To the Editor:

The patient is a 79-year-old Caucasian man, who was in his usual state of health until August 2017, when he reported sore teeth during the fitting of a continued positive airway pressure machine. He developed a yellow nasal discharge and was treated with antibiotics. In November 2017, the patient reported left-sided facial numbness and bulging of the left cheek. Computed tomography (CT) scan of the face showed a 4.5 × 4 cm left maxillary mass with maxillary bone destruction (Figure 1(A)). A biopsy of the mass revealed large malignant cells with oval to round nuclear contours, open chromatin, variably conspicuous eosinophilic nucleoli, and moderately abundant cytoplasm. There is frequent individual cell necrosis, increased mitotic figures, and large areas of zonal tumor necrosis. Tumor cells were positive for CD138, MUM1, and CD4 and negative for PAX5, CD20, CD30, CD3, CD34, ALK, EBV LMP1, and HHV8 LANA1. There was a weak, variable expression of EMA and CD45. Epstein–Barr virus-encoded RNA (EBER) in situ hybridization was strongly positive. There was a clonal immunoglobulin heavy chain gene rearrangement. Serology studies for HIV, hepatitis B, and hepatitis C were nonreactive. Serum lactate dehydrogenase level was within normal limits. Positron emission tomography (PET)/computed tomography (CT) showed 18-F fluorodeoxyglucose (FDG) avidity in the left maxillary sinus extending into the left orbital region and did not show additional areas of disease. A bone marrow biopsy did not show evidence of lymphoma. These findings were consistent with an HIV-negative, stage I plasmablastic lymphoma (PBL).¹ His International Prognostic Index (IPI) score was low-risk. The patient was started on bortezomib plus cyclophosphamide, doxorubicin, vincristine, and prednisone (V-CHOP).² In March 2018, a PET/CT scan after four cycles of V-CHOP showed no residual 18-F FDG avidity, consistent with a complete metabolic response. Radiotherapy was planned as consolidation. However, there was a recurrence of nasal congestion and left maxillary fullness before radiotherapy initiation. Given rapid progression after an anti-lymphoma regimen, the patient was started on daratumumab, lenalidomide, and dexamethasone, an anti-myeloma regimen, and received two cycles in April 2018 without evidence of clinical improvement. A PET/CT scan showed persistent 18F-FDG avidity in the left maxillary sinus (Figure 1(B)). A repeat biopsy showed diffuse infiltrate of large plasmacytoid cells with eccentric nuclei, irregular nuclear borders, and abundant cytoplasm occurring in sheets, consistent with PBL relapse. Immunohistochemical studies (Figure 1, bottom) show that the tumor cells were positive for CD138 (subset), MUM1, and EBER. The Ki-67 proliferation index was 80%. PDL1 was strongly positive on a subset of tumor cells (5%-10%) and tumor-infiltrating macrophages, mainly in a perivascular pattern. Based on PDL1 expression by the tumor cells, the patient was started on intravenous (IV) pembrolizumab 200 mg every 3 weeks in June 2018. Within four cycles of therapy, there was a subjective improvement in nasal congestion and left maxillary fullness. The patient received adjuvant radiotherapy at 30 Gy in August 2018, and pembrolizumab continued. After six cycles of pembrolizumab, the patient attained a partial response based on PET/CT scan (Figure 1(C)). Pembrolizumab therapy was complicated by recurrent urinary tract infections, pneumonia, and ophthalmic herpes zoster infection. In August 2019, the patient developed shortness of breath and pleural effusions due to heart failure with a left ventricular ejection fraction (LVEF) of 10%. The patient was managed medically and received methylprednisolone 1 g IV once daily for 3 days followed by a prednisone taper. Pembrolizumab was stopped after 18 cycles of therapy. A PET/CT scan in June 2020 showed no evidence of 18F-FDG avidity, consistent with a complete response (Figure 1(D)). In December 2020, the patient's LVEF had improved to 45%. In June 2021, a PET/CT scan showed no evidence of 18-F FDG-avid disease, consistent with a sustained complete response, 43 months from the initial diagnosis of PBL and 22 months from the last dose of pembrolizumab.

Plasmablastic lymphoma is a rare and aggressive CD20-negative lymphoma variant associated with a poor prognosis, which has been reported in HIV-infected, immunosuppressed (other than HIV infection) as well as immunocompetent individuals.³ The management of PBL is not standardized, and current guidelines recommend chemotherapy combination treatments. These recommendations, however, are made based on consensus and small retrospective experience. At our institution, we introduced the use of the proteasome inhibitor bortezomib in combination with chemotherapy in patients with PBL, based on previously published data suggesting a 5-year overall survival rate of 60%.⁴ Patients with an early stage at diagnosis and low-risk IPI scores have had better outcomes. The management of relapsed PBL is challenging, however, as most patients end up succumbing because of disease progression.

