本文關(guān)鍵詞：重型地中海貧血造血干細(xì)胞移植后血細(xì)胞減少原因的臨床研究　出處：《南方醫(yī)科大學(xué)》2013年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 地中海貧血 造血干細(xì)胞移植 血細(xì)胞減少 HLA不相合 移植物抗宿主病

【摘要】：研究背景 重型β地中海貧血(thalassemia major)是β-珠蛋白鏈合成減少或消失,導(dǎo)致a-珠蛋白鏈不平衡和無效紅細(xì)胞被破壞產(chǎn)生溶血性貧血的一種遺傳性疾病。雖然規(guī)律輸血加去鐵治療已顯著改善了患者預(yù)期壽命。然而與鐵過載相關(guān)的并發(fā)癥并不能通過去鐵治療治愈,同時(shí)一生輸血很難遵守,唯一根治療法依然是通過異基因造血干細(xì)胞移植替代缺陷紅細(xì)胞生成。我中心使用獨(dú)倉NF-08-TM新預(yù)處理方案包括加強(qiáng)預(yù)防急性移植物抗宿主病,通過克服異基因移植高排斥率,明顯提高了無關(guān)供者外周血干細(xì)胞移植和HLA全相合同胞供者移植效果。然而移植后隨診過程中我們觀察到少數(shù)病人出現(xiàn)血細(xì)胞減少,目前病因并不清楚。可能的病因包括預(yù)處理時(shí)使用骨髓毒性藥物、病毒感染及與移植相關(guān)的一些因素,如供者年齡、HLA配型,供受者CMV狀態(tài),干細(xì)胞來源和慢性移植物抗宿主病。因此找出病因十分重要,有人認(rèn)為可能與使用環(huán)胞素A導(dǎo)致自身免疫抑制有關(guān),另有人認(rèn)為可能與慢性移植物抗宿主病或其它病因有關(guān)。至目前,尚未有關(guān)于重型地中海貧血造血干細(xì)胞移植后血細(xì)胞減少的報(bào)道及其病因,因此,我們對(duì)我中心行造血干細(xì)胞移植重型地中海貧血187例患兒資料進(jìn)行總結(jié)、分析。 研究目的 本課題旨在探討重型地中海貧血患兒在異基因造血干細(xì)胞移植28天后發(fā)生血細(xì)胞少的原因,通過對(duì)與血細(xì)胞減少的相關(guān)危險(xiǎn)因素進(jìn)行分析,以便找出與血細(xì)胞減少相關(guān)的危險(xiǎn)因素,以此為臨床治療提供指導(dǎo)。 研究方法 我們回顧性的分析2009年1月～2012年11月于我中心行造血干細(xì)胞移植重型β-地中海貧血患兒187例,其中男117例,女70例,年齡2.0～16歲,中位年齡6歲。中位隨訪時(shí)間19個(gè)月(范圍1-44個(gè)月)。120例接受變更供者移植(alternative donor transplant ADT)(無關(guān)供者109例,父母供者11例),67例行同胞移植。其中發(fā)生血細(xì)胞減少的共39例,我們對(duì)39例發(fā)生血細(xì)胞減少病人與148例未發(fā)生血細(xì)胞減少病人進(jìn)行比較、分析。根據(jù)地貧患兒年齡、肝臟大小和鐵蛋白水平,將重型地中海貧血分為Ⅰ度、Ⅱ度和Ⅲ度。與血細(xì)胞減少的相關(guān)危險(xiǎn)因素包括：供受者年齡、性別、血清中巨細(xì)胞病毒感染情況,HLA配型、ABO血型、干細(xì)胞來源、移植類型、急性移植物抗宿主病及慢性移植物抗宿主病。 預(yù)處理方案、GVHD預(yù)防 所有患兒均采用我中心NF-08-TM新預(yù)防處理方案,新方案主要由環(huán)磷酰胺CY(-10天～-9天),氟達(dá)拉濱Flu(-8天～-4天),靜脈馬利蘭Bu(-8天～-6天),塞替哌TT(-5天)組成,其中馬利蘭的藥物劑量根據(jù)患兒年齡制定。馬利蘭的穩(wěn)態(tài)血液濃度維持在300-600ng/m1為宜,當(dāng)小于300ng/ml或大于600ng/ml時(shí)亦進(jìn)行藥量調(diào)整,即總量再增加或減少1.2mg/kg,增加或減少的劑量在-6d分次給藥。所有的病人在移植前-45天時(shí)開始服用硫唑嘌呤3mg/kg/d及羥基脲30mg/kg/d。GVHD的預(yù)防采用聯(lián)合多種免疫抑制劑,包括環(huán)胞素A(Cs-A)、嗎替麥考酚酯(MMF)及短療程的甲氨喋呤,具體方法是靜脈應(yīng)用環(huán)胞素A(Cs-A)-10天～-2天、劑量為1.5mg/kg.d,在-1d天～+25天劑量為3mg/kg.d,之后口服給藥,使血藥濃度維持在200±50ng/ml。MMF在+1天到+30天序貫給藥,劑量為15mg/kg.d、分兩次口服,條件是移植后沒有Ⅱ度以的GVHD(graft-versus-host disease), MTX是在移植后+1天、+3天、+6天靜脈給藥,劑量分別是10mg/m2、10mg/m2、10mg/m2。在變更供者移植組,所有病人均接受外周血干細(xì)胞移植,且大部分患兒接受的是無關(guān)供者。 