Single vs Double Umbilical Cord Blood Transplants in Children With High Risk Leukemia and Myelodysplasia (BMT CTN 0501)
Multi-center, Open Label, Randomized Trial Comparing Single Versus Double Umbilical Cord Blood (UCB) Transplantation in Pediatric Patients With High Risk Leukemia and Myelodysplasia (BMT CTN #0501)
調査の概要
状態
詳細な説明
BACKGROUND:
In nearly every large single center or registry analysis of outcomes after UCB transplantation, cell dose is identified as an important factor influencing the incidence and rate of hematopoietic recovery, risk of transplant-related mortality, and probability of survival. Pilot data suggest that infusion of two partially human leukocyte antigen (HLA)-matched UCB units, which always augments the graft cell dose, is safe and may improve neutrophil recovery and survival. To determine whether the infusion of two UCB units enhances survival, a multi-center, open-label, randomized trial is proposed. As adequate single UCB units can be identified for more than 80% of pediatric recipients (in contrast to less than 30% for adults), this study will be open only to pediatric patients. The population will be restricted to patients with high-risk hematologic malignancy, the most common indication of UCB transplantation in children.
DESIGN NARRATIVE:
Participants will include patients 1 to 21 years of age with a diagnosis of hematological malignancy and with two partially HLA-matched UCB units. Units must be HLA-matched at 3 of 6 HLA-A and B (intermediate resolution molecular typing) and DRB1 (high resolution molecular typing) with each other and 4 of 6 with the recipient. Two appropriately HLA-matched units must be available such that one unit delivers a pre-cryopreserved, nucleated cell dose of at least 2.5 x 10^7 per kilogram and the second unit delivers at least 1.5 x 10^7 per kilogram.
Patients will be randomized no more than 14 days prior to initiation of conditioning. UCB units will be shipped prior to initiation of conditioning.
The preparative regimen will consist of the following:
- Fludarabine: 25 mg/m2/day IV on Days -10, -9, and -8.
- Total Body Irradiation (TBI): 165 cGy twice daily on Days -7, -6, -5, and -4.
- Cyclophosphamide: 60 mg/kg/day x 2 on Days -3 and -2.
- Day 0 will be the day of the UCB transplant. The Graft-vs-Host-Disease (GVHD) prophylaxis regimen will be mycophenolate mofetil (MMF) 15 mg/kg IV BID on Day -3 to Day + 45 and cyclosporine A (CSA) to maintain level 200-400 ng/mL beginning on Day -3.
Patients will be followed for at least 24 months post-transplant.
研究の種類
入学 (実際)
段階
- フェーズ 3
連絡先と場所
研究場所
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Alabama
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Birmingham、Alabama、アメリカ、35294
- University of Alabama
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Arizona
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Phoenix、Arizona、アメリカ、85016
- Phoenix Children's Hospital
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California
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Duarte、California、アメリカ、91010
- City of Hope National Medical Center
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Oakland、California、アメリカ、94609
- Childrens Hospital at Oakland
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San Diego、California、アメリカ、92123
- UCSD/Rady Childrens Hospital
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San Francisco、California、アメリカ、94143
- University of California, San Francisco (Peds)
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Colorado
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Denver、Colorado、アメリカ、80218
- The Children's Hospital of Denver
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District of Columbia
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Washington、District of Columbia、アメリカ、20010
- Children's National Medical Center
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Florida
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Gainesville、Florida、アメリカ、32610
- University of Florida College of Medicine (Shands)
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Jacksonville、Florida、アメリカ、32207
- Nemours Childrens Clinic
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Miami、Florida、アメリカ、33136
- University of Miami
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Saint Petersburg、Florida、アメリカ、33710
- All Children's Hospital
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Georgia
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Atlanta、Georgia、アメリカ、30322-1062
- Children's Healthcare of Atlanta
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Indiana
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Indianapolis、Indiana、アメリカ、46202
- Indiana University Medical Center
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Kentucky
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Louisville、Kentucky、アメリカ、40202
- University of Louisville/Kosiar Children's Hospital
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Louisiana
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New Orleans、Louisiana、アメリカ、70118
- Children's of New Orleans
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Massachusetts
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Boston、Massachusetts、アメリカ、02115
- DFCI/Children's Hospital of Boston
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Michigan
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Ann Arbor、Michigan、アメリカ、48109
- University of Michigan Medical Center
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Detroit、Michigan、アメリカ、48201
- Karmanos Cancer Institute/Children's Hospital of Michigan
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Minnesota
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Minneapolis、Minnesota、アメリカ、55455
