71例原发颅内中枢神经系统DLBCL预后分析

目的 探讨原发颅内中枢神经系统弥漫性大B细胞淋巴瘤(DLBCL)的预后因素。 方法 回顾分析1991—2015年间收治的经病理和临床证实的 71例原发颅内中枢神经系统DLBCL临床资料。全组患者均进行了化疗,59例进行了放疗,化疗方案以HD-MTX (HD-MTX,66/71)为主,放疗方案以全脑放疗 ±局部推量为主。Kaplan-Meier法计算生存率,Logrank法检验和单因素预后分析,Cox模型多因素预后分析。 结果 放化疗结束时 58例CR, 10例PR,3例PD。5年生存率为43%;5年无疾病进展率为34%。单因素分析显示年龄、KPS评分、单发与多发、是否放疗、放化疗完成时评价、有无复发是影响OS的因素(P=0.000~0.047),多因素分析显示年龄、KPS评分、有无复发是影响OS的因素(P=0.000~0.022)。单因素分析化疗方案、是否放疗、总放疗剂量、全脑剂量、放化疗完成时评价、有无复发是影响PFS的因素(P=0.000~0.028);多因素分析KPS评分、有无复发是影响PFS的因素(P=0.000~0.011)。 结论 年轻、KPS评分高、无复发患者总生存更好,单发、接受放疗、放化疗后疗效好的患者可能更好;KPS评分高、放化疗后疗效好、无复发患者PFS更好,接受含HD-MTX化疗、接受放疗、总的放疗剂量和全脑剂量越高患者PFS可能更好。化疗达CR后是否还放疗及放疗靶区、剂量需进一步研究。     

Identifying and addressing barriers to the delivery of optimal therapy for primary central nervous system lymphoma in the broader community

Despite recent advances in the management of primary central nervous system lymphoma (PCNSL), recent population-based studies suggest that prognosis in the broader community has not improved substantially over the last 20 years. It is possible that this difference in outcome reflects a significant selection bias in the clinical series and trials reported. However, there is also preliminary evidence suggesting that patients in the community may not receive optimal management. There are many possible reasons that might account for disparities in care and outcome, but these have not been specifically addressed with regard to PCNSL. We have sought to elaborate some potential causes of these disparities; however, future studies are needed to identify and address specific barriers to care in the community.     

Bcl-6 predicts improved prognosis in primary central nervous system lymphoma

BACKGROUND: In systemic non-Hodgkin lymphoma (NHL), tumors that resemble germinal center B-cells are less aggressive than tumors that resemble postgerminal center B-cells. However, the value of B-cell differentiation markers in primary central nervous system lymphoma (PCNSL) is less clear. The objectives of this study were to characterize the immunophenotypes of PCNSL samples and to determine their utility in predicting clinical outcomes. METHODS: The immunohistochemical staining profile of PCNSL was determined from 66 immunocompetent patients. Then, the authors evaluated whether the expression of these proteins was associated with progression-free or overall survival. RESULTS: Only 8% of PCNSL samples were positive for the cluster designation (CD) germinal center marker CD10. Another germinal center marker, bcl-6, was positive in 47% of samples. Ninety-four percent of samples expressed significant levels of the postgerminal center marker melanoma-associated antigen (MUM-1). In univariate analyses, only bcl-6 staining had a significant effect on progression-free survival (median, 20.5 months in bcl-6-positive patients vs 10.1 months in bcl-6-negative patients; P = .02). There was a nonsignificant trend toward improved overall survival in patients who had bcl-6 expressing tumors. Older age and poorer performance status, as observed previously, were associated with reduced survival. CONCLUSIONS: Bcl-6 expression was associated with a better prognosis in patients with PCNSL.     

Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma

Treatment for patients with refractory or relapsed primary CNS lymphoma (PCNSL) remains unsatisfactory. Topotecan is an intravenous topoisomerase I inhibitor with good CSF penetration and documented efficacy in patients with relapsed systemic non-Hodgkin’s lymphoma. In this study 15 patients with refractory or relapsed PCNSL were treated with intravenous topotecan (1.5 mg/m²) for five consecutive days during each 21-day cycle. All 15 patients had measurable, contrast-enhancing tumor on cranial MRI at the time of relapse. Three (20%) patients achieved a complete response after one, three and four cycles, respectively, while three (20%) patients achieved a partial response after two cycles each, for a total response proportion of 40%. Three patients had stable disease at the end of topotecan treatment. Six patients (40%) had progressive disease during treatment. Median overall survival was 981 days (95% CI: 275, NA) and median progression free survival was 60 days (95% CI: 46, 945). Three out of 15 patients had grade 3 thrombocytopenia. Six out of 15 patients had grade 3 neutropenia, while 5/15 patients had grade 4 neutropenia, and 13/15 patients received g-CSF at some point during treatment. There were no deaths directly related to treatment toxicity. Our study shows that topotecan, as a salvage therapy in patients with relapsed or refractory PCNSL, is associated with an overall response proportion of 40% and should be considered in patients who have failed prior methotrexate-based chemotherapy and/or whole brain irradiation. However, progression is frequent and early and most patients required growth factor support due to myelotoxicity.     

Rituximab in primary central nervous system lymphoma—A systematic review and meta‐analysis

The CD‐20 antibody rituximab is a standard component of treatment of non‐Hodgkin B‐cell lymphomas, including diffuse large B‐cell lymphoma (DLBCL). Primary DLBCL of the central nervous system, also called primary central nervous system lymphoma (PCNSL), is a DLBCL confined to the central nervous system. There has been debate whether intravenous rituximab accumulates sufficiently in the central nervous system to exert an effect. In this systematic review, we assess the benefits and harms of rituximab in the treatment of immunocompetent patients with PCNSL. By searching MEDLINE, CENTRAL, and ClincialTrials.gov up to March 2019, we identified randomized controlled trials (RCTs) investigating the effect of rituximab in patients with PCNSL. We extracted study characteristics and results, assessed risk of bias, performed trial‐level random‐effects meta‐analyses, and graded the certainty of evidence. The protocol was registered with PROSPERO (CRD42019121965). Main outcomes were overall survival (time to death), progression‐free survival (time to progression or death), quality of life, grades 3 and 4 toxicity, and treatment‐related mortality. We included two RCTs with a total of 343 participants. Overall survival was not statistically significantly improved (HR 0.76; 95% CI, 0.52‐1.12; low certainty), with 187 fewer to 39 more deaths after 2 years in 1000 treated patients. Low certainty of evidence indicated that rituximab improved progression‐free survival (HR 0.65; 95% CI, 0.45‐0.95), which translated into 137 fewer progressions or deaths after 2 years in 1000 treated patients (231 to 18 fewer). None of the RCTs provided data on quality of life. We found no evidence that rituximab increased grades 3 and 4 toxicity or treatment‐related mortality (RR 0.53; 95% CI, 0.20‐1.37; low certainty). Overall, the available evidence suggests with low certainty that rituximab in combination with methotrexate‐based chemotherapy may improve progression‐free survival in immunocompetent patients with newly diagnosed PCNSL, the pooled effect estimates did not show evidence for improvement of overall survival.     

Recurrent or refractory primary central nervous lymphoma: therapeutic considerations

Primary central nervous system lymphoma (PCNSL) is an uncommon variant of extranodal non-Hodgkin lymphoma (NHL) that involves the brain, leptomeninges, eyes or spinal cord without evidence of systemic disease. Despite the high complete remission rate achieved with aggressive first-line therapy, 10–35% of PCNSL are treatment refractory and 35–60% of patients relapse. Standard therapy for recurrent or refractory disease has not yet been established, although retrospective data suggests improvement in survival with salvage therapy. The reported survival after relapse of PCNSL varies between 2 months and 24 months, with most series reporting an average of 4–12 months. The outcomes depend on whether treatment is instituted or not, suggesting a need for treatment guidelines for these patients. We review therapeutic approaches and their outcomes in recurrent or refractory PCNSL.     