植入證據(jù)檢測 移植后常規(guī)于28天、第2月、第3月、第6月及移植后1年行植入證據(jù)檢測,如果一個(gè)患兒植入不佳,可能隨時(shí)進(jìn)行植入證據(jù)檢測。供受者間性別不同者以FISH檢查染色體變化為依據(jù),性別相同者進(jìn)行HLA定量監(jiān)測DNA短程串聯(lián)重復(fù)序列多態(tài)性分析。植入成功的標(biāo)準(zhǔn)有間接指標(biāo)和直接指標(biāo)。(1)、間接指標(biāo)：移植后臨床存活時(shí)間超過21天；各造血系統(tǒng)恢復(fù)正常,包括紅系、粒系、淋巴系、巨核系等；臨床上發(fā)生GVHD。中大的肝脾回縮至正常大小；乳酸脫氫酶(LDH)降至正常水平。(2)、直接指標(biāo)：紅細(xì)胞抗原(ABO和Rh型轉(zhuǎn)換成供者血型)、細(xì)胞遺傳學(xué)標(biāo)記(外周血或骨髓性染色體轉(zhuǎn)變成供者型)、HLA抗原(在HLA配型不全相合的病例中,HLA抗原轉(zhuǎn)換為供者型)、分子遺傳學(xué)證據(jù)(應(yīng)用PCR擴(kuò)增短串聯(lián)重復(fù)序歹PCR-STR分析移植后病例外周血中,供者的遺傳學(xué)標(biāo)記及所占的比例)。 血細(xì)胞減少定義 滿足以下標(biāo)準(zhǔn)之一我們就定義為移植28天后血細(xì)胞減少；1)外周血白細(xì)胞計(jì)數(shù)小于3G/L,持續(xù)4周或4周以上；2)中性粒細(xì)胞計(jì)數(shù)小于0.5G/L,持續(xù)4周或4周以上；3)血紅蛋白小于9.0g/dl,持續(xù)4周或4周以上；4)血小板小于20.0×107mm3,持續(xù)4周或4周以上；身免疫性溶血性貧血(AIHA)定義為臨床上有明確的溶血,且實(shí)驗(yàn)室檢查Coombs試驗(yàn)陽性。 統(tǒng)計(jì)學(xué)分析 單因素和多因素logistic回歸模型評(píng)估了與上述定義的血細(xì)胞減少相關(guān)風(fēng)險(xiǎn)因素的優(yōu)勢比及其95%置信區(qū)間。協(xié)變量(與血細(xì)胞減少的相關(guān)危險(xiǎn)因素)包括供者年齡、受者年齡、供者性別、受者性別、供受者ABO血型是否相合、供受者巨細(xì)胞病毒感染狀態(tài),HLA配型、干細(xì)胞來源、移植類型、急性移植物抗宿主病及慢性移植物抗宿主病。如果單因素分析單個(gè)協(xié)變量時(shí),其P值小于0.05,此協(xié)變量即納入多因素分析,所有P值均為雙側(cè)檢驗(yàn)。此外,我們采用混合效應(yīng)模型進(jìn)一步探討了外周血白細(xì)胞計(jì)數(shù)與環(huán)胞素A血藥濃度、甲強(qiáng)劑量之間的關(guān)系,同時(shí)x2比較了變更供者移植組與同胞供者移植組兩組血細(xì)胞減少發(fā)病率。我們采用統(tǒng)計(jì)學(xué)軟件SPSS13.0和SAS9.2進(jìn)行的分析。結(jié)果 187例重型地中海貧血造血干細(xì)胞移植的患兒,共39例在移植28天后發(fā)生血細(xì)胞減少,累積一年發(fā)病率20.9%(95%置信區(qū)間11.5%-26.7%)。血細(xì)胞減少發(fā)生的中位時(shí)間為移植后102天(范圍48天～189天),血細(xì)胞減少持續(xù)的中位時(shí)間70天(范圍28天～308天)。39例發(fā)生血細(xì)胞減少的患兒,白細(xì)胞計(jì)數(shù)小于3G/L、2G/L、1G/L,分別有24例、9例、3例,其中有34例僅白細(xì)胞減少、2例AIHA、1例血小板減少、1例白細(xì)胞減少合并AIHA,還有1例白細(xì)胞+血小板減少。我們比較了ADT組與MST組兩組的發(fā)病率,結(jié)果顯示ADT組發(fā)病率明顯高于MST組(25.8%vs.11.9%,P=0.025),具有統(tǒng)計(jì)學(xué)意義,這可能與ADT組中HLA不相合的例數(shù)多有關(guān)。我們進(jìn)一步分析了ADT組中HLA配型相合與否的發(fā)病率,結(jié)果顯示HLA不相合的發(fā)病率明顯高于相合發(fā)病率(31/120,36.4%vs8/67,19.7%,P=0.045)。我們進(jìn)一步比較了C1C1純合子受者與C1C2雜合子受者發(fā)病率,結(jié)果顯示前者發(fā)病率明顯高于后者(P=0.018)。 單因素分析結(jié)果顯示,與血細(xì)胞減少相關(guān)的危險(xiǎn)因素有HLA配型不相合(尤其A、DR位點(diǎn)不相合)和干細(xì)胞來源(同胞移植與變更供者移植相比,同胞移植傾向于不易發(fā)生血細(xì)胞減少,OR=0.389,P=0.028),因HLA配型B、C位點(diǎn)不相合例數(shù)太少,并沒有納入分析。