Prospective monitoring of human adenovirus in pediatric allogeneic hematopoietic cell transplant recipients

강지만 성균관대학교 일반대학원 2017 국내박사

Background: Human adenovirus (HAdV) can cause severe illness in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients. The epidemiology of HAdV in HCT recipients varies in different regions or countries, and the relationships between HAdV types and clinical severity has not been established. The objective of this study was to investigate the epidemiology of HAdV in Korean pediatric recipients and to explore the clinical correlations of HAdV types. Methods: A prospective monitoring of HAdV infection was conducted in allogeneic HCT recipients (< 19 years) between April 2012 and September 2014 at Samsung Medical Center, Seoul, Korea. HAdV in blood, urine, and stool specimens was monitored weekly from transplantation to post-HCT day 100. Respiratory specimens were also tested if respiratory symptoms were present as a part of routine-care practice. We performed further tests when HAdV infection was clinically suspected during the post-HCT follow-up period. Results: A total of 1,734 specimens were included among 57 consecutively enrolled recipients. The cumulative incidence rates of HAdV infection and viremia at 2 years after HCT were 22.9% and 8.3% respectively. Median time from HCT to first HAdV detection was 113 days (range, 7-591 days). All HAdV viremia cases were caused by HAdV B3, whereas several types were detected in stool specimens. Two of four patients with HAdV viremia died of disseminated HAdV infection. Multiple types of HAdV were detected in two patients. Lower absolute lymphocyte counts (ALC) and extensive chronic graft-versus-host disease (GVHD) were significantly associated with HAdV viremia in recipients who had HAdV infection (P=0.028 in lower ALC and P=0.006 in extensive chronic GVHD, respectively). Extensive chronic GVHD was identified as a risk factor for HAdV viremia in univariable analysis (P=0.013). Conclusion: This was the first study to investigate the epidemiology of HAdV infection in Korean HCT recipients. Watchful monitoring for HAdV viremia is recommended in high-risk allogeneic HCT recipients to provide information facilitating timely decisions regarding preemptive treatment and/or modulation of immunosuppressive agents. 연구 배경: 아데노바이러스 감염증은 소아 동종조혈모세포이식 환자에서 중증 감염질환 및 심각한 합병증을 유발할 수 있다. 아데노바이러스 감염증의 역학은 지역 및 국가별로 다를 수 있으며, 아형에 따른 중증도 및 파종성 질환으로 진행여부 등은 아직 명확하게 밝혀진 바 없다. 본 연구는 우리나라 소아 동종조혈모세포이식 환자를 대상으로 아데노바이러스 감염증에 대한 역학 및 아형에 따른 임상양상을 살펴보고자 하였다. 연구 방법: 2012년 4월에서 2014년 9월까지 삼성서울병원 소아조혈모세포이식 병동에서 동종조혈모세포이식을 받은 만 19세 미만의 소아청소년을 대상으로 진행하였다. 말초혈액, 대변, 소변 검체는 이식일로부터 이식 후 100일까지 매주 전향적으로 수집하였으며, 중합효소연쇄반응을 통해 바이러스 핵산을 증폭하여 검사하였다. 호흡기 검체를 통한 검사는 임상 진료의 일환으로 시행되었으며, 연구 기간 동안 임상적으로 의심되는 경우, 이식 후 100일이 경과하였어도 검체를 수집하여 검사를 진행하였다. 연구 결과: 총 57명의 환자가 연구에 참여하였으며, 총 1,734개의 검체가 분석에 사용되었다. 이식 후 2년까지의 아데노바이러스 감염의 누적 발생률은 22.9%였으며, 아데노바이러스 혈증의 누적 발생률은 8.3%였다. 아형으로는 B3가 가장 많았으며(총 5건), 다음으로는 C1(총 3건)였다. 아데노바이러스 혈증은 총 4명에서 발생하였으며 모두 B3 아형으로 그 중 2명이 파종성 아데노바이러스감염증 및 폐렴으로 연관되어 사망하였다. 중증 림프구감소증이나 중증 만성 이식편대숙주질환이 동반된 아데노바이러스감염증의 경우, 파종성 질환으로 진행할 수 있는 아데노바이러스 혈증과 유의한 상관관계를 보였다. (중증 림프구감소증의 경우, P=0.028 및 중증 만성 이식편대숙주질환이 동반된 경우, P=0.006) 결론: 본 연구는 우리나라 소아 동종조혈모세포이식 환자를 대상으로 아데노바이러스 감염증에 대한 역학을 살펴본 국내 최초의 연구이다. 선제적 항바이러스제 치료의 적절한 시작 시점을 결정하기 위해서는 아데노바이러스 혈증에 대한 주의 깊은 모니터링이 중요하며, 아형에 따른 임상적 의의에 대한 추가적인 연구가 필요하다.