原发中枢神经系统淋巴瘤研究进展

原发中枢神经系统淋巴瘤(PCNSL)是原发于颅内的结外非霍奇金淋巴瘤,是一种罕见的高侵袭性淋巴瘤,预后较差.近年来,关于PCNSL的治疗方案尚无定论,以往的治疗包括手术、放疗、化疗等.目前大多认为综合治疗可以提高患者的生存率,而联合化疗药物的选择和预防性鞘内注射化疗药物在其治疗中占有重要地位.     

原发中枢神经系统淋巴瘤放疗作用观察

目的 探索放疗在原发中枢神经系统淋巴瘤治疗中的作用。方法 回顾分析2010年9月至2017年12月确诊的免疫功能正常的原发中枢神经系统淋巴瘤60例资料,其中50例经由手术或立体定向活检后病理诊断,10例影像学临床诊断。52例患者接受了化疗,其中45例为大剂量甲氨喋呤为主方案,25例为含利妥昔单抗方案。27例患者行计划性放疗,33例未行计划性放疗,其中治疗失败后9例接受了挽救性放疗。结果 中位随访时间28个月(5~70个月)。全组中位生存、中位无进展生存期分别为22个月(5~65个月)、13个月(5~55个月),4年总生存率、无进展生存率分别为61%、33%。计划性放疗组、非计划性放疗组4年总生存率分别为68%、54%(P=0.083),无进展生存率分别为47%、20%(P=0.014)。挽救性放疗组与计划性放疗组4年总生存率差异无统计学意义(P=0.398),全脑放疗≤36Gy、>36Gy组4年总生存率差异也无统计学意义(P=0.136)。结论 放疗是原发中枢神经系统淋巴瘤的综合治疗的一部分,计划性放疗可能使患者在综合治疗中获益,较高的照射剂量不能使患者获益。     

The utility of body FDG PET in staging primary central nervous system lymphoma

(18)F-Fluorodeoxyglucose (FDG) PET has become an important tool in the management of non-Hodgkin's lymphoma (NHL), but its role in the evaluation of primary CNS lymphoma (PCNSL) has not been established. We investigated the ability of body FDG PET to detect systemic disease in the staging and restaging of PCNSL. The records of 166 PCNSL patients seen at Memorial Sloan-Kettering Cancer Center were examined. Forty-nine patients who underwent body FDG PET for staging of PCNSL were identified. Clinical data were reviewed to determine FDG PET results and their influence on therapy. Body FDG PET disclosed a systemic site of malignancy in 15% of patients. NHL was found in 11% of all patients, 7% of patients at diagnosis, and 27% of patients at CNS relapse. Four percent had a second systemic neoplasm. Workup with conventional staging did not reveal systemic disease, and in 8% of patients, body FDG PET was the only abnormal diagnostic exam suggestive of lymphoma. FDG PET findings altered patient treatment and resulted in additional chemotherapy, surgery, or radiotherapy. Our findings suggest that FDG PET may be more sensitive than conventional body staging and may disclose higher rates of concomitant systemic disease at PCNSL diagnosis. Body FDG PET may be an important noninvasive adjunct to conventional PCNSL staging, and its utility should be evaluated prospectively.     