多因素分析結(jié)果顯示僅HLA不相合具有統(tǒng)計(jì)學(xué)意義(OR=2.561,P=0.023),同時(shí)混合效應(yīng)模型結(jié)果顯示白細(xì)胞計(jì)數(shù)與環(huán)胞素A(β=0.002037P0.001)、甲強(qiáng)劑量(β=0.6053P0.001)具有顯著統(tǒng)計(jì)學(xué)差異,與患兒年齡亦有統(tǒng)計(jì)學(xué)差異(β=0.1357P=0.0364),但甲強(qiáng)劑量與患兒年齡之間存在交互效應(yīng)(β=-0.04345P0.001),與患兒性別沒有統(tǒng)計(jì)學(xué)差異(P=0.7241)。 34例僅有白細(xì)胞減少的病人,我們通過調(diào)整環(huán)胞素A和(或)甲強(qiáng)劑量,或者改環(huán)胞素A為他克莫司膠囊,有些病人需要聯(lián)合甲氨喋呤治療。經(jīng)過治療后,其中有30例病人經(jīng)過中位時(shí)間70天(范圍28天-308天)白細(xì)胞均恢復(fù)正常。39例中其中有2例白細(xì)胞減少病人予兔抗人胸腺細(xì)胞免疫球蛋白(Thymoglobuline)(總量5mg/kg),1例病人白細(xì)胞已恢復(fù)正常,另1例血象仍在2G/L左右,此外還有3例病人移植后已3月余,至此次研究結(jié)束時(shí)白細(xì)胞減少未恢復(fù)正常。39例血細(xì)胞減少患兒僅1例于移植后5月余死于繼續(xù)性糖尿病和肺部感染。 結(jié)論 ADT供者、HLA不相合、對(duì)免疫抑制劑治療反應(yīng)良好、減Cs-A和MP劑量過程中出現(xiàn)皮疹、白細(xì)胞計(jì)數(shù)與Cs-A濃度相關(guān)、C1C1受者血細(xì)胞減少的高發(fā)病率及血細(xì)胞減少發(fā)生的時(shí)間)這些通常與惡性疾病造血干細(xì)胞移植后cGVHD有關(guān)�；谶@些原因,我們認(rèn)為移植28天后血細(xì)胞減少這一并發(fā)癥,可能是年齡較小患兒在接受異基因造血干細(xì)胞移植后一種cGVHD的表現(xiàn),盡管按現(xiàn)在美國西雅圖或美國國立衛(wèi)生研究院的標(biāo)準(zhǔn)并不能診斷為cGVHD。
[Abstract]:Research background
Beta thalassemia major (thalassemia major) is the beta globin chain synthesis to reduce or disappear, resulting in a- globin chain imbalance and ineffective erythropoiesis destroyed a hereditary disease of hemolytic anemia. Although regular blood transfusion and iron therapy has significantly improved the life expectancy. However not associated with complications and iron overload by iron treatment. At the same time, it is difficult to comply with the life of blood transfusion, the only method is still the root treatment by allogeneic hematopoietic stem cell transplantation is defective erythropoiesis. Use only the new warehouse NF-08-TM pretreatment program I center including the strengthening of the prevention of acute graft-versus-host disease, by overcoming the high rejection rate of allogeneic transplantation and obviously improves the unrelated HLA transplantation and peripheral blood stem cells matched sibling donor transplantation. However in the process of follow-up after transplantation, we observed a few patients less blood cells, At present, the etiology is not clear. The possible causes include the use of bone marrow toxicity