Reduced Intensity Conditioning (RIC) Regimen for Patients With Non-malignant Disorders

NCT01050855 | Completed Phase 2 Results

• 2 other identifiers: 08-005658CHP 894
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

This Phase II pilot study evaluates the safety and effectiveness of reduced-intensity conditioning (RIC) regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric and young adult patients with non-malignant disorders, including immunodeficiencies and hemoglobinopathies. The study examines different conditioning approaches that vary in the timing and dosing of alemtuzumab (Campath), as well as disease-specific modifications for beta thalassemia major and infants. The primary objective is to assess donor engraftment and event-free survival at one year following transplant. The study aims to determine whether RIC regimens can reduce toxicity while maintaining successful engraftment and disease control.

Conditions

Non Malignant Diseases; Immunodeficiencies; Hemoglobinopathies

Keywords

Non-malignant diseases; Immune deficiencies; Hemoglobinopathies; Reduced Intensity Conditioning(RIC)

Outcome Measures

Primary Outcomes (1)

• Engraftment

  engraftment of patients with non-malignant disorders will be evaluated using a reduced-intensity conditioning regimen

  Post Transplant -100 days

Secondary Outcomes (1)

• Event-free Survival

  1 year post transplant

Study Arms (1)

Reduced-Intensity Conditioning (RIC) HSCT

EXPERIMENTAL

Participants receive reduced-intensity conditioning with alemtuzumab-, fludarabine-, and melphalan-based regimens, varying by timing of alemtuzumab (distal or intermediate). Regimens are based on established protocols used in non-malignant disorders. Alemtuzumab is administered prior to other agents to reduce risk of declining donor chimerism. Participants then undergo allogeneic stem cell transplantation with standard post-transplant care.

Drug: Reduced-Intensity Conditioning

Interventions

Reduced-Intensity Conditioning DRUG

A pre-transplant conditioning approach designed to provide sufficient immunosuppression to enable donor cell engraftment while minimizing regimen-related toxicity compared to myeloablative conditioning. Regimens are adapted based on patient age and underlying disease characteristics using the following agents: Campath, Fludarabine, Melphalan, Cyclosporine, Cellcept (MMF).

Also known as: RIC

Reduced-Intensity Conditioning (RIC) HSCT

Eligibility Criteria

• Age: 6 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age \>6 months- 25 years
• Diseases eligible for Distal Alemtuzumab:
• Immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome
• Sickle cell disease (Neurologic: history of stroke or any neurologic defect lasting \>24 hours accompanied by infarct on MRI; or abnormal transcranial Doppler, or abnormal MRI with cerebral vasculature stenosis. OR minimum 2 episodes of acute chest syndrome in preceding 2 year period OR history 3 or more severe pain events/year in the 2 years prior to transplant.)
• Thalassemia major
• Bone marrow failure, including Kostmann's, amegakaryocytic thrombocytopenia, Blackfan-Diamond syndrome
• Diseases eligible for Intermediate Alemtuzumab
• Hemophagocytic lymphohistiocytosis other macrophage activation syndromes, severe Langerhans histiocytosis
• Severe combined immune deficiency, adenosine deaminase deficiency, common variable immunodeficiency
• Wiskott-Aldrich syndrome
• Organ criteria:
• Cardiac: Echocardiogram shortening fraction \>27%
• Pulmonary: for those with pulmonary function tests: DLCO/VA \>40% If DLCO/VA is not reported this is considered inability to perform the test. In this case Pulse Ox and Respiratory Exam will be used as evaluation criteria.
• Renal: Serum creatinine \<1.5 x upper limit of normal for age
• Hepatic:; ALT and AST \<5 x upper limit of normal

You may not qualify if:

• Uncontrolled bacterial, fungal or viral infections.
• Bare lymphocyte syndrome (MHC class II deficiency)

Sponsors & Collaborators

• Children's Hospital of Philadelphia: lead

Study Sites (1)

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (27)

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  PMID: 12931121 BACKGROUND

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• Friedrich W, Goldmann SF, Vetter U, Fliedner TM, Heymer B, Peter HH, Reisner Y, Kleihauer E. Immunoreconstitution in severe combined immunodeficiency after transplantation of HLA-haploidentical, T-cell-depleted bone marrow. Lancet. 1984 Apr 7;1(8380):761-4. doi: 10.1016/s0140-6736(84)91277-7.

  PMID: 6143084 BACKGROUND

• Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002 Aug;39(8):537-45. doi: 10.1136/jmg.39.8.537.

  PMID: 12161590 BACKGROUND

• Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, Shenoy S. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1;109(1):383-5. doi: 10.1182/blood-2006-05-025072. Epub 2006 Sep 21.

  PMID: 16990602 BACKGROUND

• Klangsinsirikul P, Carter GI, Byrne JL, Hale G, Russell NH. Campath-1G causes rapid depletion of circulating host dendritic cells (DCs) before allogeneic transplantation but does not delay donor DC reconstitution. Blood. 2002 Apr 1;99(7):2586-91. doi: 10.1182/blood.v99.7.2586.

