Labile CD22 and CD19 expression in a case of Philadelphia chromosome-like acute lymphoblastic leukemia.
Labile CD22 and CD19 expression in a case of Philadelphia chromosome-like acute lymphoblastic leukemia.
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费城染色体样急性淋巴细胞白血病病例中 CD22 和 CD19 表达不稳定。
DOI：
10.1080/10428194.2022.2116936
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Doki N
中科院分区：
文献类型：
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作者：
Mukae J;Sadato D;Toya T;Watanabe S;Hirama C;Konuma R;Shimizu H;Najima Y;Kobayashi T;Kato M;Ohki K;Oboki K;Harada H;Ohashi K;Deguchi T;Harada Y;Doki N
Blinatumomab（一种抗CD 19/CD 3的双特异性T细胞增殖剂抗体）和inotuzumab ozogamicin（InO）（一种与加利车霉素偶联的抗CD 22抗体）在复发性/难治性B-ALL患者中显示出显著的生存获益[2，3]。然而，在CD 19靶向治疗后报告了许多CD 19阴性（CD 19 neg）复发病例[4]，确切机制尚不清楚。在此，我们介绍了1例Blinatumomab治疗后CD 19阴性Ph样ALL复发的病例，该病例成功接受了InO治疗，随后进行了异基因造血干细胞移植（图1（A））。有趣的是，尽管Blinatumomab治疗前流式细胞术（FCM）中不存在表面CD 22表达，但Blinatumomab复发后存在CD 22。全外显子组测序（WES）揭示了CD 19阴性复发时CD 19中出现了一种新的点突变，RNA测序证实了CD 19表达的负转换。本研究获得了东京都驹形医院伦理委员会的批准，并获得了患者的书面知情同意书。一名19岁的男子被转移到我们的医院，因为发烧和白色血细胞计数升高。骨髓（BM）穿刺显示骨髓细胞过多，过氧化物酶阴性淋巴母细胞占95.6%。流式细胞术显示CD 10、CD 19、CD 20、CD 22、CD 34和CD 79 a阳性，髓过氧化物酶（MPO）和CD 3阴性（图1（B）;补充图1）。G显带核型为46，XY，t（8; 9）（p21; p24）。逆转录聚合酶链反应检测主要/次要BCR/ABL融合基因均为阴性。断裂荧光原位杂交（FISH）分析显示JAK 2易位（图1（E））。患者被诊断为Ph样ALL，并开始诱导化疗。血液学完全缓解（hCR），虽然FCM可测量的残留疾病（MRD）持续存在。第三次巩固治疗后，疾病复发。出乎意料的是，FCM显示淋巴母细胞对CD 22呈阴性，但对CD 19仍呈阳性（图1（C））。开始Blinatumomab治疗并确认hCR。然而，在第二个周期后，BM抽吸显示BM细胞略多，原始细胞占81.8%。增加的淋巴母细胞数量对CD 19呈阴性，但对CD 22呈阳性（图1（D））。给予一个周期的InO，并实现FCM-MRD阴性缓解。患者接受了来自HLA匹配兄弟的骨髓移植（BMT）。预处理方案包括环磷酰胺（120 mg/kg）和全身照射（12 Gy）。移植物抗宿主病（GVHD）预防包括环孢素和短期甲氨蝶呤给药。在第23天植入中性粒细胞。第1阶段皮肤和胃肠道急性GVHD的发展和成功治疗泼尼松龙0.5毫克/公斤/天和倍氯米松
Blinatumomab, a bispecific T cell engager antibody against CD19/CD3, and inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, showed significant survival benefits among patients with relapsed/refractory B-ALL [2, 3]. However, many cases of CD19 negative (CD19neg) relapses have been reported after CD19-targeted therapy [4] and the exact mechanisms are not sufficiently clear. Here, we present a case of CD19neg relapse of Ph-like ALL after blinatumomab therapy, which was successfully treated with InO, followed by allogeneic hematopoietic stem cell transplantation (Figure 1 (A)). Interestingly, although surface CD22 expression was absent in flow cytometry (FCM) before blinatumomab treatment, CD22 was present after blinatumomab relapse. Whole-exome sequencing (WES) revealed the emergence of a novel point mutation in CD19 at CD19neg relapse, and RNA sequencing confirmed the negative conversion of CD19 expression. This study was approved by the Ethics Committee of the Tokyo Metropolitan Komagome Hospital, and written informed consent was obtained from the patient. A 19-year-old man was transferred to our hospital because of fever and an elevated white blood cell count. Bone marrow (BM) aspiration revealed hypercellular BM with 95.6% peroxidase-negative lymphoblasts. Flow cytometry revealed positivity for CD10, CD19, CD20, CD22, CD34, and CD79a and negativity for myeloperoxidase (MPO) and CD3 (Figure 1 (B); Supplemental Figure 1). The karyotype was 46, XY, t (8; 9)(p21; p24) identified by G-banding. The major/minor BCR/ABL fusion genes were negative by reverse-transcriptase polymerase chain reaction. Break-apart fluorescence in situ hybridization (FISH) analysis revealed JAK2 translocation (Figure 1 (E)). The patient was diagnosed with Ph-like ALL, and induction chemotherapy was initiated. Hematological complete remission (hCR) was achieved, although FCM-measurable residual disease (MRD) persisted. After the third consolidation therapy session, the disease relapsed. Unexpectedly, FCM revealed that the lymphoblasts were negative for CD22, but remained positive for CD19 (Figure 1 (C)). Blinatumomab treatment was initiated and hCR was confirmed. However, after the second cycle, BM aspiration showed slightly hypercellular BM with 81.8% blasts. The increased number of lymphoblasts was negative for CD19 but positive for CD22 (Figure 1 (D)). One cycle of InO was administered, and FCM-MRD-negative remission was achieved. The patient underwent bone marrow transplantation (BMT) from an HLA-matched brother. The conditioning regimen consisted of cyclophosphamide (120mg/kg) and total-body irradiation (12Gy). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and shortterm methotrexate administration. Neutrophils were engrafted on day 23. Stage 1 skin and gastrointestinal acute GVHD developed and was successfully treated with prednisolone 0.5 mg/kg/day and beclomethasone