drug pretreatment, virus infection and some factors associated with transplantation, such as donor age, donor recipient HLA matching, CMV, source of stem cells and chronic graft-versus-host disease. Therefore, to find out the cause is very important, some people think that may be related to the use of cyclosporin A leads to autoimmune inhibition, others believe that may be associated with chronic graft-versus-host disease or other causes. At present, there has not been a severe Mediterranean anemia after hematopoietic stem cell transplantation hematocytopenia reports and etiology, therefore, our analysis of our center for hematopoietic stem cell transplantation for thalassemia 187 cases of data summary.
research objective
The purpose of this study is to investigate thalassemia major in allogeneic hematopoietic stem cell transplantation after 28 days causes less blood cells, the relevant risk reduction and blood cell factor analysis, in order to find out the risk factors associated with blood cells decreased, so as to provide guidance for clinical treatment.
research method
We conducted a retrospective analysis of January 2009 ~ November 2012 in our center for hematopoietic stem cell transplantation in children with beta thalassemia major in 187 cases, male 117 cases, female 70 cases, aged 2 to 16 years old, the median age was 6 years. The median follow-up time was 19 months (range 1-44 months).120 patients undergoing change donor transplantation (alternative donor transplant ADT (109 cases), unrelated donor parents for 11 cases), 67 cases which occurred compatriots transplantation. Blood cells to reduce the total of 39 cases, we in 39 cases of pancytopenia patients and 148 patients without hematocytopenia were compared, according to the analysis of children with thalassemia. Age, liver size and ferritin levels, the thalassemia major is divided into first degree, second degree and third degree. Including the related risk factors and reduce blood cells: donor age, sex, human cytomegalovirus infection in serum, HLA type, ABO type, source of stem cells, migration Graft type, acute graft versus host disease and chronic graft versus host disease.