정상 핵형의 급성 골수성 백혈병 환자에서 CEPBA 이중 돌연변이가 예후에 미치는 영향 및 공고요법으로 동종조혈모세포이식의 효용성 재고

김재용 전남대학교 2015 국내석사

Background: The CCAAT/enhancer binding protein α (CEBPA) mutations are found in 7%-11% of all AML patients, predominantly in cases carrying normal karyotype (NK-AML). NK-AML with CEBPA mutations is known to present a more favorable prognosis. However, direct comparison of clinical significance according to consolidation therapy has not been widly examined in patients with NK-AML. Methods: A total of 404 patients with NK-AML who received intensive induction chemotherapy were included in the present study. Diagnostic samples from the patients were evaluated for CEBPA, FLT3-ITD, NPM1, TET2, DNMT3A, IDH1/2, WT1, NRAS, FAT2, ASXL2, DNAH11 and GATA2 mutations by direct sequencing. Long-term outcomes were also analyzed. The author compared the treatment outcomes of consolidation chemotherapy alone or allogeneic hematopoietic cell transplantation (HCT) in patients with CEBPA double mutations (dm) using propensity score matching (PSM) analysis. Results: CEBPA mutations were observed in 78/404 patients (19.3%). CEBPA single (sm) or double mutation (dm) was observed in 27 (6.7%) and 51 (12.6%) patients, respectively. CEBPAdm was associated with GATA2mut and less frequently with FLT3-ITDpos, NPM1mut and DNMT3Amut in comparison with CEBPAwild, or CEBPAsm (all p < 0.05). CEBPAdm was observed in younger patients incomparison with CEBPAwild (OR: 0.952) and CEBPAsm (OR: 0.956). Of 404 patients receiving induction chemotherapy, CEBPAdm showed higher CR rate in comparison with CEBPAwild (96.3% vs. 78.4%, p = 0.002). On multivariate analysis, CEBPAdm (p = 0.007, OR: 39.593) was confirmed as an independent risk factor for achievement of CR. with median follow-up of 59.4 months, CEBPAdm showed a statistically favorable overall survival (OS), event free survival (EFS) and lower relapse incidence (RI) in comparison with CEBPAwild (all, p < 0.005). Comparison of clinical outcome analyses (between consolidation chemotherapy and allogeneic HCT) identified the role of consolidation treatment in patients with CEBPAdm. Both treatments showed similar OS and non-relapse mortality (NRM) (all p > 0.05). However, EFS and RI were significantly improved in patients receiving allogeneic HCT (all, p < 0.05). Allogeneic HCT showed a trend of lower relapse risk and higher NRM on paired PSM analysis in 14 patients. However, there was no statistical difference in OS and EFS. Conclusion: CEBPAdm was associated with other molecular mutations. Consolidation chemotherapy alone may overcome higher relapse rates by reducing the treatment mortality and increasing survival after relapse events in patients with CEBPAdm in NK-AML. This study suggested that CEBPAdm may improve the prognosis and stratification of consolidation therapy in NK AML.

Prevention of graft-versus-host disease with a novel synthetic microtubule-binding agent IC229

이선미 인제대학교 일반대학원 2014 국내박사

Efficacy of preemptive treatment with a half-dose of ganciclovir for CMV infection after pediatric allogeneic hematopoietic stem cell transplantation : 소아 동종 조혈모세포이식 후 발생한 거대세포바이러스 감염에서 절반 용량 ganciclovir preemptive treatment의 효과