In the present case, we illustrate the clinical course of an elderly HIV-negative patient with early-stage disease who attained a short-lived response to the combination of bortezomib and chemotherapy. The patient was also refractory to daratumumab, lenalidomide, and dexamethasone. It is possible that radiotherapy enhanced the efficacy of pembrolizumab in this case, as there are mounting data supporting a synergistic effect of ionizing radiation in combination with PD1/PDL1 blockade.⁵ High-dose steroids might also have played a role. The standard management of a relapsed aggressive lymphoma would have been additional chemotherapy, followed, if responsive, by higher doses of chemotherapy and an autologous stem cell transplant. Our patient would not have been an optimal candidate for this approach given his age and chemoresistant disease. One prior case has been reported on the use of nivolumab in a 34-year-old woman with HIV-negative PBL after progressing after dose-adjusted EPOCH; carfilzomib, lenalidomide plus dexamethasone; and ifosfamide, carboplatin plus etoposide.⁶ Nivolumab induced a partial response and the patient underwent a myeloablative conditioning regimen followed by a matched related allogenetic stem cell transplant.

A recent study reported not only an increased expression of PD1/PDL1 in malignant cells and tumor-associated macrophages in PBL, but also a worse survival associated with PD1/PDL1 expression.⁷ Herein, we report the first case of PBL treated with the anti-PD1 monoclonal antibody pembrolizumab at standard doses approved for use in patients with relapsed or refractory Hodgkin lymphoma. The expression of PDL1 in the malignant cells and the tumor-associated macrophages served as the biological basis for our intervention. No treatment intervention is without potential toxicity, however. Our patient experienced a number of adverse events probably related to PD1 blockade. Cardiomyopathy with LVEF at 10% developed after 18 cycles of pembrolizumab therapy prompting permanent discontinuation. Cardiomyopathy with left ventricular systolic dysfunction appears to be a late adverse event associated with PD1 blocking agents.⁸ Fortunately, the cardiomyopathy improved after drug discontinuation.

Our experience suggest that anti-PD1 monoclonal antibody therapy could be effective in the management of patients with PBL with PDL1 expression, especially in patients who might not be optimal candidates for combination chemotherapy or autologous stem cell transplantation.