Preprocessing scheme, GVHD prevention
All patients were treated with the new scheme to prevent the center of NF-08-TM, the new scheme is mainly composed of CY (cyclophosphamide -10 days to -9 days), Flu (-8 ~ -4 days of fludarabine, intravenous busulfan (Bu days) -8 days to -6 days), tespamin TT (-5 days), the dosage of busulfan based on children age set. Steady blood concentration of busulfan maintenance in 300-600ng/m1 is appropriate, when less than 300ng/ml or greater than 600ng/ml for dose adjustment, the total increase or decrease 1.2mg/kg, increase or decrease the dose of -6d in divided doses. All patients started taking azathioprine 3mg/kg/d and hydroxyurea prevention by 30mg/kg/d.GVHD combined with a variety of immunosuppressive agents in the -45 days before transplantation, including cyclosporine A (Cs-A), mycophenolate mofetil (MMF) and short course methotrexate, the specific method of intravenous cyclosporin A (Cs-A) -10 days to -2 days, the dose of 1.5mg/kg.d, in -1d days ~ +25 day dose of 3mg/kg.d after oral administration, the blood concentration was maintained at 200 + 50ng/ml.MMF in +1 days to +30 days sequential therapy, the dose of 15mg/kg.d, two times a day, there is no second degree in the condition of GVHD after transplantation (graft-versus-host disease), MTX + 1 days after transplantation +3 days, +6 days intravenous dose were 10mg/m2,10mg/m2,10mg/m2. changes in the donor transplantation group, all patients received peripheral blood stem cell transplantation, and most of the children accept is unrelated donors.
Implantable evidence detection
On the 28 day after transplantation routine, second months, third months, sixth months and 1 years after transplantation for implantation of evidence detection, if a patient implanted poor may be detected at any time. Evidence of implantation between donor and recipient gender difference in FISH examination of chromosomal changes on the basis of the same sex were HLA DNA short tandem quantitative monitoring repeat polymorphism analysis. Implantation of the standard of success has indirect index and direct index. (1), indirect index: transplantation survived more than 21 days; the normal hematopoietic system, including erythroid, myeloid, lymphoid, megakaryocyte; clinical occurrence of GVHD. retraction to normal size; lactate dehydrogenase (LDH) decreased to normal level. (2), a direct indicator: red cell antigens (ABO and Rh into the donor's blood type), cytogenetic markers (change of peripheral blood or myeloid chromosomes of donor HLA antigen (HLA), in the match is not full Matched cases, HLA antigen into donor type), molecular genetic evidence (PCR amplification of short tandem repeat sequence or PCR-STR analysis after transplantation of peripheral blood disease, genetic markers of the donor and the proportion).
Definition of hemocyte reduction
Meet the following criteria is defined as one of our 28 days after transplantation of blood cells decreased; 1) peripheral white blood cell count is less than 3G/L, for 4 weeks or 4 weeks; 2) neutrophil count is less than 0.5G/L, for 4 weeks or 4 weeks; 3) hemoglobin less than 9.0g/dl, for 4 weeks or 4 weeks 4); platelet is less than 20 * 107mm3, 4 weeks or 4 weeks; autoimmune hemolytic anemia (AIHA) is defined as a clear clinical and laboratory examination of hemolytic, positive Coombs test.
Statistical analysis
Univariate and multivariate logistic regression models were evaluated and defined above hematocytopenia related risk factors of odds ratio and 95% confidence intervals (covariate related risk reduction and blood cell factors) including donor age and recipient age, donor recipient gender, gender, donor recipient ABO blood is consistent and the state of cytomegalovirus infection in donor, HLA typing, source of stem cells, transplantation, acute graft-versus-host disease and chronic graft-versus-host disease. If the single factor analysis of individual covariates, the P value is less than 0.05, the covariates that included in the multivariate analysis, all P values are bilateral test. In addition, we use the mixed effect model to further explore the peripheral white blood cell count and cyclosporine A blood concentration, the relationship between a strong dose of X2, and compared the change of donor transplantation group and sibling donor transplantation blood cells of two groups decreased The incidence of the disease. We used statistical software SPSS13.0 and SAS9.2 analysis.