주희영 서울대학교 대학원 2014 국내석사

Introduction: Cytomegalovirus (CMV) infection remains a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Ganciclovir has potent activity against CMV and has been used successfully to treat CMV infection in immunocompromised recipients. However, the suppression of bone marrow function associated with ganciclovir treatment has been of particular concern. We did acyclovir prevention in all patients, and preemptive treatment of CMV infection with a half-dose of ganciclovir in asymptomatic recipients of HSCT when CMV antigenemia level was under 10/200,000 cells. Methods: Preventive acyclovir was administered at all of the HSCT patients. Patients received a preemptive half-dose of IV ganciclovir (5mg/kg once daily, 6 days a week) when CMV antigenemia had been detected at least once in less than 10/200,000 cells. If CMV antigenemia had been detected in more than or equal to 10/200,000 cells, conventional ganciclovir induction therapy (5mg/kg every 12 hours) was administered. When the CMV antigenemia was checked to be negative twice at the routine antigenemia test per 3 days, we concluded that the antigenemia was cleared and terminated the treatment. Results: A total of 130 patients were evaluated. CMV antigenemia was detected in 87 (66.9%) patients. The median day of CMV detection was 31 (11-300) days after transplantation, and the median number of cells in CMV antigenemia was 2 (1-49)/200,000 cells. Seventy-four patients (85.1%) received preemptive treatment with a half-dose of ganciclovir. Twenty-three (31.1%) patients of those who initially received half-dose of ganciclovir needed following induction therapy because of increase in CMV antigenemia over 10/200,000 cells in spite of the preemptive treatment. In fifty-one (68.9%) patients, viral clearance was achieved which meant half dose GCV was sufficient for the treatment of CMV infection. Only two (2.7%) patient who started with half-dose ganciclovir treatment developed CMV retinitis. Conclusions: This article conclude preemptive treatment with half-dose ganciclovir for patients with CMV antigenemia whose level is under 10/200,000 cells could be a successful and safe approach for CMV infection after HSCT.

HLA-일치 혈연공여자가 없는 소아 백혈병 환아의 이식:혈청학적-불일치 제대혈이식 혹은 대립유전자-일치 혹은-불일치 비혈연공여자 중 누구를 선택할 것인가?

김현정 전남대학교 대학원 2010 국내박사

Purpose: The choice of the best donor for hematopoietic stem cell transplantation (HSCT) is often difficult for pediatric patients lacking HLA-matched related donors (MRDs). The aim of this study was to compare the clinical outcomes of allele-matched (M)-unrelated donor (UD) or -mismatched (MM)-UD transplantation and those of unrelated umbilical cord blood (UCB) transplantation in children with leukemia. Materials and Methods: The author retrospectively evaluated 34 children with leukemias transplanted from UDs at Chonnam National University Hospital between Jan., 1996 and July, 2009. And the results were compared with those from 35 MRD transplants. All UCBs were typed for HLA-A, ?CB, and ?CDR at antigen levels. UDs were matched based on allele typing of HLA-A, -B, -C and -DRB1. Allele-MM UDs were accepted for transplantation only when they were 6/6 matched at antigen levels (HLA-A, -B, and DRB1). Results: The numbers of transplants were as follows: Allele-M-UD, 10; MM-UD, 13; UCB, 11. In MM-UD group, one allele locus was mismatched in 7, two loci in 5, and three in 1. Most UCBs (n=9) were one antigen mismatched. UCB units were chosen primarily based on cell dose. Median day to absolute neutrophil count (ANC) ◎ 0.5x109/L was 15 in MRD, 16 in M-UD, 18 in MM-UD, and 21 in UCB group (P=.01). Median day to platelet ◎ 20x109/L was 19, 23, 30 and 45, respectively (P=.003). Acute graft-versus-host disease (GvHD) of grade II-IV was found in 11.4%, 30.0%, 15.4%, and 36.4%, respectively (P=.124). The incidence of chronic GvHD was 20.3%, 27.1%, 37.7%, and 28.6%, respectively (P=.403). The 5-year Kaplan-Meier overall survival (OS) rate was 77.1% for MRD, 53.8% for M-UD, 71.8% for MM-UD, and 45.5% for UCB (P=.050). MRD group showed higher OS and LFS rate than UCB group (P=.013, P=.017, respectively). However, the OS rate of M- and MM-UD together (65.7%) was not different from that of MRD group (77.1%, P=.270), or from that of UCB (45.5%, P=.153). The cumulative incidence of relapse at 5 years was 18.6%, 25.0%, 10.0%, and 0%, respectively (P=.530). The cumulative incidence of 100-day transplant-related mortality (TRM) was 2.9%, 22.2%, 7.7%, and 36.4%, respectively (P=.011). Conclusion: The outcome of HSCT in children using alternative donors has improved significantly in recent years, now approaching to that from MRDs. MM-UD transplants showed at least comparable survival to M-UD transplants, if serologically 6/6 matched. The benefit of low relapse rate in UCB group was offset by a high TRM in early postransplant period, probably secondary to a slower engraftment. UD transplant, even mismatched, should be pursued in patients who lack MRD. Improvement in the selection of UCB units and supportive measures should result in a better outcome in UCB transplantation. These results justified the simultaneous search of unrelated BM donors and unrelated UCB units when a child with acute leukemia is in need of an alternative transplants. The decision should be based on the number of HLA disparities, the urgency of the transplant, and cell contents of the graft.