Diagnosis and management of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non‐Hodgkin lymphoma (NHL) that is confined to the brain, eyes, spinal cord, or leptomeninges without systemic involvement. The overall prognosis, diagnosis, and management of PCNSL differ from those for other types of NHL. Prompt diagnosis and initiation of treatment are vital for improving clinical outcomes. PCNSL is responsive to radiation therapy; however, whole‐brain radiotherapy (WBRT) inadequately controls the disease when it is used alone, and its delayed neurotoxicity causes neurocognitive impairment, especially in elderly patients. High‐dose methotrexate (HD‐MTX)–based induction chemotherapy with or without autologous stem cell transplantation (ASCT) or reduced‐dose WBRT leads to durable disease control and less neurotoxicity. The optimal treatment has yet to be defined; however, HD‐MTX–based induction chemotherapy is considered standard for newly diagnosed PCNSL. Ongoing randomized trials are addressing the roles of rituximab and consolidative treatment with ASCT or reduced‐dose WBRT. Despite high tumor response rates with the initial treatment, many patients relapse with a very poor prognosis. The optimal treatment for refractory or relapsed PCNSL is poorly defined. The choice of salvage treatment depends on a patient's age, previous treatment and response, performance status, and comorbidities at the time of relapse. This review provides an overview of the clinical features, diagnosis, pathology, and management of PCNSL in immunocompetent patients, and it focuses on recent advances in treatment. Cancer 2017;123:4314‐24 . © 2017 American Cancer Society.     

原发性中枢神经系统淋巴瘤的放射治疗进展

原发性中枢神经系统淋巴瘤(PCNSL)是指发生在脑、脊髓、脑膜或眼的罕见侵袭型非霍奇金淋巴瘤,以弥漫大B细胞淋巴瘤占绝大多数,其中又以Non-GCB亚型多见。未经治疗的患者中位生存期仅为3个月,单纯的手术切除肿瘤并没有明显的生存获益。早期单独使用全脑放疗(WBRT),缓解率高,但持续时间短,且延迟性神经系统不良反应是一...     

原发性中枢神经系统淋巴瘤的临床特征及预后分析

目的:探讨原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）患者的临床病理和分子学特征及预后影响因素。方法:收集2013年03月至2021年05月山西省人民医院35例PCNSL患者的临床资料及组织标本,总结其临床病理特征并应用二代测序技术检测淋巴瘤相关基因,分析年龄、病灶部位、乳酸脱氢酶（lactate dehydrogenase,LDH）、免疫组化等指标对预后的影响,比较不同基因突变组及治疗方案之间的总生存（overall survival,OS）差异。结果:最常见的基因突变为MYD88（66.7%,12/18）,IGLL5、PIM1（38.9%,7/18）;PIM1突变组、IGLL5突变组OS差于未突变组,差异均有统计学意义（P=0.019和0.021）;多因素Cox回归分析显示LDH、不同的治疗方案是PCNSL患者独立的预后影响因素（P=0.007和0.002）;接受大剂量甲氨蝶呤（methotrexate,MTX）、利妥昔单抗（rituximab,R）治疗组OS明显优于未接受组,差异均有统计学意义（P=0.005和＜0.001）;使用布鲁顿酪氨酸激酶抑制剂（broughton tyrosine kinase inhibitor,BTKi）组与未接受组相比,有生存获益的趋势,但未显示出统计学差异。结论:血清LDH升高与不良预后显著相关,PIM1及IGLL5突变患者生存较差,含MTX、R治疗方案可改善患者生存。     

替莫唑胺联合利妥昔单抗对复发的老年原发中枢神经淋巴瘤的应用

Objective: The aim of our study was to analyze the long-term results of rituximab combined with temozolomide in treatment of elderly patients (> 60 years) with relapsed primary central nervous system lymphoma (PCNSL). Methods: Twelve postoperative elderly patients (> 60 years) were treated between August 2004 and October 2009. Temozolomide 100 mg/m2 to 200 mg/m2 days 1 to 7 and 15 to 21 and rituximab 375 mg/m2 days 1, 5, 8, 22. The maximum number of rituximab cycles was two. After one or two cycles of this ...     

