The Lancet Haematology最新文献

Triplet therapy for advanced BCR::ABL1 positive myeloid leukaemias. 晚期BCR::ABL1阳性髓性白血病的三联疗法。

The Lancet Haematology

Pub Date : 2024-09-17 DOI: 10.1016/s2352-3026(24)00282-5

Mhairi Copland

引用次数: 0

Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial. 地西他滨、venetoclax和泊纳替尼治疗晚期慢性髓性白血病和费城染色体阳性急性髓性白血病：单臂、单中心2期试验。

The Lancet Haematology

Pub Date : 2024-09-17 DOI: 10.1016/s2352-3026(24)00250-3

Nicholas J Short,Daniel Nguyen,Elias Jabbour,Jayastu Senapati,Zhihong Zeng,Ghayas C Issa,Hussein Abbas,Cedric Nasnas,Wei Qiao,Xuelin Huang,Gautam Borthakur,Kelly Chien,Fadi G Haddad,Naveen Pemmaraju,Omer S Karrar,Danielle Nguyen,Marina Konopleva,Hagop Kantarjian,Farhad Ravandi

BACKGROUNDAdvanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases.METHODSFor this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing.RESULTSBetween July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, an

背景：晚期费城染色体阳性髓系疾病--包括处于髓系胚泡期和加速期的慢性髓性白血病以及费城染色体阳性急性髓性白血病--与不良预后有关。虽然以往的研究表明化疗和 BCR::ABL1 酪氨酸激酶抑制剂联合治疗有一定的疗效，但最佳治疗方案尚不确定，而且针对这类罕见疾病的前瞻性研究也很少。临床前和回顾性临床数据表明，BCL-2抑制剂venetoclax与BCR::ABL1酪氨酸激酶抑制剂之间可能存在协同作用。因此，我们旨在设计一项研究，以评估地西他滨、venetoclax 和第三代 BCR::ABL1 酪氨酸激酶抑制剂 ponatinib 新型组合治疗晚期费城染色体阳性髓系疾病的安全性和活性。方法在这项2期研究中，年龄在18岁或18岁以上、既往未经治疗或复发或难治性髓性慢性髓性白血病-播散期、慢性髓性白血病-加速期或晚期费城染色体阳性急性髓性白血病患者，以及东部合作肿瘤学组表现状态为0-3的患者均符合条件。无论患者之前接受过多少种疗法或之前是否服用过泊纳替尼，均符合条件。第1周期（诱导）包括每天口服波纳替尼45毫克，为期7天（第1-7天），然后在第8-12天静脉注射地西他滨20毫克/平方米，在第8-28天每天口服venetoclax，逐渐增加到最大剂量400毫克，在第8-28天每天口服波纳替尼45毫克。第2-24周期包括第1-5天静脉注射地西他滨20毫克/平方米，第1-21天口服400毫克venetoclax，第1-28天每天口服泊纳替尼。在巩固治疗周期中，采用基于反应的帕纳替尼剂量，达到完全缓解或完全缓解但血液学未完全恢复的患者，帕纳替尼剂量减至每天30毫克；检测不到BCR::ABL1转录物的患者，帕纳替尼剂量减至每天15毫克。主要终点是意向治疗人群中完全缓解或完全缓解伴不完全血液学恢复的复合率。安全性在意向治疗人群中进行评估。该试验已在ClinicalTrials.gov（NCT04188405）注册，目前仍在进行中。结果2020年7月12日至2023年7月8日期间，20名患者接受了治疗（14名慢性髓性白血病-播散期患者、4名慢性髓性白血病-加速期患者和2名费城染色体阳性急性髓性白血病晚期患者）。中位年龄为 43 岁（IQR 32-58）；13 名（65%）患者为男性，7 名（35%）为女性；12 名（60%）患者为白人，3 名（15%）为西班牙裔，4 名（20%）为黑人，1 名（5%）为亚裔。12名患者（60%）曾接受过两种或两种以上的BCR::ABL1酪氨酸激酶抑制剂治疗，14名患者（70%）至少有一种高风险染色体异常或复杂核型。中位随访时间为 21-2 个月（IQR 14-1-24-2）。完全缓解或完全缓解但血液学未完全恢复的比例为 50%（20 例患者中有 10 例）；1 例患者完全缓解[5%]，9 例患者完全缓解但血液学未完全恢复[45%]。另有 6 名患者（30%）在形态学上无白血病。最常见的 3-4 级非血液学不良反应是 8 名（40%）患者出现发热性中性粒细胞减少，6 名（30%）患者出现感染，5 名（25%）患者出现丙氨酸或天冬氨酸转氨酶升高。8名患者（40%）至少发生过一次任何程度的心血管事件。有三例研究中死亡病例，其中无一例与研究治疗有关，均死于难治性白血病背景下的感染。有必要开展进一步研究，评估化疗和基于venetoclax、使用新一代BCR::ABL1酪氨酸激酶抑制剂的联合策略。