TLR2 신호에 의한 G-CSF 결집 말초골수세포 생착 촉진 효능 증강

오경희 인제대학교 2012 국내석사

A high frequency of G-CSF-mobilized myeloid cells (gMCs) in a donor graft accelerates hematopoietic recovery after peripheral blood stem cell transplantation (PBSCT). However, because of the limited functional efficacy of gMCs, repeated transfusions of gMCs are frequently required. In this study, we investigated a strategy to improve the functional capacity of gMCs during hematopoietic engraftment after allogeneic transplantation. We found that toll-like receptor 2 (TLR2) is constitutively expressed on gMCs. Treating gMCs with the synthetic TLR2 ligand Pam3CSK4 (PAM) dramatically enhanced IL-10 and TNF-α production. However, PAM treatment does not induce substantial cellular maturation. Moreover, PAM treatment significantly improved gMC survival. PAM treated gMCs significantly promoted myeloid differentiation of donor hematopoietic stem cells (HSCs), resulting in accelerated engraftment after allogeneic transplantation. Our data suggest that TLR2-stimulated gMCs may be a novel cellular therapeutic for increasing the efficiency of allogeneic hematopoietic stem cell transplantation (HSCT) by reducing infectious complications associated with delayed engraftment.

소아 백혈병에서 동종조혈모세포이식 후 조기림프구 회복의 의의

김소연 전남대학교 대학원 2010 국내박사

Background: The repopulating lymphocytes after allogeneic hematopoietic stem cell transplantation (HSCT) have an important role not only on the prevention of serious infections in the early transplantation period, but on killing the residual leukemic cells by graft-versus-leukemia effect. Previous studies have suggested that earlier lymphocyte recovery after HSCT was associated with a lower relapse and a better survival in adult patients. The aim of this study was to analyze the impact of lymphocyte recovery after HSCT in children with hematologic malignancies. Patients and Methods: The author retrospectively evaluated 69 children transplanted for acute lymphoblastic leukemia (ALL, n=34), acute myeloid leukemia (AML, n=26), chronic leukemia (n=7) and juvenile myelomonocytic leukemia (n=2) at the Chonnam National University Hospital between Jan. 1996 and Mar. 2008. Stem cell sources were: bone marrow (BM) (n=46), peripheral blood stem cell (PBSC) (n=10), umbilical cord blood (n = 12), and BM + PBSC (n=1). Matched sibling donor was used in 26, while unrelated donors in 43. The patients were grouped based on absolute lymphocyte count (ALC) <500/&micro;L or ≥500/&micro;L at D+21 and D+30 after transplant: Low at D+21 (n = 28) vs. High at D+21 (n = 41); Low at D+30 (n = 19) vs. High at D+30 (n = 49). The impact of lymphocyte recovery after HSCT on predicting the survival, relapse, transplant-related mortality (TRM), and graft versus host disease (GVHD) was retrospectively analyzed in children with hematologic malignancies. Results: The patients were 41 males and 28 females. The median age at transplant was 7.1 years (range, 0.4-18.2). Patients with High ALC at D+21 and D+30 had faster neutrophil and platelet engraftment: The median day of neutrophil engraftment (>1,000/&micro;L) was D+16 for High at D+21 vs. D+21 for Low at D+21 (P =.001); and D+17 for High at D+30 vs. D+20 for Low at D+30 (P =.02), respectively; The median time of platelet engraftment (>20,000/&micro;L) was D+19 for High at D+21 vs. D+38 for Low at D+21 (P =.04); and D+22 for High at D+30 vs. D+40 for Low at D+30 (P =.07), respectively. The High at D+30 group exhibited a better 5 year overall survival (71% vs 53%, P =. 043) and event free survival (72% vs 53%, P =. 065) than Low at D+30 group. The incidence of grade II-IV aGVHD and cGVHD was not different by the ALC counts. Also relapse rate was not different between ALC groups. But the Low at D+30 group was associated with a significantly increased risk of TRM (P=.019). Nine of 19 (47.4%) in Low at D+30 died, while 14 of 49 (28.6%) in High at D+30 died. In univariate analysis, factors associated with decreased survival were Low ALC at D+30 and high risk in ALL patients, and grade II-IV aGVHD in both ALL and AML. Grade II-IV aGVHD was the only variable with a significantly negative impact on survival by multivariate Cox regression analysis. Conclusion: In this study, the author found that earlier lymphocyte recovery greater than 500/μL on D+30 was associated with faster neutrophil and platelet engraftment, decreased TRM, and better survival without increasing the incidence of GVHD. However, faster lymphocyte recovery was not translated into decreased relapse rate. Serial lymphocyte measurement early posttransplant would be a simple but useful method for predicting transplant outcomes. Further studies incorporating larger number of cases and longer follow-up are warranted in children.