Utility of post-therapy brain surveillance imaging in the detection of primary central nervous system lymphoma relapse

BackgroundThe optimal follow-up strategy for primary central nervous system lymphoma (PCNSL) patients after first-line therapy is unclear. The goal of this study is to determine the utility of planned brain surveillance imaging in the detection of relapse in a retrospective cohort of PCNSL patients.MethodsPatients were consecutive PCNSL cases treated in Leon Berard Cancer Centre, Lyon, France, from 1985 to 2011. Histology was diffuse large B-cell lymphoma in 94%. Patients were treated by methotrexate (92%) and cytarabine (63%) based-chemotherapy followed by radiotherapy for 108 patients (51%). Clinical records were reviewed for details at relapse and relationship to planned imaging. The imaging follow-up strategy was performed according to each treating physicians.ResultsAmong 209 PCNSL patients, 127 complete response patients entered in post-treatment observation and 63 (50%) subsequently relapsed. Among the 125 evaluable patients, the majority of relapses (N = 49, 80%) was asymptomatic and identified before the planned brain imaging. Surveillance imaging detected relapses before symptoms in 12 patients who entered in post-therapy observation (10%). The median number of brain imaging during the follow-up was 7 (0–13). A total of 819 MRI/CT-scan were performed leading to the detection of 12 asymptomatic relapses. The one year OS rates were 41% and 58% for symptomatic and non-symptomatic relapses, respectively (P = 0.21).ConclusionThe majority of PCNSL relapses occurred outside planned follow-up with no difference in patient outcome between symptomatic and asymptomatic relapses. The role of brain imaging for the detection of relapses in the follow-up of PCNSL patients remains to be clarified.     

原发性睾丸淋巴瘤及原发性中枢神经系统淋巴瘤研究进展：第19届欧洲血液学会年会报道

原发性睾丸淋巴瘤（PTL）是一类少见的结外淋巴瘤,进展迅速,预后不良.对于早期局限性病变,可联合应用以蒽环类为基础的化疗、利妥昔单抗、鞘内注射甲氨蝶呤后行对侧睾丸放疗等.中枢神经系统复发风险极高,鞘内注射甲氨蝶呤可能是最好的防治方法.原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性淋巴瘤,预后较差,对现有非霍奇金淋巴瘤标准治疗方案均不敏感,甲氨蝶呤联合阿糖胞苷是目前的标准诱导方案.抗CD20单克隆抗体虽然脑脊液含量低,但仍有治疗效果.高剂量化疗联合自体造血干细胞移植缓解率高,3年总生存率可达87％.     

