STI571 (Glivec^(�))에 의하여 빠른 치료 반응을 보인 불응성 Gastrointestinal stromal tumor

윤경원,이제중,김여경,황호인,이병환,조상희,정익주,김형준 全南大醫大 2001 전남의대학술지 Vol.37 No.4

진행성 비호지킨 림프종 환자에서 ICE 구제 요법에 의한 조혈모세포 가동화 후 자가 말초혈액 조혈모세포이식

이제중,이병환,김여경,변정래,이일권,박무림,정익주,김형준 대한조혈모세포이식학회 2003 대한조혈모세포이식학회지 Vol.8 No.1

연구배경: 비호지킨 림프종에서 자가 말초혈액 조혈모세포이식술이 폭넓게 이용됨으로 인해서, 높은 치료효과뿐만 아니라 조혈모세포의 가동화 효율이 높은 구제 요법이 요구되었다. 방법: 본 연구에서는 진행성 비호지킨 림프종에서 ICE 요법을 이용하여 조혈모세포를 가동화시킨 후 자가 말초혈액 조혈모세포이식이 시행하였던 환자를 후향적으로 분석하였다. 결과: 대상 환자의 중앙 연령은 38세(범위, 16~61)였으며, ICE 요법은 환자당 4주기(범위, 1~6주기)가 투여되었고, 투여 간격은 중앙값이 24일(범위, 16~36일)이었다. 고위험도 관해군을 제외한 13예의 환자 중 완전반응은 7예(53.8%), 부분반응은 4예(30.8%), 진행성질환은 2예(15.4%)를 보였다. 치료에 따른 3~4등급의 혈액학적 독성은 중성구감소증이 13예(81.3%), 혈소판감소증이 7예(42.8%)에서 관찰되었다. 조혈모세포 채집은 ICE 요법 후 중앙값이 12일(범위, 6~20일)에 시행되었고, 각 ICE 요법당 채집한 단핵구치는 중앙값이 5.75× 10^(8)/체중, CD34^(+) 세포는 중앙값이 1.25× 10^(6)/체중, CFU-GM치는 중앙값이 1.19× 10^(5)/체중이었다. 조혈모세포이식은 11예에서 시행되었고, 중앙 추적기간 401일에 평가한 2년 전체생존율은 70.1±14.7%, 1년 및 2년 무사건생존율은 각각 60.7±15.4%와 32.3±17.1%를 보였다. 결론: ICE 요법은 재발성/불응성 비호지킨 림프종 환자에서 높은 치료 반응률과 만족할 만한 조혈모세포 가동화를 보여 주었지만, 치료에 대한 순응도가 낮아서 투여 간격이 연장되는 문제점을 안고 있어서, 우리나라 환자의 실정에 적합한 구제요법에 대한 연구가 필요할 것으로 생각된다. Background: Due to the extensive application of high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT), a salvage chemotherapeutic regimen with high response rate as well as effective capacity of PBSC mobilization is needed in non-Hodgkin's lymphoma (NHL). Methods: We analyzed the applicability of ICE (ifosphamide, carboplatin, and etoposide) regimen in NHL patients who underewent autologous PBSCT. Results: The median age was 38 years (range, 16~61 years), the patients received median 4 cycles (range, 1~6 cycles) of ICE regimen, and the median interval between each chemotherapeutic cycle was 24 days (range, 16~36 days). There were 7 (53.8%) complete responses, 4 (30.8%) partial responses, and 2 (15.4%) progressive diseases after ICE regimen. Toxicity included grade 3/4 neutropenia and throm bocytopenia in 13 (81.3%) and 7 (42.8%) patients, respectively. PBSC collection began on median day 12 (range, 6~20 days) after ICE therapy. The median number of mononuclear cells, CD34+ cells, and CFU-GM was 5.75× 10^(8)/kg, 1.25× 10^(6)/kg, and 1.19× 10^(5)/kg, respectively. With a median follow- up of 401 days, the patients who underwent autologous PBSCT had overall survival with 70.1±14.7% at 2 year and event free survival with 60.7±15.4% and 32.3±17.1% at 1 year and 2 years, respectively. Conclusion: ICE chemotherapy is an effective cytoreduction and mobilization regimen in patients with NHL, but profound myelosuppression with delayed recovery might pose difficulties in applying for Korean patients. Further evaluation for appropriate salvage regimens in Korean patients should be needed.