소아에서 동종 조혈모세포 이식 후 림프구 면역의 재구축에 영향을 미치는 인자에 관한 연구

배근욱 울산대학교 2010 국내석사

Immune reconstitution after hematopoietic stem cell transplantation (HSCT) has been known to reduce transplantation-related complications such as infections and improve HSCT outcomes. We have retrospectively analyzed lymphocyte reconstitution in 38 pediatric patients with 38 allogeneic HSCT performed for hematologic malignant diseases from April 2006 to July 2008. Peripheral blood samples at pre-HSCT, three months and one year post-transplant were assessed for each subset of lymphocytes (CD3+, CD3+/CD4+, CD4+/CD8+, CD16/56+, and CD19+ lymphocytes). Correlations between reconstitution of each lymphocyte subset and HSCT outcomes were statistically analyzed. The median age of the patients included in the study was 101.5 months (range 10~195), while median follow-up was 25.5 months. Stem cell sources were bone marrow (BM) in 14 cases, peripheral blood stem cells (PBSC) in 24, and cord blood (CB) in eight cases. At 3 months post-transplant, 47%, 13%, 76%, 92%, and 6% of patients showed reconstitution of CD3+, CD3+/CD4+, CD3+/CD8+, CD16+/CD56+, and CD19+ lymphocyte subset, respectively. At one year post-transplant, 88%, 88%, 95%, 93%, and 69% of patients showed reconstitution of CD3+, CD3+/CD4+, CD3+/CD8+, CD16+/CD56+, and CD19+ lymphocyte subset, respectively. Reconstitutions of CD16+/CD56+ and CD3+/CD8+ lymphocyte were achieved rapidly, whereas CD3+/CD19+ lymphocyte was the most latest reconstituted. Age was not related to reconstitution of any lymphocyte subset. TBI and ATG administration were shown to be related to delayed reconstitution of some lymphocyte subset(s). Reconstitutions of CD3+/CD4 lymphocyte and CD3+/CD8+ lymphocytes were significantly delayed in patients who received CB. In patients with cGVHD, recovery of total lymphocyte count and CD19+ lymphocyte at three months post-transplant were significantly delayed than in patients without cGVHD. However, aGvHD and CMV reactivation were not shown to influence any lymphocyte subset. A tendency of lower CD3+ lymphocytes was noted in patients who died of transplant-related complications, though not statistically significant. OS did not differ between the group of patients who achieved reconstitution at three months post-transplant and the group who did not, for any lymphocyte subtype.

Single-nucleotide polymorphism-based risk model to predict the reactivation of cytomegalovirus in allogeneic hematopoietic stem cell recipients