  PMID: 11895797 BACKGROUND

• Chakraverty R, Peggs K, Chopra R, Milligan DW, Kottaridis PD, Verfuerth S, Geary J, Thuraisundaram D, Branson K, Chakrabarti S, Mahendra P, Craddock C, Parker A, Hunter A, Hale G, Waldmann H, Williams CD, Yong K, Linch DC, Goldstone AH, Mackinnon S. Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen. Blood. 2002 Feb 1;99(3):1071-8. doi: 10.1182/blood.v99.3.1071.

  PMID: 11807015 BACKGROUND

• Morris EC, Rebello P, Thomson KJ, Peggs KS, Kyriakou C, Goldstone AH, Mackinnon S, Hale G. Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood. 2003 Jul 1;102(1):404-6. doi: 10.1182/blood-2002-09-2687. Epub 2003 Mar 6.

  PMID: 12623851 BACKGROUND

• Chakrabarti S, Mackinnon S, Chopra R, Kottaridis PD, Peggs K, O'Gorman P, Chakraverty R, Marshall T, Osman H, Mahendra P, Craddock C, Waldmann H, Hale G, Fegan CD, Yong K, Goldstone AH, Linch DC, Milligan DW. High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. Blood. 2002 Jun 15;99(12):4357-63. doi: 10.1182/blood.v99.12.4357.

  PMID: 12036862 BACKGROUND

• Chakrabarti S, Avivi I, Mackinnon S, Ward K, Kottaridis PD, Osman H, Waldmann H, Hale G, Fegan CD, Yong K, Goldstone AH, Linch DC, Milligan DW. Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality. Br J Haematol. 2002 Dec;119(4):1125-32. doi: 10.1046/j.1365-2141.2002.03992.x.

  PMID: 12472597 BACKGROUND

• Shah AJ, Kapoor N, Crooks GM, Weinberg KI, Azim HA, Killen R, Kuo L, Rushing T, Kohn DB, Parkman R. The effects of Campath 1H upon graft-versus-host disease, infection, relapse, and immune reconstitution in recipients of pediatric unrelated transplants. Biol Blood Marrow Transplant. 2007 May;13(5):584-93. doi: 10.1016/j.bbmt.2007.01.076. Epub 2007 Mar 23.

  PMID: 17448918 BACKGROUND

• Shenoy S, Grossman WJ, DiPersio J, Yu LC, Wilson D, Barnes YJ, Mohanakumar T, Rao A, Hayashi RJ. A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. Bone Marrow Transplant. 2005 Feb;35(4):345-52. doi: 10.1038/sj.bmt.1704795.

  PMID: 15592491 BACKGROUND

• Jacobsohn DA, Duerst R, Tse W, Kletzel M. Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children. Lancet. 2004 Jul 10-16;364(9429):156-62. doi: 10.1016/S0140-6736(04)16628-2.

  PMID: 15246728 BACKGROUND

• Horn B, Baxter-Lowe LA, Englert L, McMillan A, Quinn M, Desantes K, Cowan M. Reduced intensity conditioning using intravenous busulfan, fludarabine and rabbit ATG for children with nonmalignant disorders and CML. Bone Marrow Transplant. 2006 Feb;37(3):263-9. doi: 10.1038/sj.bmt.1705240.

  PMID: 16327813 BACKGROUND

• Amrolia P, Gaspar HB, Hassan A, Webb D, Jones A, Sturt N, Mieli-Vergani G, Pagliuca A, Mufti G, Hadzic N, Davies G, Veys P. Nonmyeloablative stem cell transplantation for congenital immunodeficiencies. Blood. 2000 Aug 15;96(4):1239-46.

  PMID: 10942363 BACKGROUND

• Del Toro G, Satwani P, Harrison L, Cheung YK, Brigid Bradley M, George D, Yamashiro DJ, Garvin J, Skerrett D, Bessmertny O, Wolownik K, Wischhover C, van de Ven C, Cairo MS. A pilot study of reduced intensity conditioning and allogeneic stem cell transplantation from unrelated cord blood and matched family donors in children and adolescent recipients. Bone Marrow Transplant. 2004 Mar;33(6):613-22. doi: 10.1038/sj.bmt.1704399.

  PMID: 14730337 BACKGROUND

• Cooper N, Rao K, Gilmour K, Hadad L, Adams S, Cale C, Davies G, Webb D, Veys P, Amrolia P. Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis. Blood. 2006 Feb 1;107(3):1233-6. doi: 10.1182/blood-2005-05-1819. Epub 2005 Oct 11.

  PMID: 16219800 BACKGROUND

• Rao K, Amrolia PJ, Jones A, Cale CM, Naik P, King D, Davies GE, Gaspar HB, Veys PA. Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Blood. 2005 Jan 15;105(2):879-85. doi: 10.1182/blood-2004-03-0960. Epub 2004 Sep 14.