- University of Minnesota
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Mississippi
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Jackson、Mississippi、アメリカ、39216
- University of Mississippi
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Missouri
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Kansas City、Missouri、アメリカ、64108
- Children's Mercy Hospital and Clinics
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New York
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Valhalla、New York、アメリカ、10595
- New York Medical College
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North Carolina
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Durham、North Carolina、アメリカ、27705
- Duke University Medical Center
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Ohio
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Columbus、Ohio、アメリカ、43205-2696
- Nationwide Children's Hospital
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Oregon
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Portland、Oregon、アメリカ、97239
- Oregon Health Sciences University
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Pennsylvania
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Philadelphia、Pennsylvania、アメリカ、19104
- Children's Hospital of Philadelphia
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South Carolina
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Charleston、South Carolina、アメリカ、29425
- Medical University of South Carolina
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Tennessee
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Nashville、Tennessee、アメリカ、37232-7610
- Vanderbilt University Medical Center
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Texas
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Dallas、Texas、アメリカ、75235
- Children's Medical Center of Dallas
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Fort Worth、Texas、アメリカ、76104
- Cook Childrens Medical Center
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San Antonio、Texas、アメリカ、78229
- Texas Transplant Institute
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Utah
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Salt Lake City、Utah、アメリカ、84132
- Utah BMT/University of Utah Medical School
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Virginia
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Richmond、Virginia、アメリカ、23298
- Virgina Commonwealth University
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Washington
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Seattle、Washington、アメリカ、98109
- Fred Hutchinson Cancer Research Center
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Wisconsin
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Milwaukee、Wisconsin、アメリカ、53211
- Medical College of Wisconsin
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New South Wales
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Westmead、New South Wales、オーストラリア、2145
- Children's Hospital at Westmead
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British Columbia
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Vancouver、British Columbia、カナダ、V5Z 4E3
- BC Cancer Agency
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参加基準
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:
- Two partially HLA-matched UCB units. Units must be HLA-matched minimally at 4 of 6 HLA-A and B (at intermediate resolution by molecular typing) and DRB1 (at high resolution by molecular typing) loci with the patient, and the units must be HLA-matched at 3 of 6 HLA- A, B, DRB1 loci with each other (using same resolution of molecular typing as indicated above). Two appropriately HLA-matched units must be available such that one unit delivers a pre-cryopreserved nucleated cell dose of at least 2.5 x 10^7 per kilogram and the second unit at least 1.5 x 10^7 per kilogram.
Acute myelogenous leukemia (AML) at the following stages:
High risk first complete remission (CR1), defined as the following:
- Having preceding myelodysplasia (MDS)
- High risk cytogenetics (high risk cytogenetics: del (5q) -5, -7, abn (3q), t (6;9) complex karyotype [at least 5 abnormalities],)the presence of a high FLT3 ITD-AR (> 0.4)
- Requiring more than 1 cycle of chemotherapy to obtain complete remission (CR);
- FAB M6
- Second or greater CR
- First relapse with less than 25% blasts in bone marrow
- Morphologic complete remission with incomplete blood count recovery
- Therapy-related AML for which prior malignancy has been in remission for at least 12 months
Acute lymphocytic leukemia (ALL) at the following stages:
High risk first remission, defined as one of the following conditions:
- Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)
- Mixed lineage leukemia (MLL) rearrangement with slow early response (defined as having M2 [5-25% blasts] or M3 [more than 25% blasts on bone marrow examination on Day 14 of induction therapy])
- Hypodiploidy (less than 44 chromosomes or DNA index less than 0.81)
- End of induction M3 bone marrow
- End of induction M2 with M2-3 at Day 42
- Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.
High risk second remission, defined as one of the following conditions:
- Philadelphia chromosome-positive adult lymphoblastic leukemia (Ph+ ALL)
- Bone marrow relapse less than 36 months from induction
- T-lineage relapse at any time
- Very early isolated central nervous system (CNS) relapse (6 months from diagnosis)
- Slow reinduction (M2-3 at Day 28) after relapse at any time
- Evidence of minimal residual disease (MRD). If a patient's only high risk criterion is MRD, approval by a protocol chair or protocol officer is required for enrollment. For COG centers, this will only be for MRD greater than 1 percent by flow MRD at the end of extended induction.