42例原发性中枢神经系统淋巴瘤患者预后影响因素分析

背景与目的：原发性中枢神经系统淋巴瘤（primary central nervous system lymphoma,PCNSL）是发生在脑、脊髓、脑膜或眼的罕见侵袭型非霍奇金淋巴瘤,无CNS之外的部位累及。PCNSL与其他类型淋巴瘤相比,患者生存期短,预后差,且复发率高,未经治疗的患者的中位生存期仅为3个月。近年来研究发现C-MYC、BCL-2、BCL-6、Ki-67等指标在一定程度上影响PCNSL患者预后。因此,通过分析PCNSL相关蛋白表达、治疗方式及其他临床因素对患者预后的影响, 希望为该病的临床治疗及预后评价进一步积累资料。方法：回顾性分析自2013年6月—2021年5月于大连医科大学附属第二医院治疗的42例经病理学检查明确诊断为原发性中枢神经系统弥漫大B细胞淋巴瘤患者的临床资料,包括性别、年龄、病灶数量、美国东部肿瘤协作组（Eastern Cooperative Oncology Group,ECOG）评分、血清乳酸脱氢酶（lactate dehydrogenase,LDH）、病灶是否累及深部脑组织、治疗方案、病理学Hans分型及C-MYC、BCL-2、BCL-6、Ki-67等生物标志物,结合随访调查,了解患者生存时间及生存状况,应用Kaplan-Meier法及log-rank检验分析影响患者无进展生存期（progression-free survival,PFS）和总生存期（overall survival,OS）的预后相关因素,多因素分析采用COX回归模型。结果：42例PCNSL患者中位发病年龄61岁,男女比例为1.33∶1.00,颅脑增强MRI病灶多呈均匀明显强化。所有患者均接受含有大剂量甲氨蝶呤（high-dose methotrexate,HD-MTX）方案化疗,治疗后评价完全缓解（complete response,CR）20例、部分缓解（partial response,PR）5例,疾病稳定（stable disease,SD）11例,疾病进展（progressive disease,PD）6例。中位PFS为21个月,中位OS为34个月,1年PFS率为63.7%,2年PFS率为47.0%;1年OS率为70.8%,2年OS率为55.6%。单因素分析结果显示,影响PFS的因素是HD-MTX多药联合化疗、鞘内化疗及联合利妥昔单抗。影响OS的因素是ECOG评分≥2、C-MYC（+）、BCL-2及C-MYC双表达、HD-MTX多药联合化疗、鞘内化疗及联合利妥昔单抗。多因素分析结果显示：利妥昔单抗治疗是影响PFS的独立预后因素（P=0.020）,ECOG评分、利妥昔单抗是影响OS的独立预后因素（P=0.007;P=0.046）。与未接受巩固治疗的患者相比,接受巩固治疗患者的中位PFS及OS较高;进一步的亚组分析显示,自体干细胞移植（autologous stem cell transplantation,ASCT）组的中位PFS及OS较全脑放疗（whole brain radiation therapy,WBRT）组高,但差异无统计学意义。结论：PCNSL多发于中老年人,男性多于女性,影像学缺乏特异性。ECOG评分≥2与PCNSL患者较差的OS相关。C-MYC（+）、BCL-2及C-MYC双表达可作为指导危险分层的预后标志物。以HD-MTX为基础的多药联合化疗已经成为PCNSL的首选治疗手段,利妥昔单抗的应用可延长生存期。在全身化疗的基础上,联合局部鞘内化疗可以改善预后。进一步的巩固治疗主要包括ASCT及WBRT,可延长PFS及OS,ASCT可以取得与WBRT相似的疗效,且可避免WBRT的晚期神经毒性,但本研究中因样本量及随访时间的限制,未得出明确的统计学结果。     

Angiogenesis in primary central nervous system lymphoma (PCNSL)

Angiogenesis and angiogenic growth factors have a major role in the pathogenesis of malignancies. However, very little is known about the clinical and histopathological relevance of angiogenesis in primary central nervous system lymphoma (PCNSL). We investigated that expression of vascular endothelial growth factor (VEGF) of the lymphoma cells and microvessel density (MVD) were examined in 19 patients with PCNSL. Additionally, the presence of the blood–brain barrier (BBB) was examined using immunohistochemistry and the electron microscopy. MVD was significantly higher in nine cases with VEGF immunoreactivity (VEGF+) than in ten cases with negative immunoreactivity for VEGF (VEGF−) (P < 0.001). VEGF expression was significantly associated with a longer survival (P < 0.005). BBB markers were negative in angiogenic vessels of VEGF+. BBB markers were identified in vessels surrounding tumor cells and tight junctions were also preserved in the capillary endothelium surrounding tumor cells in VEGF−. Angiogenesis is associated with VEGF expression and an absent BBB in the vessels of PCNSL. The BBB may be preserved in lesions with lymphoma cell infiltration, especially in VEGF− PCNSL. VEGF may have a prognostic effect in PCNSL.     

Prognostic implication of p27 expression in primary central nervous system lymphoma

To clarify the role of p27/Kip1 (p27) in primary central nervous system lymphomas (PCNSLs), we examined p27 expression by immunohistochemical methods in a series of 22 patients with PCNSL. We attempted to correlate the expression of p27 with proliferation potential and prognosis. Although the MIB-1 labeling index (LI) was lower in tumors with low p27 expression (26.7% ± 17.2% vs 38.1% ± 16.3%), it was not significantly different from that of tumors with high p27 expression (P = 0.1253). Survival analysis revealed that high p27 expression was significantly associated with poorer overall prognosis (P = 0.0011); however, the MIB-1 LI were not associated with prognosis. Our results suggest p27 as a predictor of prognosis in patients with PCNSL.     

Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.