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引用次数: 0

Efficacy and safety of fedratinib in patients with myelofibrosis previously treated with ruxolitinib (FREEDOM2): results from a multicentre, open-label, randomised, controlled, phase 3 trial. 既往接受过鲁索利替尼治疗的骨髓纤维化患者服用非瑞替尼的疗效和安全性（FREEDOM2）：一项多中心、开放标签、随机对照、三期试验的结果。

The Lancet Haematology

Pub Date : 2024-09-09 DOI: 10.1016/s2352-3026(24)00212-6

Claire N Harrison,Ruben Mesa,Moshe Talpaz,Haifa Kathrin Al-Ali,Blanca Xicoy,Francesco Passamonti,Francesca Palandri,Giulia Benevolo,Alessandro Maria Vannucchi,Clemence Mediavilla,Alessandra Iurlo,InHo Kim,Shelonitda Rose,Patrick Brown,Christopher Hernandez,Jia Wang,Jean-Jacques Kiladjian

BACKGROUNDMost patients with myelofibrosis develop ruxolitinib intolerance or disease that is relapsed or refractory, and survival rates after ruxolitinib discontinuation are poor. We aimed to evaluate the safety and efficacy of fedratinib versus best available therapy (BAT) in patients with myelofibrosis previously treated with ruxolitinib.METHODSFREEDOM2 was a multicentre, open-label, randomised, controlled, phase 3 trial in 86 clinics in 16 countries, in which patients aged at least 18 years with intermediate-2 or high-risk myelofibrosis that was relapsed or refractory or intolerant to ruxolitinib with Eastern Cooperative Oncology Group performance status 0-2 were stratified by spleen size by palpation, platelet count, and previous ruxolitinib treatment, and randomly assigned 2:1 by interactive response technology to receive fedratinib 400 mg per day (4 × 100 mg capsules orally once daily, open-label) or BAT. Patients received prophylactic antiemetics and thiamine supplementation, and symptomatic antidiarrhoeals as required. Primary endpoint was proportion of patients reaching spleen volume reduction (SVR) of at least 35% (SVR35) at end of cycle 6 in the intention-to-treat population. This manuscript reports the primary analysis of the trial; follow-up is ongoing. This trial is registered at clinicaltrials.gov, NCT03952039.FINDINGSBetween Sept 9, 2019 and June 24, 2022, of 316 patients screened, 201 were randomly assigned and treated (134 to fedratinib, 67 to BAT [including 52 receiving ruxolitinib]); 46 patients from the BAT group crossed over to fedratinib. Approximately half of enrolled patients were male (fedratinib 75 [56%] of 134; BAT 30 [45%] of 67) and most were White (fedratinib 106 [79%] of 134; BAT 58 [87%] of 67). At data cutoff (Dec 27, 2022), median survival follow-up was 64·5 weeks (IQR 37·9-104·9). SVR35 at end of cycle 6 was seen in 48 (36%) of 134 patients receiving fedratinib versus four (6%) of 67 patients receiving BAT (30% difference; 95% CI 20-39; one-sided p-value <0·0001). During the first six cycles 53 (40%) of 134 patients in the fedratinib group and 8 (12%) of 67 patients in the BAT group had grade 3 or greater treatment-related adverse events, most frequently anaemia (fedratinib 12 [9%] of 134; BAT 6 [9%] of 67) and thrombocytopenia (fedratinib 16 [12%] of 134; BAT 2 [3%] of 67); one patient in the fedratinib group died from acute kidney injury suspected to be related to study drug (no treatment-related deaths in the BAT group). Gastrointestinal adverse events occurred more frequently in the fedratinib group compared with the BAT group, but were mostly grade 1-2 in severity and more frequent in early cycles, and were less frequent than in prior clinical trials. A total of 28 (21%) of 134 patients in the fedratinib group and 3 (4%) of 67 patients in the BAT group had thiamine levels below lower limit of normal per central laboratory assessment, with only one case of low thiamine in the fedratinib arm after the intro