- Any third or subsequent CR
- NK cell lymphoblastic leukemia in any CR
- Biphenotypic or undifferentiated leukemia in any CR or if in first relapse must have less than 25% blasts in bone marrow (BM)
- Myelodysplastic syndrome (MDS) at any stage
- Chronic myelogenous leukemia (CML) in chronic or accelerated phase
- All patients with evidence of CNS leukemia must be treated and be in CNS CR to be eligible for study.
- Patients 16 years old or older must have a Karnofsky score of at least 70% and patients younger than 16 years old must have a Lansky score of at least 70%.
Patients with adequate physical function as measured by:
- Cardiac: Left ventricular ejection fraction greater than 40% or shortening fraction greater than 26%
- Hepatic: Bilirubin no more than 2.5 mg/dL; alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) no more than 5 times the upper limit of normal (ULN)
- Renal: Serum creatinine within normal range for age, or if serum creatinine is outside normal range for age, then renal function (creatinine clearance or GFR) greater than 70 mL/min/1.73 m^2
- Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO), forced expiratory volume in one second (FEV1), or forced vital capacity (FVC) greater than 50% of predicted value (corrected for hemoglobin); if unable to perform pulmonary function tests, then O2 saturation greater than 92% of room air
Exclusion Criteria:
- Pregnant (β-positive human chorionic gonadotropin [HCG]) or breastfeeding
- Evidence of HIV infection or HIV positive serology
- Current uncontrolled bacterial, viral, or fungal infection (currently taking medication and progression of clinical symptoms)
- Autologous transplant less than 12 months prior to enrollment
- Prior autologous transplant for the disease for which the UCB transplant will be performed
- Prior allogeneic hematopoietic stem cell transplant
- Active malignancy other than the one for which the UCB transplant is being performed within 12 months of enrollment
- Inability to receive TBI
- Requirement of supplemental oxygen
- HLA-matched related donor able to donate
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:ランダム化
- 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)
武器と介入
参加者グループ / アーム |
介入・治療 |
---|---|
実験的:Single Cord Blood Transplant
Unrelated donor, single umbilical cord blood unit transplant; conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
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Unrelated donor, single umbilical cord blood unit; conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.
他の名前:
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.
他の名前:
Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8.
Fludarabine will not be dose adjusted for body weight.
他の名前:
CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods).
CSA can be administered per institutional practice.
他の名前:
MMF will be given at a dose of 1 gram IV q 8 hours if > 50 kg or 15 mg/kg IV q 8 hours if < 50 kg beginning the morning of Day -3.
他の名前:
|
実験的:Double Cord Blood Transplant
Unrelated donor, double umbilical cord blood unit transplant; Conditioning regimen: Total Body Irradiation/cyclophosphamide/fludarabine; GVHD prophylaxis: Cyclosporine A/Mycophenolate Mofetil
|
The TBI will be delivered from either a linear accelerator or cobalt source at a dose rate of between 4 and 26 cGy/minute using energies of between 1 and 25 MV.
他の名前:
Cyclophosphamide 60 mg/kg/day will be administered as a 2 hour intravenous infusion with a high volume fluid flush on Days -3 and -2.
他の名前:
Fludarabine 25 mg/m2/day will be administered over 30-60 minutes intravenous infusion on Days -10 through -8.
Fludarabine will not be dose adjusted for body weight.
他の名前:
CSA will be administered beginning on Day -3 and doses will be adjusted to maintain a level of 200-400 ng/mL by TDX method (or 100-250 ng/mL by Tandem MS or equivalent level for other CSA testing methods).
CSA can be administered per institutional practice.
他の名前:
MMF will be given at a dose of 1 gram IV q 8 hours if > 50 kg or 15 mg/kg IV q 8 hours if < 50 kg beginning the morning of Day -3.
他の名前:
Unrelated donor, double umbilical cord blood unit; Conditioning regimen: TBI/cyclophosphamide/fludarabine; GVHD prophylaxis: cyclosporine/MMF
|
この研究は何を測定していますか?
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
---|---|---|
Percentage of Participants With Overall Survival
時間枠:1 year post-randomization
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Overall survival is defined as survival of death from any cause.
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1 year post-randomization
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
---|---|---|
Percentage of Participants With Disease-free Survival
時間枠:1 year post-randomization
|
Disease-free survival is defined as survival without relapse of the primary disease.
|
1 year post-randomization
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Percentage of Participants With Neutrophil and Platelet Engraftment
時間枠:Days 42 and 100
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Neutrophil engraftment is defined as achieving an absolute neutrophil count greater than 500x10^6/liter for three consecutive measurements on different days.