187 cases of children with thalassemia major hematopoietic stem cell transplantation, 39 cases occurred after 28 days of blood cells decreased, a year cumulative incidence rate of 20.9% (95% confidence interval 11.5%-26.7%). Blood cells decreased as the median time of occurrence in the 102 day after transplantation (range 48 ~ 189 days), median hematocytopenia the duration of 70 days (range 28 ~ 308 days).39 cases of pancytopenia in children, white blood cell count is less than 3G/L, 2G/L, 1G/L, there were 24 cases, 9 cases, 3 cases, of which 34 cases only leukopenia, 2 cases AIHA, 1 cases of thrombocytopenia, 1 cases of white the cell associated with a reduction in AIHA, there are 1 cases of white blood cells + thrombocytopenia. We compared ADT group and MST group the incidence of patients in the two groups, results showed that the incidence of ADT group was significantly higher than that of MST group (25.8%vs.11.9%, P=0.025), with statistical significance, which may be related to ADT and HLA in the group of mismatched cases we more. Further analysis of the ADT group Consistency in HLA typing and the incidence, the results showed that the onset of mismatched HLA was significantly higher than that of the matched incidence (31/120,36.4%vs8/67,19.7%, P=0.045). We compared C1C1 homozygous recipients with C1C2 heterozygous recipients of incidence, the results suggest that the incidence rate is significantly higher than the latter (P=0.018).
Univariate analysis showed that blood cells decreased and related risk factors of HLA mismatch (especially A, unrelated DR) and the source of stem cells (donor transplantation and transplantation compatriots change compared to sibling transplants tend not to occur hematocytopenia, OR=0.389, P=0.028, HLA) for type B unrelated C cases, too few, and not included in the analysis. The results of multivariate analysis showed that only HLA was not consistent with statistical significance (OR=2.561, P=0.023), and mixed effects model showed that white blood cell count and cyclosporin A (beta =0.002037P0.001), a high dose (beta =0.6053P0.001) with significant statistical differences. The age of children, and there were significant differences (P =0.1357P=0.0364), but there is a strong interaction between dose and age (P =-0.04345P0.001), no statistically significant differences between gender and children (P=0.7241).
Only 34 patients with leukopenia, we adjust the cyclosporin A and (or) a strong dose, or cyclosporin A for Tacrolimus Capsules, some patients need combined with methotrexate treatment. After treatment, the 30 patients after a median of 70 days (range, 28 days -308 days) of white blood cells were normal in.39 cases, including 2 cases of leukopenia treated with rabbit antithymocyte globulin (Thymoglobuline) (total 5mg/kg), 1 cases of white blood cells the patient has returned to normal, the other 1 cases of blood is about 2G/L, in addition to 3 cases of patients after transplantation was 3 times more than a month, at the end of the study when leukopenia did not restore normal.39 patients hypocytosis were only 1 cases in 5 months after transplantation to diabetic and died of pulmonary infection.
conclusion
ADT donor, HLA mismatched, good response to immunosuppressive therapy, rash Cs-A and MP dose reduction process, white blood cell count and Cs-A concentration, C1C1 recipients of blood cells to reduce the high incidence and blood cells to reduce the occurrence of time) these are usually malignant diseases and hematopoietic stem cell transplantation on cGVHD. Based on these reasons, we believe that 28 days after transplantation of blood cells to reduce the complications, may be smaller children in an expression of a cGVHD after allogeneic hematopoietic stem cell transplantation, although by now the United States of Seattle or the National Institutes of health standards and can not be diagnosed as cGVHD.

【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R725.5

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