背景大多数骨髓纤维化患者会出现鲁索利替尼不耐受或疾病复发或难治的情况，而停用鲁索利替尼后的生存率很低。我们旨在评估曾接受过鲁索利替尼治疗的骨髓纤维化患者使用非瑞替尼与最佳可用疗法（BAT）的安全性和有效性。方法FREEDOM2是一项多中心、开放标签、随机对照的3期试验，在16个国家的86家诊所进行。在这项试验中，年龄至少18岁的中-2级或高风险骨髓纤维化患者复发或对Ruxolitinib治疗难治或不耐受，且东方合作肿瘤学组表现状态为0-2级，根据触诊脾脏大小、血小板计数和既往Ruxolitinib治疗情况进行分层，并随机分配2：通过交互反应技术，以 2：1 的比例随机分配患者接受非瑞替尼 400 毫克/天（4 × 100 毫克胶囊，口服，每天一次，开放标签）或 BAT 治疗。患者接受预防性止吐药和硫胺素补充剂，并根据需要接受对症止泻药。主要终点是在意向治疗人群中，第6周期结束时脾脏体积缩小（SVR）达到至少35%（SVR35）的患者比例。本手稿报告了试验的主要分析结果；后续工作仍在进行中。该试验已在 clinicaltrials.gov 注册，编号为 NCT03952039。研究结果在 2019 年 9 月 9 日至 2022 年 6 月 24 日期间，在筛选出的 316 名患者中，201 名患者被随机分配并接受治疗（134 名患者接受了 fedratinib 治疗，67 名患者接受了 BAT 治疗[包括 52 名接受 ruxolitinib 治疗的患者]）；46 名来自 BAT 组的患者交叉接受了 fedratinib 治疗。约半数入组患者为男性（134 名患者中有 75 名[56%]接受了 fedratinib 治疗；67 名患者中有 30 名[45%]接受了 BAT 治疗），大多数患者为白人（134 名患者中有 106 名[79%]接受了 fedratinib 治疗；67 名患者中有 58 名[87%]接受了 BAT 治疗）。数据截止日期（2022 年 12 月 27 日）为 64-5 周（IQR 37-9-104-9）。在接受费瑞替尼治疗的134例患者中，有48例（36%）在第6周期结束时达到SVR35，而在接受BAT治疗的67例患者中，有4例（6%）达到SVR35（差异为30%；95% CI为20-39；单侧P值<0-0001）。在前六个周期中，费拉替尼组 134 例患者中有 53 例（40%）发生了 3 级或更严重的治疗相关不良事件，BAT 组 67 例患者中有 8 例（12%）发生了 3 级或更严重的治疗相关不良事件，其中最常见的是贫血（费拉替尼组 134 例患者中有 12 例[9%]，BAT 组 67 例患者中有 6 例[9%]）；BAT 组 67 例中有 6 例[9%]）和血小板减少症（非瑞替尼组 134 例中有 16 例[12%]；BAT 组 67 例中有 2 例[3%]）；非瑞替尼组有 1 例患者死于急性肾损伤，怀疑与研究药物有关（BAT 组无治疗相关死亡病例）。与BAT组相比，非瑞替尼组的胃肠道不良反应发生率更高，但严重程度大多为1-2级，且更多发生在早期周期，发生率低于之前的临床试验。根据中心实验室的评估，在134例fedratinib组患者中，有28例（21%）患者的硫胺素水平低于正常下限；在67例BAT组患者中，有3例（4%）患者的硫胺素水平低于正常下限。阐释FREEDOM2的研究结果支持将非瑞替尼作为二线Janus激酶抑制剂，用于减少骨髓纤维化患者鲁索利替尼失败或不耐受后的脾脏大小，并显示了通过预防、监测和治疗管理胃肠道不良事件和低硫胺素浓度的有效策略。