동종 골수이식 후 만성 이식편대숙주질환과 동반된 그레이브스병

황호인,이제중,조상희,김여경,이병환,정익주,김형준 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.1

저자들은 중증 재생불량성빈혈로 동종 골수이식 및 추가적인 동종 말초혈액 조혈모세포이식을 시행 받은 후 만성 이식편대숙주질환이 발생하여 면역억제제로 조절되었으나 자가면역성 갑상선기능항진증이 병발한 1예를 경험하였기에 이를 보고하는 바이다. Chronic graft-versus-host disease (GVHD), which is a frequent complication following bone marrow transplantation (BMT), is characterized by fibrosis of the skin, liver, lungs, and gastrointestinal tract, immunodeficiency, and the production of autoantibodies. Endocrine dysfunction, in particular thyroid disease, has been described following BMT, but this has previously meant hypothyroidism secondary to total body irradiation or transfer of autoimmune hyperthyroidism from a donor with Graves’ disease rather than in association with chronic GVHD. We report a case of a 26-year-old man who developed Graves’ disease eight years after BMT and who had remission of chronic GVHD. He received an allogeneic BMT for severe aplastic anemia. Eighteen months after BMT, diarrhea and chronic GVHD developed and were treated with cyclosporine and steroid. Four years after ceasing the cyclosporine, the patient developed weight loss, palpitations, fever, and anterior neck swelling, and was diagnosed with Graves’ disease based on typical thyroid function tests. The signs and symptoms in the patient improved with propylthiouracil and propranolol.

동종 골수이식을 시행받은 환자에서 폐색성 세기관지염에 의하여 발생한 자발성 기종격동과 피하 기종

이병환,이제중,이연경,안재숙,김여경,황호인,박무림,조상희,정익주,김형준 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.2

저자들은 만성골수성백혈병으로 동종 골수이식과 이식편 부전으로 인하여 추가적인 말초혈액 조혈모세포이식을 시행 받은 환자에서 만성 이식편대숙주질환과 그 폐 합병증인 폐색성 세기관지염에 동반된 자발성 기종격동과 피하 기종이 병발한 1예를 경험하였기에 이를 보고하는 바이다. Obstructive lung disorders following after allogeneic bone marrow transplantation (BMT) in association with graft- versus-host disease (GVHD) contribute significant morbidity and mortality. We report a case of a 28-year-old man who developed spontaneous pneumomediatinum and subcutaneous emphysema complicating bronchiolitis obliterans after allogeneic BMT. He received an allogeneic BMT for chronic phase of chronic myeloid leukemia. Five months after BMT, he was boostered by allogeneic peripheral blood stem cells from the same donor due to graft failure. One month after the boostering, chronic GVHD developed and were treated with cyclosporine and steroid. The patients developed spontaneous pneumomediatinum and subcutaneous emphysema secondary to severe bronchiolitis obliterans 4 months after boostering donor cells. The air-leak syndromes were recovered by conservative management, including high-flow oxygen.

악성 혈액질환에서 성공적인 동종골수이식 후 숙주 기질 미세환경의 구축

조상희,이제중,남찬은,최경상,정익주,이일권,김진희,박종태,김형준 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.1

인체의 골수는 간엽모세포를 함유하고 있으며 이들은 골수미세환경의 주된 세포들로 분화가 가능하여 조혈기능을 지지한다. 본 연구에서는 성별이 다른 동종조혈모세포이식 환경에서 조혈모세포의 완전 생착을 보이고, 이식 후 1년에서 8년이 지난 11예의 재생불량성 빈혈 및 백혈병 환자들을 대상으로 하여 골수에서 MSC를 분리하고 체외 확장을 통해 배양된 MSC에서 X 염색체 탐식자를 이용한 FISH 및 microsatellite polymorphism PCR 기법으로 그 기원을 확인하였다. 그 결과 조혈모세포는 완전히 공여자 기원으로 대치되었음에도 불구하고 MSC는 모두 수여자 기원임을 알 수 있어, 동종조혈모세포이식에서 미세환경의 구축은 수여자의 자가 생산에 의한 골수 간질세포에 의한 것으로 생각된다. Background: Human bone marrow (BM) contains mesenchymal stem cells (MSC) that can differentiate into various cells of mesenchymal origin. It remains a matter of controversy whether donor-derived stromal cells are capable of engraftment following hematopoietic stem cell transplantation (HSCT) or not. Methods: To determine if donor-derived stromal cells are transferred to the recipients of allogeneic HSCT, we investigated the characterization of MSC in 11 patients 1 to 8 years after sex mis-matched allogeneic HSCT in severe aplastic anemia and leukemia. Results: All patients had complete engraftment with donor- derived stem cells as shown by detection of donor type DNA in peripheral blood mononuclear cells. Following culture, MSC showed the expression of SH2 and SH4, but none of the hematopoietic markers of CD14, CD34, or CD45. MSC which can be differentiated to osteogenic lineage showed the genotype of recipient completely using FISH or PCR analysis. Conclusion: This study confirmed that MSC isolated from recipients of allogeneic HSCT in severe aplastic anemia and leukemia are not of donor genotype despite of full hematopoietic engraftment with donor type. Donor cells did not contribute to reconstitute the marrow microenvironment.

