伴N-RAS及CBL突变的幼年型粒单核细胞白血病快速急变后单倍体移植1例报告并文献复习
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摘要
目的减少对幼年型粒单核细胞白血病(JMML)的误诊,探讨单倍体造血干细胞移植治疗急变后未获得完全缓解JMML的可行性,并分析JMML快速急变的原因。方法 3岁患儿历经误诊为免疫性血小板减少症(ITP)和传染性单核细胞增多症后确诊为JMML,伴有N-RAS及CBL基因突变,但快速急变为急性髓细胞性白血病AML-M4型,伴有EVI1阳性表达。患儿接受母亲单倍体(HLA 7/10相合)造血干细胞移植,预处理方案为阿糖胞苷+白舒非+猪抗人T细胞免疫球蛋白+环磷酰胺,移植后采用环孢素A+霉酚酸酯(MMF)+短程甲氨蝶呤+甲基强的松龙方案预防移植物抗宿主病(GVHD)。结果移植后+14d白细胞植活,+18d血小板植活,未发生重度GVHD。移植后2个月减停全部免疫抑制剂,随访至2018年8月1日,患儿无病存活。结论 JMML急变后未获得完全缓解行单倍体造血干细胞移植治疗是可行的,同时存在N-RAS及CBL基因突变且有EVI1阳性可能是患儿快速急变的原因。
Objective To reduce the chance of misdiagnosis on juvenile myelomonocytic leukemia(JMML),investigate the feasibility of haploidentical transplantation for JMML transformed acute myeloid leukemia(AML) and analyze the cause of JMML transformation to AML rapidly. Methods A 3 years old girl was misdiagnosed as immune thrombocytopenia and infectious mononucleosis before the diagnosis of JMML with the N-RAS and CBL gene mutations. However, it rapidly transformed to AML-M4 with EVI1 gene positive expression. The patient was treated with haploidentical transplantation from her mother( HLA7/10 match). The pretreatment scheme was Ara-C + BU + ATG + Cy, and GVHD prophylaxis was carried out using a regimen consisting of CsA, MMF, MTX and methylprednisolone. Results The time of neutrophil more than 0. 5 x 10~9/L and platelet more than 20 x 10~9/L were 14 days and 18 days post transplantation. No severe GVHD occurred. All immunosuppressive drugs were discontinued after 2 months post transplantation. The patient was disease free survival till now. Conclusions Haploidentical transplantation is a feasible treatment for JMML transformed AML. N-RAS and CBL gene mutations cooperate with EVI1 gene expression may cause the rapid leukemic transformation.
Objective To reduce the chance of misdiagnosis on juvenile myelomonocytic leukemia(JMML),investigate the feasibility of haploidentical transplantation for JMML transformed acute myeloid leukemia(AML) and analyze the cause of JMML transformation to AML rapidly. Methods A 3 years old girl was misdiagnosed as immune thrombocytopenia and infectious mononucleosis before the diagnosis of JMML with the N-RAS and CBL gene mutations. However, it rapidly transformed to AML-M4 with EVI1 gene positive expression. The patient was treated with haploidentical transplantation from her mother( HLA7/10 match). The pretreatment scheme was Ara-C + BU + ATG + Cy, and GVHD prophylaxis was carried out using a regimen consisting of CsA, MMF, MTX and methylprednisolone. Results The time of neutrophil more than 0. 5 x 10~9/L and platelet more than 20 x 10~9/L were 14 days and 18 days post transplantation. No severe GVHD occurred. All immunosuppressive drugs were discontinued after 2 months post transplantation. The patient was disease free survival till now. Conclusions Haploidentical transplantation is a feasible treatment for JMML transformed AML. N-RAS and CBL gene mutations cooperate with EVI1 gene expression may cause the rapid leukemic transformation.
引文
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2. Matsuda K, Shimada A, Yoshida N,et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood,2007, 109:5477-5480.
3. Bunda S, Qin K, Kommaraju K, et al. Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway. Oncogene, 2015, 34:789-797.
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5. Kurokawa M, Mitani K, Yamagata T,et al. The Evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J, 2000, 19:2958-2968.
6. Izutsu K, Kurokawa M, Imai Y, et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood, 2001,97:2815-2822.
7. Hinai AA, Valk PJ. Review:Aberrant Evi-1 expression in acute myeloid leukaemia. Br J Haematol, 2016, 172:870-878.
8. Ogawa S, Kurokawa M, Tanaka T,et al. Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia. Leukemia, 1996, 10:788-794.
9. Carapeti M, Goldman JM, Cross NC. Overexpression of Evi-1 in blast crisis of chronic myeloid leukemia. Leukemia, 1996,10:1561.