엄지은 성균관대학교 일반대학원 2016 국내박사

목적: 이 연구의 목적은 동종조혈모세포 이식 후에 발생하는 거대세포바이러스(cytomegalovirus, CMV) 재활성화와 연관된 single-nucleotide polymorphism (SNP) 표지자를 확인하고 임상 위험 인자와 결합한 위험 모형을 구축하는 것이다. 방법: 2001년 3월부터 2007년 10월까지 Princess Margaret Cancer Centre (Toronto, ON, Canada)에서 혈연간 혹은 비혈연간 동종 조혈모세포이식을 받고, 이식 전에 공여자와 환자에게서 DNA 검체를 채취하였던 317명의 환자를 대상으로 분석을 시행하였다. 53개 유전자의 248개의 SNPs에 대한 유전자형을 분석하였고, CMV 재활성화와 관련된 위험도를 분석하였다. 위험 모형은 임상 인자와 유전적 SNP 표지자를 모두 이용하여 만들었다. 결과: 이식 후 100일 째 CMV 무활성 생존율 (CMV-free survival, CFS)는 65% (95% confidence interval [CI], 59.3-70.0%)였다. 단변량 분석에서 확인된 CMV 재활성화와 연관된 임상 요인은 환자가 이식 전 CMV 혈청학 양성인 경우와 급성이식편대숙주병 2-4등급이었다. CMV 혈청학적 상태와 급성이식편대숙주병 외에, 환자의 나이 50세 이상도 임상적 위험 인자로 분석에 포함되었다. 9개의 SNP가 위험 모형을 위해 선택되었다; 환자의 IL12RB1 (rs11575926), IKK1 (rs3808916), IFNG (rs2183959), PDGFRB (rs2302273) 및 공여자의 TLR4 (rs11536889), TGFB1 (rs1800469), NFKBIB (rs136645), PDGFD (rs1053861). 3개의 임상 요소와 9개의 SNP를 결합하여 위험 점수를 계산하였고, 환자의 CMV 혈청학적 상태를 제외한 모든 요소에 1점이 부여되었다. 환자의 CMV 혈청학적 상태의 CFS에 대한 조정된 위험 비율이 18.27 (95% CI, 8.48-39.17)이었기 때문에, 환자의 CMV 혈청학적 상태에는 3점이 부과되었다. 나머지 위험 인자들의 조정된 위험 비율은 1.27에서 2.08 사이였다. 점수를 계산한 뒤, 세 그룹으로 다시 분류하였다: 저위험군 (점수 0-6, n=126), 중위험군 (점수 7-9, n=129), 고위험군 (점수≥10, n=62). Time-dependent ROC 분석에서 SNP와 임상 요소를 통합한 위험 모형이 임상요소만 사용한 모형, 혹은 SNP만 사용한 모형보다 CFS의 예측률이 높은 것으로 확인되었다. 결론: 임상 위험 인자와 유전자 위험 인자를 결합한 모형을 통해 CMV 재활성화 예측력을 향상시킬 수 있었다. Purpose: The aim of this study was to identify potential single-nucleotide polymorphism (SNP) markers associated with the reactivation of cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (allo-HCT) and to generate the risk stratification model combined with the clinical risk factors. Methods: A total of 317 patients who received related or unrelated allo-HCT between March 2001 and October 2007 at the Princess Margaret Cancer Centre, Toronto, ON, Canada and had archived DNA samples from donors and recipients prior to allo-HCT were included for the analysis. A total of 248 SNPs were genotyped in 53 genes an evaluated for their associated risk of CMV viremia. Risk models were generated using both clinical factors and genetic SNP markers. Results: The CMV-free survival (CFS) at 100 days post allo-HCT was 65.0% (95% confidence interval [CI], 59.3-70.0%). The clinical variables associated with the risk of CMV reactivation were CMV positive recipient before transplant and the development of acute GVHD grade 2-4 according to the univariate analysis. In addition to CMV serostatus and acute GVHD, age ≥50 was used for clinical risk factor. Nine SNPs were selected for the risk stratification model; IL12RB1 (rs11575926), IKK1 (rs3808916), IFNG (rs2183959), PDGFRB (rs2302273) of recipients and TLR4 (rs11536889), TGFB1 (rs1800469), NFKBIB (rs136645), PDGFD (rs1053861) of donors. The risk score was calculated by using these nine SNPs in combination with three clinical factors. All risk factors except CMV seropositivity of recipients were given score of 1. The CMV seropositivity of recipients was given score of 3 since its adjusted hazard ratio (HR) for CFS was 18.27 (95% CI, 8.48-39.17). The adjusted HR of the rest were ranged between 1.27 and 2.08. Then, patients were separated into three groups: low risk (score 0-6, n=126), intermediate risk (score 7-9, n=129) and high risk (score ≥10, n=62). The risk stratification model was well correlated with CFS (p<0.001). The time-dependent ROC analysis showed the risk model combined with SNPs and clinical factors predicted CFS better than clinical risk only model or SNPs only model. Conclusion: The incorporation of genetic risk factors in the clinical factors risk model improved stratification power for CMV reactivation. A genome-wide SNP-based risk model was suggested to improve risk stratification of CMV viremia post allo-HCT.