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引用次数: 0

Ixazomib as consolidation and maintenance versus observation in patients with relapsed multiple myeloma eligible for salvage autologous stem-cell transplantation (Myeloma XII [ACCoRD]): interim analysis of a multicentre, open-label, randomised, phase 3 trial. 伊沙佐米对符合自体干细胞移植挽救条件的复发性多发性骨髓瘤患者的巩固和维持治疗与观察治疗（骨髓瘤 XII [ACCoRD]）：一项多中心、开放标签、随机、3 期试验的中期分析。

The Lancet Haematology

Pub Date : 2024-09-06 DOI: 10.1016/s2352-3026(24)00249-7

Gordon Cook,A John Ashcroft,Ethan Senior,Catherine Olivier,Anna Hockaday,Jeanine Richards,Jamie D Cavenagh,John A Snowden,Mark T Drayson,Ruth de Tute,Lesley Roberts,Roger G Owen,Kwee Yong,Mamta Garg,Kevin Boyd,Hamdi Sati,Sharon Gillson,Mark Cook,David A Cairns,Christopher Parrish,

BACKGROUNDThe efficacy of consolidation and maintenance in the context of salvage autologous haematopoietic stem-cell transplantation (HSCT) for relapsed multiple myeloma remains unclear. We aimed to assess whether consolidation after salvage autologous HSCT, using ixazomib, thalidomide, and dexamethasone, followed by maintenance with single agent ixazomib is superior to observation.METHODSThis is an interim analysis of Myeloma XII (ACCorD; referred to as ACCorD hereafter), an open-label, randomised, controlled, phase 3 trial done at 79 hospitals in the UK. Eligible patients were aged 18 years or older, had relapsed multiple myeloma with measurable disease, an ECOG performance status of 2 or less with adequate renal, hepatobiliary, pulmonary, and cardiac function, and required treatment for first progressive disease occurring at least 12 months after first autologous HSCT. In a first randomisation, patients were assigned (1:1) to receive either conventional autologous HSCT with melphalan or augmented autologous HSCT with melphalan and ixazomib. In the second randomisation, reported here, patients were assigned (1:1) to consolidation using ixazomib, thalidomide, and dexamethasone (oral ixazomib 4 mg per day on days 1, 8, and 15, oral thalidomide 100 mg per day on days 1-28, and oral dexamethasone 40 mg per day on days 1, 8, 15 and 22 of 28-day cycles), followed by maintenance with single agent ixazomib (oral ixazomib 4 mg per day on days 1, 8, and 15 of 28-day cycles until disease progression or intolerance), or observation. The primary endpoint was progression-free survival, analysed by intention-to-treat. Safety was analysed per-protocol. This study is registered with ISRCTN, ISRCTN10038996, and EudraCT, 2016-000905-35, and recruitment is complete.FINDINGSBetween Dec 12, 2017, and April 21, 2023, 206 patients entered the second randomisation (103 in the consolidation and maintenance group and 103 in the observation group). This prespecified interim analysis (data cutoff April 21, 2023), was done at a median follow-up of 27 months (IQR 13-38). Median progression-free survival was 20 months (95% CI 15-29) in the consolidation and maintenance group and 13 months (11-18) in the observation group (hazard ratio 0·55 [95% CI 0·39-0·78]; p=0·0006). Serious adverse events were reported in 29 (32%) of 92 patients in the consolidation and maintenance group compared with seven (7%) of 103 patients in the observation group. The most common serious adverse events were infections and infestations in both the consolidation and maintenance group and the observation group. The most common grade 3, 4, or 5 adverse events for patients in the consolidation and maintenance group were upper respiratory infection (seven [8%] of 92 patients). No deaths in the consolidation and maintenance group were deemed treatment related.INTERPRETATIONACCorD provides evidence that an orally administered, deliverable, and tolerable post-salvage autologous HSCT treatment regimen can im