A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia

Kim, Dong Hwan (Dennis),Lee, Seung-Tae,Won, Hong-Hee,Kim, Seonwoo,Kim, Min-Ji,Kim, Hee-Jin,Kim, Sun-Hee,Kim, Jong-Won,Kim, Hyeoung-Joon,Kim, Yeo-Kyeoung,Sohn, Sang Kyun,Moon, Joon Ho,Jung, Chul Won,Li American Society of Hematology 2011 Blood Vol.117 No.25

<B>Abstract</B><P>In the current study, we identified 2 genetic markers for susceptibility to chronic myeloid leukemia (CML) using a genome-wide analysis. A total of 2744 subjects (671 cases and 2073 controls) were included, with 202 Korean CML patients and 497 control subjects enrolled as a discovery set. Significant findings in the discovery set were validated in a second Korean set of 237 patients and 1000 control subjects and in an additional Canadian cohort of European descent, including 232 patients and 576 control subjects. Analysis revealed significant associations of 2 candidate loci, 6q25.1 and 17p11.1, with CML susceptibility, with the lowest combined P values of 2.4 × 10−6 and 1.3 × 10−12, respectively. Candidate genes in those regions include RMND1, AKAP12, ZBTB2, and WSB1. The locus 6q25.1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML.</P>

KIT D816 mutation associates with adverse outcomes in core binding factor acute myeloid leukemia, especially in the subgroup with RUNX1/RUNX1T1 rearrangement.

Kim, Hee-Jin,Ahn, Hee Kyung,Jung, Chul Won,Moon, Joon Ho,Park, Chang-Hun,Lee, Ki-O,Kim, Sun-Hee,Kim, Yeo-Kyeoung,Kim, Hyeoung-Joon,Sohn, Sang Kyun,Kim, Sung Hyun,Lee, Won Sik,Kim, Kyoung Ha,Mun, Yeung Springer International 2013 Annals of hematology Vol.92 No.2

<P>Core binding factor (CBF)-positive acute myeloid leukemia (AML) presents a favorable prognosis, except for patients with KIT mutation, especially D816 mutation. The current retrospective study attempted to validate a prognostic role of KIT mutation in 121 Korean patients with CBF AML. The study patients consisted of 121 patients with CBF AML (82 patients with RUNX1/RUNX1T1 [67.8?%] and 39 patients with CBFB/MYH11 [32.2?%]) recruited from eight institutions in Korea. All patients received idarubicin plus cytarabine or behenoyl cytosine arabinoside 3?+?7 induction chemotherapy. The KIT gene mutation status was determined by direct sequencing analyses. A KIT mutation was detected in 32 cases (26.4?%) in our series of patients. The KIT mutation was most frequent in exon 17 (n?=?18, 14.9?%; n?=?16 with D816 mutation), followed by exon 8 (n?=?10, 8.3?%). The presence of KIT D816 mutation was associated with adverse outcomes for the event-free survival (p?=?0.03) and for the overall survival (p?=?0.02). The unfavorable impact of D816 mutation was more prominent when the analysis was confined to the RUNX1/RUNX1T1 subtype. The KIT mutation was detected in 26.4?% of Korean patients with CBF AML. The KIT D816 mutation demonstrated an unfavorable prognostic implication, particularly in the RUNX1/RUNX1T1 subtype.</P>

선택적으로 분리된 CD34 양성 자가 조혈모세포이식 후 면역기능의 회복

이은희,김도현,정재학,박준성,김현수,홍대식,박성규,김형준,홍영선,김춘추,김효철,김원석,박찬형 대한조혈모세포이식학회 2002 대한조혈모세포이식학회지 Vol.7 No.2

