Itacitinib

点上方蓝字“ioncology”关注我们， 然后点右上角“…”菜单，选择“设为星标” 前言：2024年世界肺癌大会（WCLC）上公布了多项晚期非小细胞肺癌（NSCLC）一线治疗重磅研究成果，《肿瘤瞭望》特将重要研究进行回顾整理，以飨读者。 01 埃万妥单抗联合Lazertinib与奥希替尼一线治疗携带EGFR突变NSCLC患者的疗效及安全性：一项III期临床研究的长期随访结果 奥希替尼是携带EGFR敏感突变患者的一线标准治疗，Lazertinib是三代EGFR-酪氨酸激酶抑制剂（TKI）类药物，埃万妥单抗是一款靶向EGFR和c-MET的双特异性抗体药物，MARIPOSA研究旨在探索双药联合治疗相较于奥希替尼单药一线治疗携带EGFR敏感突变晚期NSCLC患者的疗效及安全性。在前期公布的数据中，联合治疗相较于奥希替尼单药展示出了更好的无进展生存期（PFS）的数据，本次旨在公布其长期随访结果和颅内随访结果。 本次数据公布时，两组颅内PFS分别为24.9个月和22.2个月，HR=0.82， P=0.165，颅内缓解持续时间（DoR）分别为未达到和24.2个月，中位至治疗终止时间分别为26.3个月和22.6个月，HR=0.80，P=0.014，至后线开启治疗时间分别为30.0个月和24.0个月，HR=0.77，P=0.005。联合治疗组和单药治疗组分别有41%和45%的患者接受含铂双药治疗，分别有12%和20%的患者接受含铂双药联合免疫或抗血管生成治疗，分别有27%和16%的患者接受了其他三代靶向药物治疗。两组PFS分别为未达到和32.4个月，HR=0.73，P=0.004。两组中位总生存期（OS）分别为未达到和37.3个月，HR=0.77，P=0.019。 两组更新后的OS数据 本届WCLC还公布了该研究中Lazertinib与奥希替尼比较的疗效数据，研究显示，奥希替尼和Lazertinib的客观缓解率（ORR）分别为85%和83%，P=0.57，均有4%的患者达到病理完全缓解（pCR），中位PFS分别为16.6个月和18.5个月，HR=0.98，P=0.86。基线有脑转移、基线有可测量循环肿瘤DNA以及基线合并TP53共突变的三个高危因素组患者，HR值分别为0.90、0.88和0.85，差异均无统计学意义。中位至症状恶化时间分别为29.3个月和未达到，HR=0.85，P=0.27。首次中期分析时，两组中位OS均未达到，HR=1.0。 两组OS数据 严重不良反应发生率分别为33%和35%，并分别导致了7%和6%的患者出现死亡事件。奥希替尼组腹泻 (44% vs 32%)，血小板降低(20% vs 9%)，中性粒细胞下降(13% vs 3%)发生率更高，而Lazertinib组皮疹(45% vs 31%)，肌肉痉挛(23% vs 7%)发生率更高。 02 SH-1028 vs 吉非替尼一线治疗EGFR突变阳性的NSCLC患者的疗效及安全性：一项多中心、双盲、随机III期临床研究 SH-1028是一款三代EGFR-TKI类药物，可以克服继发性T790M突变。本研究旨在比较该药与一代靶向药物吉非替尼的疗效及安全性。研究纳入局部晚期或转移性NSCLC患者，携带19del或21L858R突变，符合入组标准的患者按2:1的比例随机分为SH-1028 200mg，口服，每日一次，或吉非替尼250mg，口服，每日一次，主要研究终点为独立评审委员会评估的PFS，次要研究终点包括ORR、DoR、安全性等。 最终，两组分别入组162例和83例患者，基线特点均衡可比。入组时，两组分别有33.3%和34.9%的患者有脑转移，两组中位PFS分别为19.3个月和9.8个月，HR=0.46，P＜0.001，中位DoR分别为20.7个月和11.1个月，12个月DoR率分别为68.4%和40.6%，24个月DoR率分别为38.5%和10.3%，疾病控制率（DCR）分别为93.8%和97.6%。 两组中位PFS 新药组较常见的3级以上不良反应包括白细胞计数下降2.5%，血肌酸激酶升高1.9%、中性粒细胞下降1.9%；吉非替尼组较常见的3级及以上不良反应包括谷丙转氨酶升高7.2%，谷草转氨酶升高4.8%和皮疹2.4%。 这项研究发现，SH-1028相较于一代靶向药物吉非替尼一线治疗治疗携带EGFR驱动基因突变的晚期NSCLC患者具有更好的疗效及安全性。 03 射频消融联合免疫治疗提高晚期且有寡残留NSCLC患者的疗效：一项II期临床研究 20%的晚期NSCLC患者经过免疫检查点抑制剂治疗后可形成寡残留状态，部分患者接受局部治疗后可观察到远隔效应，本研究旨在探索晚期接受免疫治疗后形成寡残留的患者，接受局部治疗的疗效和安全性。