진단 당시 동종 조혈모세포이식을 계획한 최고 위험군 소아 급성 림프구성 백혈병의 치료 성적

이민주 아주대학교 대학원 2012 국내석사

The prognosis of very high risk group acute lymphoblastic leukemia (VHR ALL) in childhood is generally poor in spite of intensive chemotherapy. Recently, allogeneic hematopoietic stem cell transplantation (Allo-HSCT) was use to treat the patients with VHR ALL. We studied the clinical course and outcomes of children with VHR ALL intended treat with Allo-HSCT after chemotherapy. 16 children who were diagnosed as VHR ALL and were intended to treat Allo-HSCT at the department of Pediatrics in Ajou University Hospital between June 2001 and June 2010. We analyzed their cumulative survival rate and clinical characteristics among them. Among 148 ALL patients, 16(10.8%) were classified as VHR ALL. Eight of them had Philadelphia chromosome, four were infant ALL with mixed lineage leukemia (MLL) gene rearrangement, seven had hyperleukocytosis. Fourteen received Allo-HSCT and the other two could not received Allo-HSCT. Bone marrow or central nervous system (CNS) relapse was the main cause of mortality in the patients who received Allo-HSCT. Event free survival (EFS) and overall survival (OS) in all patients were 64.7% and 57.7%, respectively. EFS in the patients Philadelphia chromosome, infant ALL with MLL gene rearrangement and hyperleukocytosis were 58.3%, 100% and 37.5% respectively. EFS in patients with hyperleukocytosis at the time of diagnosis is as low. Therefore novel or additional ggressive treatment modalities may be required in hyperleukocytosis patients. However infant ALL with MLL gene rearrangement was used bulsulfan/cyclophosphamide as a conditioning regimens may have promising survival outcomes. 본 연구에서는 진단 당시 최고위험군 소아 ALL로 진단되어 항암치료 후 동종조혈모세포이식을 계획했던 환아들의 임상경과와 치료결과에 대해 보고하였다. 최고위험군 소아 ALL은 Philadelphia chromosome 양성, MLL gene rearrangement가 동반된 영아형 ALL, 진단 시 백혈구 수치가 20,000/&micro;L 이상인 경우, 관해유도 항암의 실패한 경우로 정의하였다. 2001년 6월부터 2010년 6월까지 아주대병원 소아청소년과에서 최고위험군 소아 ALL로 진단된 16명의 환아를 대상으로 의무기록을 후향적으로 분석 조사 후 고찰하였다. 148명의 환아 중 16명의 환아가 최고위험군 소아 ALL로 진단되었다. 그 중 Ph+은 8례, MLL유전자 재배열이 동반된 영아형 ALL은 4례, 과백혈구증가증은 7례(이 중 세포유전학적 이상이 동반되었던 환아는 3례), 관해유도 항암이 실패한 경우는 없었다. 이중 14명의 환아가 동종조혈모세포이식을 받았고 남은 2명의 환아는 항앙치료요법만을 받았다. 동종조혈모세포이식은 혈연간 이식이 2례, 비혈연간 이식이 12례였고 조혈모세포원으로 골수조혈모세포가 11례, 제대혈조혈모세포가 3례였다. 이식받은 환아 중 10례가 생존해 있고 4례는 사망하였고 항암치료만 받은 환아는 1명은 생존해 있고 1명은 사망하였다. 이식 후 사망한 환아나 항암치료요법만 받은 환아 모두 골수나 중추신경계 재발이 원인이었다. 전체 환자의 무사건 생존율은 64.7%, 전체 생존율은 57.7%이다. 각 최고위험군 인자인 Ph+, MLL+인 영아형 ALL, 과백혈구증가증의 무사건 생존율은 각각 58.3%, 100%, 37.5%였다. 본 연구의 MLL 유전자 재배열이 동반된 영아형 ALL에서 동종 조혈모세포이식을 시행할 때 TBI를 사용하지 않고 Bu-Cy를 이용하여 뇌손상을 최소화하였고 재발이나 치료 관련 합병증없이 치료 성적을 높일 수 있었다. 그러나 과백혈구증가증이 동반된 환자의 경우 무사건 생존률이 37.5%로 낮아 적극적으로 동종조혈모세포 이식을 추진하고 이식 외의 공격적인 치료법을 모색해야 할 것으로 생각된다. 전체적인 생존률을 보았을 때 57.7% 로 동종조혈모세포이식 외에도 생존률을 높일 수 있는 추가적인 방법이 필요할 것으로 사료된다.