The first of the three days will be designated the day of neutrophil engraftment.
Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions.
The first of the 7 days will be designated the day of platelet engraftment.
Subjects must not have had platelet transfusions during the preceding 7 days.
|
Days 42 and 100
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Time to Neutrophil and Platelet Engraftment
時間枠:2 years post-transplant
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Platelet engraftment is defined as achieving platelet counts greater than 50,000/microliter for consecutive measurements over 7 days without requiring platelet transfusions.
The first of the 7 days will be designated the day of platelet engraftment.
Subjects must not have had platelet transfusions during the preceding 7 days.
|
2 years post-transplant
|
Percentage of Participants With Acute Graft-versus-host Disease (GVHD)
時間枠:Day 100 post-randomization
|
Acute GVHD is graded according to the scoring system proposed by Przepiorka et al.1995: Skin stage: 0: No rash
Liver stage (based on bilirubin level)*: 0: <2 mg/dL
GI stage*: 0: No diarrhea or diarrhea <500 mL/day
GVHD grade: 0: All organ stages 0 or GVHD not listed as an etiology I: Skin stage 1-2 and liver and GI stage 0 II: Skin stage 3 or liver or GI stage 1 III: Liver stage 2-3 or GI stage 2-4 IV: Skin or liver stage 4 |
Day 100 post-randomization
|
Percentage of Participants With Chronic GVHD
時間枠:1 year post-randomization
|
Incidences of chronic GVHD will be graded per Shulman et al. 1980.
This reference categorizes chronic GVHD as either limited or extensive.
For this outcome, participants developing either type are considered to have a chronic GVHD event.
|
1 year post-randomization
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Number of Infections Per Participant
時間枠:2 years post-randomization
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2 years post-randomization
|
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Percentage of Participants With Relapse
時間枠:1 year post-randomization
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Relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, or MDS consistent with pre-transplant features.
Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after transplantation.
|
1 year post-randomization
|
Percentage of Participants With Treatment-related Mortality
時間枠:1 year post-randomization
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Treatment related mortality is defined as death without relapse of the primary disease.
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1 year post-randomization
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Number of Participants With Engraftment Syndrome
時間枠:Day 100 post-transplant
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Day 100 post-transplant
|
協力者と研究者
出版物と役立つリンク
一般刊行物
- Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi MS, Storb R, Thomas ED. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980 Aug;69(2):204-17. doi: 10.1016/0002-9343(80)90380-0.
- Wagner JE Jr, Eapen M, Carter S, Wang Y, Schultz KR, Wall DA, Bunin N, Delaney C, Haut P, Margolis D, Peres E, Verneris MR, Walters M, Horowitz MM, Kurtzberg J; Blood and Marrow Transplant Clinical Trials Network. One-unit versus two-unit cord-blood transplantation for hematologic cancers. N Engl J Med. 2014 Oct 30;371(18):1685-94. doi: 10.1056/NEJMoa1405584.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
- 免疫系疾患
- 組織型別の新生物
- 新生物
- リンパ増殖性疾患
- リンパ疾患
- 免疫増殖性疾患
- 骨髄疾患
- 血液疾患
- 骨髄増殖性疾患
- 白血病、リンパ
- 骨髄異形成症候群
- 白血病
- 白血病、骨髄性
- 白血病、骨髄性、急性
- 前駆細胞リンパ芽球性白血病-リンパ腫
- 白血病、骨髄性、慢性、BCR-ABL陽性
- 薬の生理作用
- 薬理作用の分子機構
- 抗感染剤
- 酵素阻害剤
- 抗リウマチ剤
- 抗悪性腫瘍薬
- 免疫抑制剤
- 免疫学的要因
- 抗悪性腫瘍薬、アルキル化
- アルキル化剤
- 骨髄破壊的アゴニスト
- 皮膚科用薬
- 抗菌剤
- 抗生物質、抗悪性腫瘍薬
- 抗真菌剤
- 抗結核剤
- 抗生物質、抗結核薬
- カルシニューリン阻害剤
- シクロホスファミド
- フルダラビン
- ミコフェノール酸
- シクロスポリン
- シクロスポリン
その他の研究ID番号
- BMTCTN0501
- 5U24CA076518 (米国 NIH グラント/契約)
- 2U01HL069294 (米国 NIH グラント/契約)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
IPD 共有時間枠
IPD 共有アクセス基準
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。
骨髄異形成症候群の臨床試験
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