10. Gerhardt TM, Schmahl GE, Flotho C,et al. Expression of the Evi-1gene in haemopoietic cells of children with juvenile myelomonocytic leukaemia and normal donors. Br J Haematol, 1997, 99:882-887.
11. Wolf S, Rudolph C, Morgan M, et al. Selection for Evi-1 activation in myelomonocytic leukemia induced by hyperactive signaling through wild-type NRas. Oncogene, 2013, 32:3028-3038.
12.杨文钰,陈晓娟,王书春,等.儿童幼年型粒单核细胞白血病突变基因型与临床特征分析.中国当代儿科杂志,2015, 1:1-5.
13. Chang TY, Dvorak CC, Loh ML. Bedside to bench in juvenile myelomonocytic leukemia:insights into leukemogenesis from a rare pediatric leukemia. Blood, 2014, 124:2487-2497.
14. Locatelli F, Niemeyer CM. How I treat juvenile myelomonocytic leukemia. Blood, 2015, 125:1083-1090.
15.周剑峰.幼年慢性粒单核细胞白血病的研究进展.国际输血及血液学杂志,2010, 33:254-257.
16. Yoshimi A, Kojima S, Hirano N. Juvenile myelomonocylic leukemia:epidemiology, etiopathogenesis, diagnosis, andmanagement considerations. Paediatr Drugs, 2010, 12:11-21.
17. Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol, 2011, 152:677-687.
18.范佳,马洁,郑杰,等.幼年型粒单核细胞白血病的基因突变与预后分析.中国小儿血液与肿瘤杂志,2018, 3:132-136.
19. Loh ML. Childhood myelodysplastic syndrome:focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. Hematology Am Soc Hematol Educ Program, 2010,2010:357-362.
20. Locatelli F, N(o|¨)llke P, Zecca M, et al. Hematopoietic stem cell transplantation(HSCT)in children with juvenile myelomonocytic leukemia(JMML):results of the EWOG-MDS/EBMT trial. Blood,2005, 105:410-419.
21. Smith FO, King R, Nelson G,et al. Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia.Br J Haematol, 2002, 116:716-724.
22. Manabe A, Okamura J, Yumura-Yagi K,et al. Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia, 2002, 16:645-649.
23.吴南海,栾佐,唐湘凤,等.幼年粒单细胞白血病造血干细胞移植疗效初探.中国小儿血液与肿瘤杂志,2010,15:108-111.
24.秦茂权.单倍体相合造血干细胞移植.中国小儿血液与肿瘤杂志,2009, 14:195-196,220.
25. Reisner Y, Aversa F, Martelli MF. Haploidentical hematopoietic stem cell transplantation:state of art. Bone Marrow Transplant,2015, 50 Suppl 2:S1-5.
26. Huang XJ. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell-depletion for the treatment of hematologic diseases. Chimerism, 2013, 4:26-28.
27.吴秉毅.HLA单倍体相合造血干细胞移植现状.实用医学杂志,2016, 32:16-18.
28. Chen H, Liu KY, Xu LP,et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of philadelphia chromosome-positive acute lymphoblastic leukemia.Biol Blood Marrow Transplant, 2015, 21:1110-1116.
29. Chang YJ, Wang Y, Huang XJ. Haploidentical stem cell transplantation for the treatment of leukemia:current status. Expert Rev Hematol, 2014, 7:635-647.
30.吴颖,王彬,秦茂权,等.幼年型粒单核细胞白血病单倍体相合造血干细胞移植1例.中国小儿血液与肿瘤杂志,2011, 16:252-255.
31.郭智,陈惠仁,刘晓东,等.单倍型造血干细胞移植治疗幼年型粒单核细胞白血病的临床研究.发育医学电子杂志,2014, 3:150-154.
32.聂豪,刘会兰,耿良权,等.挽救性单倍体移植治疗幼年型粒单核细胞白血病1例.临床输血与检验,2014, 16:56-60.
33.丁丽,朱恒,韩冬梅,等.单倍体相合造血干细胞移植治疗幼年型粒单核细胞白血病的临床研究.中国实验血液学杂志,2017,5:1524-1527.
2. Matsuda K, Shimada A, Yoshida N,et al. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood,2007, 109:5477-5480.
3. Bunda S, Qin K, Kommaraju K, et al. Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway. Oncogene, 2015, 34:789-797.
4. Sanada M, Suzuki T, Shih LY,et al. Gain-of-function of mutated CCBL tumour suppressor in myeloid neoplasms. Nature, 2009, 460:904-908.
5. Kurokawa M, Mitani K, Yamagata T,et al. The Evi-1 oncoprotein inhibits c-Jun N-terminal kinase and prevents stress-induced cell death. EMBO J, 2000, 19:2958-2968.