致编辑：

患者是一名 79 岁的白人男性，在 2017 年 8 月之前一直处于正常健康状态，当时他报告在安装持续气道正压通气机期间牙齿酸痛。他出现了黄色的鼻涕，并接受了抗生素治疗。2017年11月，患者诉左侧面部麻木，左脸颊隆起。面部计算机断层扫描 (CT) 扫描显示左侧上颌骨肿块 4.5 × 4 cm，上颌骨破坏（图 1（A））。肿块活检显示大的恶性细胞，核轮廓为椭圆形至圆形，染色质开放，嗜酸性核仁明显不同，细胞质中等。经常出现单个细胞坏死、有丝分裂数增加和大面积的带状肿瘤坏死。肿瘤细胞 CD138、MUM1、CD4 和 PAX5、CD20、CD30、CD3、CD34、ALK、EBV LMP1 和 HHV8 LANA1 阴性。EMA 和 CD45 有弱的、可变的表达。Epstein-Barr 病毒编码的 RNA (EBER) 原位杂交呈强阳性。存在克隆性免疫球蛋白重链基因重排。HIV、乙型肝炎和丙型肝炎的血清学研究没有反应。血清乳酸脱氢酶水平在正常范围内。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。EMA 和 CD45 有弱的、可变的表达。Epstein-Barr 病毒编码的 RNA (EBER) 原位杂交呈强阳性。存在克隆性免疫球蛋白重链基因重排。HIV、乙型肝炎和丙型肝炎的血清学研究没有反应。血清乳酸脱氢酶水平在正常范围内。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。EMA 和 CD45 有弱的、可变的表达。Epstein-Barr 病毒编码的 RNA (EBER) 原位杂交呈强阳性。存在克隆性免疫球蛋白重链基因重排。HIV、乙型肝炎和丙型肝炎的血清学研究没有反应。血清乳酸脱氢酶水平在正常范围内。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。存在克隆性免疫球蛋白重链基因重排。HIV、乙型肝炎和丙型肝炎的血清学研究没有反应。血清乳酸脱氢酶水平在正常范围内。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。存在克隆性免疫球蛋白重链基因重排。HIV、乙型肝炎和丙型肝炎的血清学研究没有反应。血清乳酸脱氢酶水平在正常范围内。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。正电子发射断层扫描 (PET)/计算机断层扫描 (CT) 显示 18-F 氟脱氧葡萄糖 (FDG) 亲合力在左上颌窦延伸到左眼眶区域，并且没有显示其他疾病区域。骨髓活检未显示淋巴瘤的证据。这些发现与 HIV 阴性的 I 期浆母细胞淋巴瘤 (PBL) 一致。¹他的国际预后指数 (IPI) 评分为低风险。患者开始服用硼替佐米加环磷酰胺、多柔比星、长春新碱和泼尼松 (V-CHOP)。²2018 年 3 月，V-CHOP 四个周期后的 PET/CT 扫描显示没有残留的 18-F FDG 亲合力，与完全代谢反应一致。放射治疗计划为巩固治疗。然而，在放射治疗开始前，鼻塞复发和左上颌丰满。鉴于抗淋巴瘤方案后进展迅速，患者开始使用达雷妥尤单抗、来那度胺和地塞米松（一种抗骨髓瘤方案），并于 2018 年 4 月接受了两个周期，但没有临床改善的证据。PET/CT 扫描显示左上颌窦持续存在 18F-FDG 亲合力（图 1（B））。重复活检显示大浆细胞样细胞弥漫性浸润，核偏心，核边界不规则，细胞质丰富，呈片状，与 PBL 复发一致。免疫组化研究（图 1，底部）显示肿瘤细胞对 CD138（子集）、MUM1 和 EBER 呈阳性。Ki-67 增殖指数为 80%。PDL1 在一部分肿瘤细胞 (5%-10%) 和肿瘤浸润巨噬细胞上呈强阳性，主要呈血管周围模式。根据肿瘤细胞的 PDL1 表达，患者于 2018 年 6 月开始静脉注射（IV）派姆单抗 200 mg，每 3 周一次。 在四个治疗周期内，鼻塞和左上颌丰满有主观改善。患者于 2018 年 8 月接受了 30 Gy 的辅助放疗，继续使用帕博利珠单抗。在 6 个周期的 pembrolizumab 后，患者根据 PET/CT 扫描获得了部分缓解（图 1（C））。帕博利珠单抗治疗因复发性尿路感染、肺炎和眼部带状疱疹感染而变得复杂。2019 年 8 月，患者因心力衰竭出现呼吸急促和胸腔积液，左心室射血分数 (LVEF) 为 10%。患者接受了药物治疗，每天一次静脉注射甲基强的松龙 1 g，持续 3 天，然后逐渐减量泼尼松。帕博利珠单抗在 18 个治疗周期后停止。2020 年 6 月的 PET/CT 扫描显示没有 18F-FDG 亲和力的证据，与完全反应一致（图 1（D））。2020 年 12 月，患者的 LVEF 已改善至 45%。2021 年 6 月，PET/CT 扫描显示无 18-F FDG 狂热疾病的证据，与持续完全反应一致，从最初诊断 PBL 开始 43 个月，从最后一剂派姆单抗开始 22 个月。患者因左心室射血分数 (LVEF) 为 10% 的心力衰竭而出现呼吸急促和胸腔积液。患者接受了药物治疗，每天一次静脉注射甲基强的松龙 1 g，持续 3 天，然后逐渐减量泼尼松。帕博利珠单抗在 18 个治疗周期后停止。2020 年 6 月的 PET/CT 扫描显示没有 18F-FDG 亲和力的证据，与完全反应一致（图 1（D））。2020 年 12 月，患者的 LVEF 已改善至 45%。2021 年 6 月，PET/CT 扫描显示无 18-F FDG 狂热疾病的证据，与持续完全反应一致，从最初诊断 PBL 开始 43 个月，从最后一剂派姆单抗开始 22 个月。患者因左心室射血分数 (LVEF) 为 10% 的心力衰竭而出现呼吸急促和胸腔积液。患者接受了药物治疗，每天一次静脉注射甲基强的松龙 1 g，持续 3 天，然后逐渐减量泼尼松。帕博利珠单抗在 18 个治疗周期后停止。2020 年 6 月的 PET/CT 扫描显示没有 18F-FDG 亲和力的证据，与完全反应一致（图 1（D））。2020 年 12 月，患者的 LVEF 已改善至 45%。2021 年 6 月，PET/CT 扫描显示无 18-F FDG 狂热疾病的证据，与持续完全反应一致，从最初诊断 PBL 开始 43 个月，从最后一剂派姆单抗开始 22 个月。患者接受了药物治疗，每天一次静脉注射甲基强的松龙 1 g，持续 3 天，然后逐渐减量泼尼松。帕博利珠单抗在 18 个治疗周期后停止。2020 年 6 月的 PET/CT 扫描显示没有 18F-FDG 亲和力的证据，与完全反应一致（图 1（D））。2020 年 12 月，患者的 LVEF 已改善至 45%。2021 年 6 月，PET/CT 扫描显示无 18-F FDG 狂热疾病的证据，与持续完全反应一致，从最初诊断 PBL 开始 43 个月，从最后一剂派姆单抗开始 22 个月。患者接受了药物治疗，每天一次静脉注射甲基强的松龙 1 g，持续 3 天，然后逐渐减量泼尼松。帕博利珠单抗在 18 个治疗周期后停止。2020 年 6 月的 PET/CT 扫描显示没有 18F-FDG 亲和力的证据，与完全反应一致（图 1（D））。2020 年 12 月，患者的 LVEF 已改善至 45%。2021 年 6 月，PET/CT 扫描显示无 18-F FDG 狂热疾病的证据，与持续完全反应一致，从最初诊断 PBL 开始 43 个月，从最后一剂派姆单抗开始 22 个月。