背景复发性多发性骨髓瘤抢救性自体造血干细胞移植（HSCT）的巩固和维持疗效仍不明确。我们旨在评估在挽救性自体造血干细胞移植后使用伊沙佐米、沙利度胺和地塞米松进行巩固治疗，然后使用单药伊沙佐米进行维持治疗是否优于观察治疗。符合条件的患者年龄在18岁或18岁以上，多发性骨髓瘤复发并伴有可测量的疾病，ECOG表现为2级或2级以下，肾、肝胆、肺和心脏功能正常，首次自体造血干细胞移植后至少12个月出现首次进展性疾病，需要接受治疗。在第一次随机分配中，患者被分配（1:1）接受常规自体造血干细胞移植与美法仑或增强型自体造血干细胞移植与美法仑和伊沙佐米。在本文报告的第二次随机分配中，患者被分配（1:1）到使用伊沙佐米的巩固治疗中：在第二次随机化中，患者被分配（1：1）接受伊沙佐米、沙利度胺和地塞米松的巩固治疗（第1、8和15天每天口服伊沙佐米4毫克，第1-28天每天口服沙利度胺100毫克，第1、8、15和22天每天口服地塞米松40毫克）、随后使用单药伊沙佐米维持治疗（口服伊沙佐米，每天4毫克，28天周期的第1、8和15天，直到疾病进展或不耐受）或观察。主要终点是无进展生存期，按意向治疗进行分析。安全性按方案进行分析。该研究已在ISRCTN（ISRCTN10038996）和EudraCT（2016-000905-35）注册，招募工作已完成。研究结果2017年12月12日至2023年4月21日期间，206名患者进入第二次随机分组（巩固和维持组103人，观察组103人）。该预设中期分析（数据截止日期为2023年4月21日）的中位随访时间为27个月（IQR为13-38）。巩固和维持组的中位无进展生存期为 20 个月（95% CI 15-29），观察组为 13 个月（11-18）（危险比 0-55 [95% CI 0-39-0-78]；P=0-0006）。在巩固和维持治疗组的 92 名患者中，有 29 人（32%）发生了严重不良事件，而在观察组的 103 名患者中，有 7 人（7%）发生了严重不良事件。在巩固和维持治疗组和观察组中，最常见的严重不良事件是感染和侵袭。巩固和维持治疗组患者最常见的 3、4 或 5 级不良反应是上呼吸道感染（92 名患者中有 7 人[8%]）。CorD提供的证据表明，口服给药、可递送、可耐受的痊愈后自体造血干细胞移植治疗方案可改善符合移植条件的首次复发患者的反应持久性。这些研究结果与在一线接受自体造血干细胞移植治疗后疾病得到持久控制的患者息息相关，是持续使用亲体给药复发疗法的可行替代方案。

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引用次数: 0

Continued need for autologous transplantation in relapsed myeloma. 复发骨髓瘤患者仍需进行自体移植。

The Lancet Haematology

Pub Date : 2024-09-06 DOI: 10.1016/s2352-3026(24)00277-1

Elias K Mai

引用次数: 0

Pembrolizumab and low-dose, single-fraction radiotherapy for patients with relapsed or refractory multiple myeloma: a prospective, single-centre, single-group, open-label, phase 2 pilot trial in the USA 针对复发或难治性多发性骨髓瘤患者的 Pembrolizumab 和低剂量单剂量放疗：在美国进行的一项前瞻性、单中心、单组、开放标签的 2 期试点试验