6. Izutsu K, Kurokawa M, Imai Y, et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood, 2001,97:2815-2822.
7. Hinai AA, Valk PJ. Review:Aberrant Evi-1 expression in acute myeloid leukaemia. Br J Haematol, 2016, 172:870-878.
8. Ogawa S, Kurokawa M, Tanaka T,et al. Increased Evi-1 expression is frequently observed in blastic crisis of chronic myelocytic leukemia. Leukemia, 1996, 10:788-794.
9. Carapeti M, Goldman JM, Cross NC. Overexpression of Evi-1 in blast crisis of chronic myeloid leukemia. Leukemia, 1996,10:1561.
10. Gerhardt TM, Schmahl GE, Flotho C,et al. Expression of the Evi-1gene in haemopoietic cells of children with juvenile myelomonocytic leukaemia and normal donors. Br J Haematol, 1997, 99:882-887.
11. Wolf S, Rudolph C, Morgan M, et al. Selection for Evi-1 activation in myelomonocytic leukemia induced by hyperactive signaling through wild-type NRas. Oncogene, 2013, 32:3028-3038.
12.杨文钰,陈晓娟,王书春,等.儿童幼年型粒单核细胞白血病突变基因型与临床特征分析.中国当代儿科杂志,2015, 1:1-5.
13. Chang TY, Dvorak CC, Loh ML. Bedside to bench in juvenile myelomonocytic leukemia:insights into leukemogenesis from a rare pediatric leukemia. Blood, 2014, 124:2487-2497.
14. Locatelli F, Niemeyer CM. How I treat juvenile myelomonocytic leukemia. Blood, 2015, 125:1083-1090.
15.周剑峰.幼年慢性粒单核细胞白血病的研究进展.国际输血及血液学杂志,2010, 33:254-257.
16. Yoshimi A, Kojima S, Hirano N. Juvenile myelomonocylic leukemia:epidemiology, etiopathogenesis, diagnosis, andmanagement considerations. Paediatr Drugs, 2010, 12:11-21.
17. Loh ML. Recent advances in the pathogenesis and treatment of juvenile myelomonocytic leukaemia. Br J Haematol, 2011, 152:677-687.
18.范佳,马洁,郑杰,等.幼年型粒单核细胞白血病的基因突变与预后分析.中国小儿血液与肿瘤杂志,2018, 3:132-136.
19. Loh ML. Childhood myelodysplastic syndrome:focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. Hematology Am Soc Hematol Educ Program, 2010,2010:357-362.
20. Locatelli F, N(o|¨)llke P, Zecca M, et al. Hematopoietic stem cell transplantation(HSCT)in children with juvenile myelomonocytic leukemia(JMML):results of the EWOG-MDS/EBMT trial. Blood,2005, 105:410-419.
21. Smith FO, King R, Nelson G,et al. Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia.Br J Haematol, 2002, 116:716-724.
22. Manabe A, Okamura J, Yumura-Yagi K,et al. Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia, 2002, 16:645-649.
23.吴南海,栾佐,唐湘凤,等.幼年粒单细胞白血病造血干细胞移植疗效初探.中国小儿血液与肿瘤杂志,2010,15:108-111.
24.秦茂权.单倍体相合造血干细胞移植.中国小儿血液与肿瘤杂志,2009, 14:195-196,220.
25. Reisner Y, Aversa F, Martelli MF. Haploidentical hematopoietic stem cell transplantation:state of art. Bone Marrow Transplant,2015, 50 Suppl 2:S1-5.
26. Huang XJ. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell-depletion for the treatment of hematologic diseases. Chimerism, 2013, 4:26-28.
27.吴秉毅.HLA单倍体相合造血干细胞移植现状.实用医学杂志,2016, 32:16-18.
28. Chen H, Liu KY, Xu LP,et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of philadelphia chromosome-positive acute lymphoblastic leukemia.Biol Blood Marrow Transplant, 2015, 21:1110-1116.
29. Chang YJ, Wang Y, Huang XJ. Haploidentical stem cell transplantation for the treatment of leukemia:current status. Expert Rev Hematol, 2014, 7:635-647.
30.吴颖,王彬,秦茂权,等.幼年型粒单核细胞白血病单倍体相合造血干细胞移植1例.中国小儿血液与肿瘤杂志,2011, 16:252-255.
31.郭智,陈惠仁,刘晓东,等.单倍型造血干细胞移植治疗幼年型粒单核细胞白血病的临床研究.发育医学电子杂志,2014, 3:150-154.
32.聂豪,刘会兰,耿良权,等.挽救性单倍体移植治疗幼年型粒单核细胞白血病1例.临床输血与检验,2014, 16:56-60.
33.丁丽,朱恒,韩冬梅,等.单倍体相合造血干细胞移植治疗幼年型粒单核细胞白血病的临床研究.中国实验血液学杂志,2017,5:1524-1527.