浆母细胞淋巴瘤是一种罕见的侵袭性 CD20 阴性淋巴瘤变异，预后不良，在 HIV 感染者、免疫抑制（HIV 感染除外）以及免疫功能正常的个体中均有报道。³ PBL的管理不规范，目前指南推荐化疗联合治疗。然而，这些建议是基于共识和小型回顾性经验提出的。在我们机构，我们根据先前公布的数据表明，5 年总生存率为 60%，我们在 PBL 患者中引入了蛋白酶体抑制剂硼替佐米联合化疗的使用。⁴早期诊断和低风险 IPI 评分的患者有更好的结果。然而，复发性 PBL 的管理具有挑战性，因为大多数患者最终因疾病进展而死亡。

在本案例中，我们说明了一名患有早期疾病的老年 HIV 阴性患者的临床病程，该患者对硼替佐米和化疗的组合获得了短暂的反应。该患者也对达雷妥尤单抗、来那度胺和地塞米松难治。在这种情况下，放疗可能增强了派姆单抗的疗效，因为越来越多的数据支持电离辐射与 PD1/PDL1 阻断组合的协同作用。⁵高剂量类固醇也可能发挥了作用。复发性侵袭性淋巴瘤的标准治疗是额外的化疗，如果有反应，随后是更高剂量的化疗和自体干细胞移植。鉴于他的年龄和化学抗性疾病，我们的患者不会是这种方法的最佳人选。之前曾报道过一例在调整剂量 EPOCH 后进展后，在 34 岁 HIV 阴性 PBL 女性中使用纳武单抗的病例；卡非佐米、来那度胺加地塞米松；异环磷酰胺、卡铂加依托泊苷。⁶纳武单抗引起部分反应，患者接受了清髓预处理方案，随后进行了匹配的相关同种异体干细胞移植。

最近的一项研究不仅报告了 PBL 中恶性细胞和肿瘤相关巨噬细胞中 PD1/PDL1 的表达增加，而且与 PD1/PDL1 表达相关的生存期也较差。⁷在此，我们报告了第一例使用抗 PD1 单克隆抗体派姆单抗治疗的 PBL 病例，标准剂量已批准用于复发或难治性霍奇金淋巴瘤患者。PDL1 在恶性细胞和肿瘤相关巨噬细胞中的表达是我们干预的生物学基础。然而，任何治疗干预都没有潜在的毒性。我们的患者经历了许多可能与 PD1 阻断相关的不良事件。18 个周期的派姆单抗治疗后出现 LVEF 为 10% 的心肌病，导致永久停药。伴有左心室收缩功能障碍的心肌病似乎是与 PD1 阻滞剂相关的晚期不良事件。⁸幸运的是，停药后心肌病有所好转。

我们的经验表明，抗 PD1 单克隆抗体疗法可有效治疗 PDL1 表达的 PBL 患者，尤其是可能不是联合化疗或自体干细胞移植的最佳候选者的患者。