非悪性疾患患者のための低強度コンディショニング (RIC) レジメン (RIC)
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.
調査の概要
状態
状態
条件
条件
介入・治療
介入・治療
詳細な説明
This Phase II, single-institution, investigator-initiated pilot study evaluates reduced-intensity conditioning (RIC) strategies in the setting of allogeneic hematopoietic stem cell transplantation (HSCT) for non-malignant disorders. The study focuses on optimizing conditioning approaches to balance adequate immunosuppression for donor engraftment with minimization of regimen-related toxicity.
RIC regimens are designed to reduce the organ toxicity and late effects associated with traditional myeloablative conditioning while maintaining sufficient host immune suppression to allow durable donor cell engraftment. This approach is particularly relevant in patients with pre-existing organ dysfunction or increased vulnerability to treatment-related complications. In non-malignant diseases, full donor chimerism may not be required for therapeutic benefit, and stable mixed chimerism may be sufficient for disease correction.
The conditioning strategies evaluated in this protocol primarily differ in the timing and administration of alemtuzumab, an anti-CD52 monoclonal antibody used to deplete host lymphocytes and reduce the risk of graft rejection and graft-versus-host disease. Earlier ("distal") administration is intended to reduce prolonged exposure at the time of stem cell infusion, thereby preserving donor immune function, while more proximal administration provides more immediate immunosuppression but may increase the risk of delayed immune recovery.
Disease-specific modifications to conditioning intensity are incorporated for select populations. Patients with beta thalassemia major receive additional cytoreductive and immunosuppressive agents to address the higher risk of graft rejection associated with intact immunity and expanded marrow space. Infants with immunodeficiencies are treated with modified regimens designed to reduce toxicity while maintaining engraftment potential.
Following conditioning, patients undergo stem cell transplantation using donor sources that may include related or unrelated donors as well as cord blood or alternative donor options based on clinical circumstances. Standard supportive care and post-transplant immunosuppression are administered according to institutional guidelines.
Patients are monitored longitudinally for engraftment, donor chimerism, immune recovery, and transplant-related complications. The study also evaluates clinical management strategies such as donor lymphocyte infusions or second transplantation in cases of declining chimerism or graft failure.
This study is intended to inform optimal conditioning approaches for patients with non-malignant disorders undergoing HSCT, with the goal of improving transplant tolerability while maintaining effective and durable engraftment.
研究の種類
研究の種類
入学 (実際)
入学
段階
段階
- フェーズ2
連絡先と場所
研究場所
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Pennsylvania
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Philadelphia、Pennsylvania、アメリカ、19104
- The Children's Hospital of Philadelphia
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参加基準
適格基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
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Age >6 months- 25 years
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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
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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
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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
- Infection: No active infections.
Exclusion criteria
- Uncontrolled bacterial, fungal or viral infections.
- Bare lymphocyte syndrome (MHC class II deficiency)
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
アーム数
武器と介入
参加者グループ / アーム参加者グループ / アーム |
介入・治療介入・治療 |
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実験的：Reduced-Intensity Conditioning (RIC) HSCT
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. |
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).
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Number of Participants With Engraftment
時間枠：Post Transplant -100 days
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engraftment of patients with non-malignant disorders will be evaluated using a reduced-intensity conditioning regimen |
Post Transplant -100 days
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二次結果の測定
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Event-free Survival
時間枠：1 year post transplant
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Event-free survival is defined as the time interval to either primary or late graft failure, disease recurrence, or death. |
1 year post transplant
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協力者と研究者
捜査官
捜査官
- 主任研究者：Timothy J Olson, MD、Children's Hospital of Philadelphia
出版物と役立つリンク
一般刊行物
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- 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.
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- 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.
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- Kean LS, Durham MM, Adams AB, Hsu LL, Perry JR, Dillehay D, Pearson TC, Waller EK, Larsen CP, Archer DR. A cure for murine sickle cell disease through stable mixed chimerism and tolerance induction after nonmyeloablative conditioning and major histocompatibility complex-mismatched bone marrow transplantation. Blood. 2002 Mar 1;99(5):1840-9. doi: 10.1182/blood.v99.5.1840.
- Fischer A, Landais P, Friedrich W, Morgan G, Gerritsen B, Fasth A, Porta F, Griscelli C, Goldman SF, Levinsky R, et al. European experience of bone-marrow transplantation for severe combined immunodeficiency. Lancet. 1990 Oct 6;336(8719):850-4. doi: 10.1016/0140-6736(90)92348-l.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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- 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.
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- 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.
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研究記録日
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研究開始
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研究の完了 (実際)
研究の完了
試験登録日
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QC基準を満たした最初の提出物
QC基準を満たした最初の提出物
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学習記録の更新
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本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
その他の研究ID番号
- 08-005658
- CHP 894 (その他の識別子：Children's Hospital of Philadelphia)
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個々の参加者データ (IPD) を共有する予定はありますか?
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