The Lancet Haematology

Pub Date : 2024-05-01 DOI: 10.1016/s2352-3026(24)00105-4

Mohammad K Khan, T. Nasti, Joshua Y Qian, T. Kleber, Jeffrey M Switchenko, J. Kaufman, Ajay J Nooka, M. Dhodapkar, Z. Buchwald, Daby Obiekwe, S. Lonial, Rafi Ahmed

引用次数: 0

Diagnosis and management of pyruvate kinase deficiency: international expert guidelines 丙酮酸激酶缺乏症的诊断和管理：国际专家指南

The Lancet Haematology

Pub Date : 2024-02-05 DOI: 10.1016/s2352-3026(23)00377-0

Hanny Al-Samkari, Nadine Shehata, Kelly Lang-Robertson, Paola Bianchi, Andreas Glenthøj, Sujit Sheth, Ellis J Neufeld, David C Rees, Satheesh Chonat, Kevin H M Kuo, Jennifer A Rothman, Wilma Barcellini, Eduard J van Beers, Dagmar Pospíšilová, Ami J Shah, Richard van Wijk, Bertil Glader, Maria Del Mar Mañú Pereira, Oliver Andres, Theodosia A Kalfa, Rachael F Grace

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

丙酮酸激酶（PK）缺乏症是全球慢性先天性非血红素溶血性贫血最常见的病因，估计发病率为十万分之一到三十万分之一。PK 缺乏症会导致慢性溶血性贫血，对健康、生活质量和死亡率造成广泛而严重的影响。丙酮酸激酶缺乏症诊断和管理国际指南》的目标是为 PK 缺乏症患者的临床治疗制定循证指南。这些临床指南是采用 GRADE 方法和 AGREE II 框架制定的。在邀请专家时，考虑了专家的专业领域、在 PK 缺乏症方面的学术贡献以及执业国家的全球代表性。专家小组成员包括来自 10 个国家的 29 名专家医师（包括成人和儿童血液科医师及其他亚专科医师）、遗传学家、实验室专家、护士、一名指南方法论专家、PK 缺乏症患者以及护理人员。专家组确定了五个关键主题领域，对关键问题进行了优先排序，并进行了系统的文献检索，以生成用于制定建议草案的证据摘要。然后，专家小组亲自开会，根据结构化共识程序最终确定建议并进行表决。专家小组必须达成大于或等于 67% 的一致意见，才能将建议纳入最终指南。专家组就五个关键主题共 31 项建议达成了一致意见：诊断和遗传学、慢性并发症的监测和管理、贫血的标准管理、靶向和先进疗法以及特殊人群。这些新指南应有助于将最佳实践和循证 PK 缺乏症护理纳入临床实践。

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引用次数: 0

Correction to Lancet Haematol 2024; 11: e38–50 Lancet Haematol 2024; 11: e38-50 更正

The Lancet Haematology

Pub Date : 2024-02-05 DOI: 10.1016/s2352-3026(24)00035-8

Abstract not available

无摘要

引用次数: 0

Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study 在高风险骨髓增生异常综合征或慢性粒细胞白血病患者中口服地西他滨加西达嘧啶和 Venetoclax：一项单中心、1/2 期研究

The Lancet Haematology

Pub Date : 2024-02-02 DOI: 10.1016/s2352-3026(23)00367-8

Alex Bataller, Guillermo Montalban-Bravo, Alexandre Bazinet, Yesid Alvarado, Kelly Chien, Sangeetha Venugopal, Jo Ishizawa, Danielle Hammond, Mahesh Swaminathan, Koji Sasaki, Ghayas C Issa, Nicholas J Short, Lucia Masarova, Naval G Daver, Tapan M Kadia, Simona Colla, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Stephany Hendrickson, Guillermo Garcia-Manero

Background

Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.

Methods

We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1–5 and venetoclax (variable doses of 100–400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants.

Findings

Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27–94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3–4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6–16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.

Interpretation

This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.

