52 antigens on B and T cells. It is increasingly used as a conditioning agent for bone marrow transplantation. We describe the case of a 37 year old woman who developed acute renal failure and disseminated intravascular coagulation (DIC) following one dose of Campath and Fludarabine. Campath was thought to be the most likely causal agent although Fludarabine alone or in combination with Campath cannot be excluded. Despite there being many documented side effects of Campath there are currently no reports in the literature of acute renal failure and DIC. The transplant had to be aborted and 9 months on the patient is still requiring dialysis twice a week.
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. [2022]Disease relapse and toxicity are the shortcomings of reduced-intensity conditioning (RIC) for allogeneic hematopoietic cell transplantation (alloHCT). We hypothesized that adding total body irradiation (TBI) to and decreasing melphalan (Mel) from a base RIC regimen of fludarabine (Flu) and Mel would increase cytoreduction and improve disease control while decreasing toxicity. We performed a phase II trial of Flu 160 mg/m2, Mel 50 mg/m2, and TBI 400 cGy (FluMelTBI-50, n = 61), followed by a second phase II trial of Flu 160 mg/m2, Mel 75 mg/m2, and TBI 400cGy (FluMelTBI-75, n = 94) as RIC for alloHCT. Outcomes were compared with a contemporaneous cohort of 162 patients who received Flu 125 mg/m2 and Mel 140 mg/m2. Eligibility criteria were equivalent for all 3 regimens. All patients were ineligible for myeloablative/intensive conditioning. The median (range) follow-up for all patients was 51 (15 to 103) months. Day 100 donor lymphoid chimerism and transplant-related mortality, neutrophil and platelet engraftment, acute and chronic graft versus host disease incidence, overall survival (OS), and progression-free survival (PFS) were equivalent between FluMel, FluMelTBI-50, and FluMelTBI-75. Stomatitis wasdecreased for FluMelTBI versus FluMel (P < .01). PFS for patients not in complete remission on alloHCT was improved for FluMelTBI-75 versus FluMel (P = .03). On multivariate analysis, OS (P = .05) and PFS (P = .05) were significantly improved for FluMelTBI-75 versus FluMel. FluMelTBI-75 is better tolerated than FluMel, with improved survival and disease control.
Population Pharmacokinetics of Alemtuzumab (Campath) in Pediatric Hematopoietic Cell Transplantation: Towards Individualized Dosing to Improve Outcome. [2023]Label="BACKGROUND AND OBJECTIVE">Alemtuzumab (Campath®) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing.
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. [2020]To evaluate the prognostic impact of melphalan dose and total body irradiation (TBI) use in acute myeloid leukemia patients undergoing reduced-intensity allogeneic transplantation, we retrospectively compared outcomes of patients receiving a higher-dose (120-140 mg/m2, n = 379) or lower-dose melphalan (80-110 mg/m2, n = 128) with or without TBI of ≤4 Gy. At 3 years, overall survival was 48.9% in the higher-dose group versus 40.3% in the lower-dose group (p = .013). This survival benefit was attributed to lower tumor-related mortality (23.9% vs. 31.7%; p = .049). Non-relapse mortality did not differ (24.8% vs. 23.5%, p = .59). The beneficial effect of a higher-dose melphalan was more evident when combined with TBI in younger patients, those not in complete remission, and those with good performance status. Our findings support the use of a higher-dose melphalan in combination with TBI for reduced-intensity conditioning in physically fit patients.
Low serum albumin level is associated with cytomegalovirus reactivation in patients with chronic lymphoproliferative diseases treated with alemtuzumab (Campath-1H)-based therapies. [2017]Alemtuzumab (Campath-1H), a monoclonal antibody that targets the CD52 antigen, has been approved for the treatment of fludarabine-refractory chronic lymphocytic leukemia. However, the profound immunosuppression caused by alemtuzumab has been associated with infectious complications.
A novel GVHD-prophylaxis with low-dose alemtuzumab in allogeneic sibling or unrelated donor hematopoetic cell transplantation: the feasibility of deescalation. [2017]Prophylaxis of acute graft-versus-host disease (aGVHD), while maintaining the graft-versus-leukemia (GVL)/lymphoma effect and preventing severe infectious diseases, remains the main challenge in allogeneic hematopoetic cell transplantation (allo-HCT). To evaluate this, we examined the feasibility of deescalating the dose of alemtuzumab (MabCampath) in combination with cyclosporine (CsA) as the sole GVHD-prophylaxis in patients after fludarabine (Flu)-based reduced-intensity conditioning (RIC) in an observational cohort study. We included 127 consecutive patients (median age 63 years) with an unrelated (UD; n=69) or related donor (SIB; n=58) after their first transplantation, mostly presenting with advanced disease. The first 30 patients received 20 mg/day on day -2 and -1 (40 mg), the following 48 patients 10 mg/day on day -2 and -1 (20 mg), and the last 49 patients 10 mg on day -1 (10 mg) alemtuzumab intravenous (i.v.) prior to transplant. We observed no statistical differences comparing the 40 mg, 20 mg, or 10 mg dose groups, in terms of cumulative incidences of aGVHD grade III-IV 7% (confidence interval [CI] 95%; 1-51), 12% (1-40), 6% (1-40), extensive chronic GVHD (cGVHD) 24.4% (3.3-55.8), 17% (2.5-42), and 14.2% (1.5-41.5) and of aGVHD grade II-IV 7 % (0-51.5), 29% (11.9-49.1), 21% (15.3-43.1), respectively. The difference between the 20-mg and 40-mg groups was significant for aGVHD grade II-IV(P
Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. [2014]BEAM is a widely used conditioning regimen for relapsed/refractory lymphoma patients undergoing auto-SCT. We conducted a multicenter study with an alternative regimen (fotemustine plus etoposide, cytarabine and melphalan (FEAM)) in which BCNU was substituted by the chloroethylnitrosourea fotemustine (FTM). Eighty-four patients with relapsed/refractory Hodgkin's (n=20) and non-Hodgkin's lymphoma (n=64) were conditioned with a FEAM regimen (FTM 150 mg/m(2) on days -7, -6, etoposide 200 mg/m(2) and cytarabine 400 mg/m(2) on days -5, -4, -3, -2 and melphalan 140 mg/m(2) on day -1). Patients were evaluated for toxicity and engraftment parameters. Median times to neutrophil (>500 x 10(9)/l) and plt (>20 000 x 10(9)/l) engraftment were 11 and 13 days, respectively. Grade 3 mucositis occurred in 19 patients (23%), while G3 nausea/vomiting and G3 diarrhea were observed in 13 (15%) and 6 (7%) patients, respectively. No severe hepatic, renal or pulmonary toxicity was detected. Seven patients (7%) experienced G4 mucositis, while no other G4 toxicities or unexpected adverse events of any grade were recorded. Transplant-related mortality was 2.4%. We conclude that a FEAM regimen is feasible and safe. Although toxicity and engraftment times compared favorably with BEAM, longer follow-up is needed to evaluate fully its efficacy and long-term safety.