연구배경: 자가말초혈액 조혈모세포이식에 있어 CD34 양성세포의 선택적 분리로 인해 1~4 logs 정도의 종양세포의 감소를 가져오며, 또한 CD34 양성세포 이식 후의 면역기능의 회복은 선택적으로 분리되지 않은 자가 조혈모세포이식 시와 거의 비슷하다는 것이 보고되어 왔다. 이에 저자들은 선택적으로 분리된 자가 CD34 양성 조혈모세포이식 후의 면역기능의 회복 양상을 알아보기 위해 다기관 연구를 시행하였다. 방법: 15명의 악성 림프종, 유방암, 다발성 골수종 환자들을 대상으로 고용량 항암요법 후 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식을 시행하였다. 이식 후 1, 2, 4, 6개월에 림프구 표현형 측정과 PHA mitogen induced T세포 증식정도를 측정하였다. 결과: 이식 후 6개월 추적 관찰 시 CD3 양성, CD4 양성 림프구의 수는 정상보다 낮았고, CD8 양성세포는 정상 수준을 보였다. 초기 CD4/CD8 비는 감소되었지만 6개월 후 정상으로 회복되는 경향을 보였으며, CD19 양성, CD56 양성세포수는 정상 수준을 나타냈다. PHA mitogen response는 12개월 추적 관찰 시까지 지속적으로 증가 추세를 보였다. 결론: 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식은 빠르고 지속적인 혈액학적 생착을 유도하는 것을 알 수 있으며, 이는 기존의 연구에서 선택되지 않은 자가 조혈모세포이식 시와 비교하여 면역기능의 회복에는 유의한 차이가 없다는 보고와 일치하는 결과이다. 그러므로 선택적으로 분리된 CD34 양성 자가말초혈액 조혈모세포이식을 통해 상당한 T 세포의 감소에도 불구하고 면역기능의 회복에 지연 없이 종양세포의 오염을 줄이는 것이 가능함을 확인하였다. Background: Positive selection of autologous peripheral blood stem cells (PBSC) for CD34-expressing cells permits 1 to 4 logs of tumor cell depletion. Hematologic recovery after CD34+ cell transplatation has been reported to be rapid and similar to results achieved in unselected autologous peripheral blood stem cell transplantation (APBSCT). We performed a multi-center study to evaluate the immune reconstitution after CD34+ immunoselected APBSCT. Methods: Fifteen patients with lymphoma, breast cancer, or multiple myeloma received high dose myeloablative chemotherapy followed by an infusion of CD34+ immunoselected PBSC. On 1, 2, 4, and 6 months after transplantation, lymphocyte phenotype was evaluated by flow cytometry and mitogen-induced T cell proliferation were measured. Results: At 6 months after transplantation, CD3+ lymphocyte subset remained below the normal range. CD4+ lymphocytes were depressed while CD8+ lymphocyte subset was in normal range. As a result, inversion of CD4/CD8 ratio was documented for first 4 months, but after 6 months follow up CD4/CD8 ratio was recovered. CD19+ B lymphocyte subset and CD56+ lymphocytes after CD34+ APBSCT were within the normal range. The PHA mitogen induced response was increased during 12 months' follow-up consistently. Phenotypic and functional reconstitution of immune cells after CD34+ cell transplantation were rapid and similar to previous studies. Conclusion: Transplantation of CD34+ immunoselected PBSC allows rapid and sustained hematologic engraftment, and there was no marked delay of immune reconstitution. The selection of CD34+ cells, although causes an extensive depletion of T lymphocytes in the graft does not represent a delayed immune recovery after transplantation.

Genome-wide high density single-nucleotide polymorphism array-based karyotyping improves detection of clonal aberrations including der(9) deletion, but does not predict treatment outcomes after imatinib therapy in chronic myeloid leukemia

Huh, Jungwon,Jung, Chul Won,Kim, Jong Won,Kim, Hee-Jin,Kim, Sun-Hee,Shin, Myung Geun,Kim, Yeo Kyeoung,Joon Kim, Hyeoung,Suh, Jang Soo,Moon, Joon Ho,Sohn, Sang Kyung,Nam, Goong Hyun,Lee, Jong-eun,Kim, Springer-Verlag 2011 Annals of hematology Vol.90 No.11

Exome sequencing reveals <i>DNMT3A</i> and <i>ASXL1</i> variants associate with progression of chronic myeloid leukemia after tyrosine kinase inhibitor therapy

Kim, TaeHyung,Tyndel, Marc S.,Zhang, Zhaolei,Ahn, Jaesook,Choi, Seunghyun,Szardenings, Michael,Lipton, Jeffrey H.,Kim, Hyeoung-Joon,Kim Dong Hwan, Dennis Elsevier 2017 Leukemia research Vol.59 No.-

<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with <I>ABL1</I> kinase domain (KD) mutations, but only around half of TKI non-responders have detectable <I>ABL1</I> KD mutations.</P> <P><B>Method</B></P> <P>We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without <I>ABL1</I> KD mutations using whole-exome sequencing.</P> <P><B>Results</B></P> <P>In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: <I>ABL1</I>, <I>ASXL1</I>, <I>DNMT3A</I>, <I>IDH1</I>, <I>SETBP1</I>, and <I>TP63</I>. We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as <I>DNMT3A</I> and <I>ASXL1</I> seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of <I>ABL1</I> KD mutations.</P> <P><B>Conclusion</B></P> <P>This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking <I>ABL1</I> KD mutations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Acquisition of somatic mutation is associated with TKI therapy failure and progression in CML patients. </LI> <LI> Exome sequencing revealed mutations in 6 genes: <I>ABL1, ASXL1, DNMT3A, IDH1, SETBP1,</I> and <I>TP63.</I> </LI> <LI> Somatic mutations is responsible for TKI resistance esp. lacking <I>ABL1</I> KD mutations. </LI> </UL> </P>