Funding

MD Anderson Cancer Center, MDS/AML Moon

背景高甲基化药物被批准用于高风险骨髓增生异常综合征。低甲基化药物与 Venetoclax 的联合治疗是急性髓性白血病的标准治疗方法。我们研究了在高风险骨髓增生异常综合征和慢性粒细胞白血病患者中首次完全口服地西他滨+西达嘧啶和venetoclax联合疗法的安全性和活性。患者均为未经治疗的高危骨髓增生异常综合征或慢性粒细胞白血病患者（根据国际预后评分系统，风险等级被归类为中级-2级或更高），并伴有过多胚泡（>5%）。治疗包括口服地西他滨35毫克加西达嘧啶100毫克（第1-5天）和venetoclax（100-400毫克不等剂量，第1-14天，28天周期）。第一阶段研究的主要结果是安全性，第二阶段研究的主要结果是总体反应。试验仍在进行中，本分析未进行预设。研究结果2021年1月21日至2023年1月20日期间，我们共招募了39名患者（1期9名，2期30名）。中位年龄为 71 岁（27-94 岁不等），28 名（72%）患者为男性，11 名（28%）患者为女性。由于未达到最大耐受剂量，第2阶段的推荐剂量被确定为口服地西他滨35毫克加西达嘧啶100毫克，疗程5天；口服venetoclax（400毫克），疗程14天。最常见的3-4级不良事件是血小板减少症（39例中有33例[85%]）、中性粒细胞减少症（29例[74%]）和发热性中性粒细胞减少症（8例[21%]）。四例与治疗无关的死亡病例分别死于败血症（2例）、肺部感染（1例）和不明原因（1例）。中位随访时间为 10-8 个月（IQR 5-6-16-4）。总体应答率为 95% (95% CI 83-99; 37/39)。解读这项早期分析表明，口服地西他滨加西达嘧啶与Venetoclax联合治疗高风险骨髓增生异常综合征和慢性粒细胞白血病对大多数患者是安全的，并具有令人鼓舞的活性。要证实这些数据，还需要更长时间的随访。资金来源：MD Anderson 癌症中心、MDS/AML Moon Shot、Genentech/AbbVie 和 Astex 制药公司。

{"title":"Oral decitabine plus cedazuridine and venetoclax in patients with higher-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: a single-centre, phase 1/2 study","authors":"Alex Bataller, Guillermo Montalban-Bravo, Alexandre Bazinet, Yesid Alvarado, Kelly Chien, Sangeetha Venugopal, Jo Ishizawa, Danielle Hammond, Mahesh Swaminathan, Koji Sasaki, Ghayas C Issa, Nicholas J Short, Lucia Masarova, Naval G Daver, Tapan M Kadia, Simona Colla, Wei Qiao, Xuelin Huang, Rashmi Kanagal-Shamanna, Stephany Hendrickson, Guillermo Garcia-Manero","doi":"10.1016/s2352-3026(23)00367-8","DOIUrl":"https://doi.org/10.1016/s2352-3026(23)00367-8","url":null,"abstract":"<h3>Background</h3><p><span>Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with </span>venetoclax<span><span> is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of </span>decitabine<span><span> plus cedazuridine and venetoclax </span>in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia.</span></span></p><h3>Methods</h3><p><span>We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1–5 and venetoclax (variable doses of 100–400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with </span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, <span>NCT04655755</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, and is currently enrolling participants.</p><h3>Findings</h3><p><span>Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27–94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3–4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study </span>drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6–16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation.</p><h3>Interpretation</h3><p>This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data.</p><h3>Funding</h3><p>MD Anderson Cancer Center, MDS/AML Moon ","PeriodicalId":501011,"journal":{"name":"The Lancet Haematology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139660421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decitabine plus cedazuridine and venetoclax: the promise of an all-oral therapy for patients with myelodysplastic syndromes and chronic myelomonocytic leukaemia 地西他滨加西达嘧啶和 Venetoclax：骨髓增生异常综合征和慢性粒细胞白血病患者的全口服疗法前景看好

The Lancet Haematology

Pub Date : 2024-02-02 DOI: 10.1016/s2352-3026(24)00001-2

Sarit Assouline

Abstract not available

无摘要

引用次数: 0