Reemergence of JAK2 V617F clone heralds extramedullary leukemia relapse after BMT for transformed essential thrombocytosis
Reemergence of JAK2 V617F clone heralds extramedullary leukemia relapse after BMT for transformed essential thrombocytosis
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JAK2 V617F 克隆的重新出现预示着转化原发性血小板增多症 BMT 后髓外白血病复发
DOI：
10.1007/s00277-006-0213-2
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发表时间：
2006
影响因子：
3.5
通讯作者：
Y. Kwong
中科院分区：
文献类型：
--
作者：
W. Au;A. Fung;A. Lie;K. Lam;C. Lam;Y. Kwong
亲爱的编辑，JAK2激酶分子中V617F突变的新发现彻底改变了骨髓增生性疾病(MPD)的疾病分类[1]。然而，在没有特定JAK2途径拮抗剂的情况下，羟基脲(Hu)、干扰素和阿格列德仍是治疗的主要药物。造血干细胞移植(HSCT)是唯一的治疗选择，保留用于原始细胞转化的病例[2]。关于使用异常JAK2突变监测MPD HSCT后残留疾病的报道很少[3]。JAK2 V617F聚合酶链式反应(PCR)检测与传统的嵌合体或形态监测相比的相对有效性尚不清楚。男，52岁，1990年起患原发性血小板增多症[血红蛋白=14.1g/dl，白细胞=26.9×109/L，血小板=1162×109/L]，骨髓细胞增多，细胞遗传学正常(图1a)。经HU治疗12年后，出现贫血(Hb=5.0g/dl，Wcc=9.1x109/L，PLT=147.0g/dl)和巨脾肿大。重复的骨髓活检显示弥漫性纤维化。他做了脾切除手术，需要定期输血。两年后发展为弗兰克白血病(Hb=9.3g/dl，WCC=3.9×109/L，22%原始细胞，PLT=60×109/L)，细胞遗传学检查显示47，XY，+der(8)t(1；8)(q21；p23)[3]。他的人类白细胞抗原(HL A)相合的兄弟进行了异基因HSCT，他的移植没有移植物抗宿主病(GVHD)。1年后骨髓形态缓解，供者完全嵌合(Hb=8.9g/dl，Wcc=8.3×109/L，Plt=317×109/L)。然而，移植后早期未发现的JAK2异常，一年后再次出现(敏感度，1/104)[4]。在16个月的随访中，他出现了进行性的、压痛的膝关节肿胀(图1b)。针吸活检显示白血病细胞(图1c)骨髓和血细胞计数正常。尽管放射治疗和免疫抑制药物停用，患者仍表现为骨髓复发。伴随而来的是JAK2突变信号的增强和嵌合体的丧失。他接受了化疗和来自同一捐赠者的更多外周干细胞的治疗，但死于暴发性移植物抗宿主病。在我们的病例中，JAK2突变的分子检测预示着髓外复发，在检测疾病方面比嵌合体研究和常规临床和血液学监测更敏感。考虑到聚合酶链式反应检测的敏感性，这并不出人意料。目前还不确定在纯合子突变的情况下，敏感度是否会进一步增加。然而，必须记住，阴性结果可能不能预防白血病复发，因为JAK2阴性的白血病克隆存在于转化的MPD中[5]。然而，对于转化后的MPD患者，HSCT的临床转归较差，且复发率较高，因此，在嵌合体丧失前早期应用供者淋巴细胞输注或化疗以抑制疾病可能是一个机会之窗。
Dear Editor, The novel finding of a V617F mutation in the JAK2 kinase molecule has revolutionized the disease classification of myeloproliferative disease (MPD)[1]. However, without specific JAK2 pathway antagonists, hydroxyurea (HU), interferon, and anagrelide remain the mainstay of treatment. Hemopoietic stem cell transplantation (HSCT), the only curative option, is reserved for cases with blastic transformation [2]. There are few reports on the use of the aberrant JAK2 mutation to monitor residual disease after HSCT for MPD [3]. The relative efficacy of JAK2 V617F polymerase chain reaction (PCR) detection versus conventional chimerism or morphology monitoring is unknown. A 52-year-old man suffered from essential thrombocytosis since 1990 [hemoglobin (Hb)= 14.1 g/dl, white cell count (WCC)= 26.9× 109/l, platelet (Plt)= 1,162× 109/l] with hypercellular marrow and normal cytogenetics (Fig. 1 a). He was treated with HU for 12 years but developed anemia (Hb= 5.0 g/dl, WCC= 9.1× 109/l, Plt= 147× 109/l) and gross splenomegaly. A repeat marrow biopsy showed diffuse fibrosis. Splenectomy was performed, and he required regular transfusion. Two years later, he developed frank leukemia (Hb= 9.3 g/dl, WCC= 3.9× 109/l, 22% blasts, Plt= 60× 109/l), and the cytogenetic study showed 47, XY,+ der (8) t (1; 8)(q21; p23)[3]. An allogeneic HSCT from his human leukocyte antigen (HLA)-identical brother was performed, and he engrafted with no graft versus host disease (GVHD). The marrow showed morphological remission and complete donor chimerism at one year (Hb= 8.9 g/dl, WCC= 8.3× 109/l, Plt= 317× 109/l). However, JAK2 aberration, undetectable early after HSCT, reappeared after one year (sensitivity, 1 in 104)[4]. At the 16-month follow-up, he developed progressive, tender knee swellings (Fig. 1 b). A needle biopsy showed leukemic cells (Fig. 1 c) with normal marrow and blood counts. Despite radiotherapy and the stopping of immunosuppressants, the patient proceeded to frank marrow relapse. This was accompanied by increasing intensity of the JAK2 mutation signal and loss of chimerism. He was treated with chemotherapy and further peripheral stem cells from the same donor but died of fulminant GVHD. The molecular detection of JAK2 mutation heralded extramedullary relapse in our case and was more sensitive than chimerism study and routine clinical and hematological monitoring in detecting disease. This is not unexpected given the sensitivity of PCR detection. It is uncertain if sensitivity is further increased in cases with homozygous mutations. However, it must be remembered that a negative result may not safeguard against leukemia relapse because JAK2 negative leukemic clones are present in transformed MPD [5]. Nevertheless, given the poor clinical outcome and high incidence of relapse for HSCT for transformed MPD, a positive PCR result may provide a window of opportunity for early use of donor lymphocyte infusion or chemotherapy for disease suppression before loss of chimerism.