  PMID: 15367433 BACKGROUND

• Kikuta A, Ito M, Mochizuki K, Akaihata M, Nemoto K, Sano H, Ohto H. Nonmyeloablative stem cell transplantation for nonmalignant diseases in children with severe organ dysfunction. Bone Marrow Transplant. 2006 Nov;38(10):665-9. doi: 10.1038/sj.bmt.1705511. Epub 2006 Oct 2.

  PMID: 17013427 BACKGROUND

• Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle JH, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C; EBMT Inborn Error and EBMT Paediatric Working Parties. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May;99(5):811-20. doi: 10.3324/haematol.2013.099747.

  PMID: 24790059 BACKGROUND

• Bhatla D, Davies SM, Shenoy S, Harris RE, Crockett M, Shoultz L, Smolarek T, Bleesing J, Hansen M, Jodele S, Jordan M, Filipovich AH, Mehta PA. Reduced-intensity conditioning is effective and safe for transplantation of patients with Shwachman-Diamond syndrome. Bone Marrow Transplant. 2008 Aug;42(3):159-65. doi: 10.1038/bmt.2008.151. Epub 2008 May 26.

  PMID: 18500373 BACKGROUND

• Marsh RA, Kim MO, Liu C, Bellman D, Hart L, Grimley M, Kumar A, Jodele S, Myers KC, Chandra S, Leemhuis T, Mehta PA, Bleesing JJ, Davies SM, Jordan MB, Filipovich AH. An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis. Biol Blood Marrow Transplant. 2013 Nov;19(11):1625-31. doi: 10.1016/j.bbmt.2013.09.001. Epub 2013 Sep 10.

  PMID: 24035782 BACKGROUND

• Parikh SH, Mendizabal A, Benjamin CL, Komanduri KV, Antony J, Petrovic A, Hale G, Driscoll TA, Martin PL, Page KM, Flickinger K, Moffet J, Niedzwiecki D, Kurtzberg J, Szabolcs P. A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases. Biol Blood Marrow Transplant. 2014 Mar;20(3):326-36. doi: 10.1016/j.bbmt.2013.11.021. Epub 2013 Dec 1.

  PMID: 24296492 BACKGROUND

• King A, Shenoy S. Evidence-based focused review of the status of hematopoietic stem cell transplantation as treatment of sickle cell disease and thalassemia. Blood. 2014 May 15;123(20):3089-94; quiz 3210. doi: 10.1182/blood-2013-01-435776. Epub 2014 Feb 7. No abstract available.

  PMID: 24511087 BACKGROUND

• Oshrine BR, Olson TS, Bunin N. Mixed chimerism and graft loss in pediatric recipients of an alemtuzumab-based reduced-intensity conditioning regimen for non-malignant disease. Pediatr Blood Cancer. 2014 Oct;61(10):1852-9. doi: 10.1002/pbc.25113. Epub 2014 Jun 17.

  PMID: 24939325 RESULT

• King AA, Kamani N, Bunin N, Sahdev I, Brochstein J, Hayashi RJ, Grimley M, Abraham A, Dioguardi J, Chan KW, Douglas D, Adams R, Andreansky M, Anderson E, Gilman A, Chaudhury S, Yu L, Dalal J, Hale G, Cuvelier G, Jain A, Krajewski J, Gillio A, Kasow KA, Delgado D, Hanson E, Murray L, Shenoy S. Successful matched sibling donor marrow transplantation following reduced intensity conditioning in children with hemoglobinopathies. Am J Hematol. 2015 Dec;90(12):1093-8. doi: 10.1002/ajh.24183. Epub 2015 Oct 6.

  PMID: 26348869 DERIVED

MeSH Terms

Conditions

Immunologic Deficiency Syndromes; Hemoglobinopathies

Condition Hierarchy (Ancestors)

Immune System Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Results Point of Contact

• Title: Timothy Olson, MD PhD
• Organization: The Children's Hospital of Philadelphia

CTTSBMTIntake@chop.edu

215-590-2820

Study Officials

• Timothy J Olson, MD

  Children's Hospital of Philadelphia

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is a single-group assignment study in which all enrolled participants receive reduced-intensity conditioning prior to allogeneic hematopoietic stem cell transplantation. The study evaluates multiple conditioning approaches that vary in the timing and components of the regimen (including alemtuzumab-based strategies and disease-specific modifications), without randomization or comparison to a separate control group. Outcomes are assessed across the entire cohort to evaluate engraftment, tolerability, and feasibility of the RIC approaches.

Study Record Dates

• First Submitted: January 15, 2010
• First Posted: January 18, 2010
• Study Start: January 1, 2008
• Primary Completion: July 1, 2024
• Study Completion: June 1, 2025
• Last Updated: July 21, 2026
• Results First Posted: July 21, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)