这是一项随机对照临床研究，纳入局部晚期或转移性NSCLC患者，患者一线接受免疫单药或免疫联合化疗，符合入组标准的患者按2:1的比例进行分组，一组接受免疫维持治疗，另一组在此基础上针对寡残留病灶接受局部治疗，主要研究终点为PFS。最终，免疫治疗组和联合治疗组分别入组42例和20例患者，腺癌占比分别为59.5%和65.0%，PD-L1≥50%的患者占比分别为23.8%和15%。联合治疗组和免疫治疗组中位PFS分别为26.7个月和11.7个月，2年PFS率分别为53%和10%，24个月OS率分别为94%和60%。 两组PFS及OS 亚组分析显示，不同临床病理特点的患者都可以从这一治疗中有获益，加上局部治疗后有1例患者出现3级气胸。 04 帕博利珠单抗联合Itacitinib治疗PD-L1表达的NSCLC患者的疗效及安全性：一项长期随访数据 基础研究显示，JAK抑制剂可以发挥免疫刺激以及免疫抑制的双向调节作用，临床前数据显示，在恶性黑色素瘤中，免疫检查点抑制剂联合延迟给药的JAK抑制剂相较于同步给药具有更好的疗效。本研究旨在探索帕博利珠单抗联合延迟给药的JAK抑制剂能否提高患者疗效。 这项研究纳入初治、转移性NSCLC患者，患者PD-L1≥50%。符合入组标准的患者首先给予两周期帕博利珠单抗治疗，在后续两周期帕博利珠单抗治疗的同时给予JAK抑制剂治疗，随后给予帕博利珠单抗维持治疗，直至疾病进展，主要研究终点为12周的ORR。 最终，研究共入组23例患者，12个月的ORR为62%，中位PFS为15.6个月，PD-L1表达在50%~89%和90%~100%的患者，中位PFS分别为6.97个月和23.41个月，中位OS为53.4个月。 患者的PFS及OS 较常见的与帕博利珠单抗相关的3级及以上不良反应包括：腹泻，肺炎，重症肌无力，各有1例患者；与Itacitinib有关的不良反应多数为1～2级。 05 HR-20013预防及治疗铂类药物诱导的恶心及呕吐的疗效及安全性：一项III期临床研究 以顺铂为基础的化疗是临床常用的治疗选择，但恶心呕吐可能会影响患者的主观体验。目前，临床常用的药物包括NK1受体拮抗剂，5HT-3阻断剂以及地塞米松，尽管这是指南推荐的治疗方案，但实际执行率并不高。本研究旨在探索HR-20013在预防铂类药物诱导的恶心及呕吐方面的疗效及安全性。研究纳入组织病理学确认的初治晚期实体瘤患者，符合入组标准的患者按1:1的比例随机分为HR-20013联合地塞米松或帕洛诺司琼联合地塞米松联合福沙匹坦治疗，主要研究终点为第1周期0~120小时的完全缓解（CR）率，该研究为非劣效设计，两组CR率预设为75%，非劣效界值为10%，把握度85%，单侧α为0.025。 最终，两组分别入组373例和377例患者，基线特点均衡可比。第一周期CR率分别为77.7%和78.2%。0~168小时CR率分别为76.4%和75.1%，急性期CR率分别为91.2%和89.9%。全因不良反应发生率分别为27.1%和27.16%，因不良反应而导致治疗终止或治疗中断的比例分别为1.3%和0.5%。 两组不同阶段的CR率 这项研究证实了HR-20013联合地塞米松非劣效于当前的标准治疗。 06 戈沙妥珠单抗联合帕博利珠单抗联合卡铂一线治疗转移性NSCLC患者的疗效及安全性：EVOKE-02研究 该研究纳入初治、转移性NSCLC患者，符合入组标准的患者按照PD-L1表达水平及组织病理类型分为4个队列：队列a为PD-L1≥50%的NSCLC患者，入组30例；队列b为PD-L1＜50%的NSCLC患者，入组60例；队列c纳入非鳞NSCLC患者，无论PD-L1表达水平，入组54例患者；队列d纳入鳞癌患者，无论PD-L1表达水平，入组41例患者。队列c或队列d接受7.5mg/kg或者10mg/kg的戈沙妥珠单抗联合帕博利珠单抗及卡铂治疗。主要研究终点为独立评审委员会评估的ORR。本次报道了队列c和队列d的数据。 最终，两组PD-L1＜50%的患者占比分别为85.2%和90.2%。ORR分别为45.1%和39.0%，中位PFS分别为8.1个月和8.3个月。中位DoR分别为未达到和11.5个月。10mg/kg和7.5mg/kg戈沙妥珠单抗治疗组的患者，3级不良反应发生率分别为93.1%和86.4%，严重不良反应发生率分别为62.1%和54.5%，因不良反应而导致死亡的患者占比分别为10.3%和7.6%。 07 SAF-189s或克唑替尼一线治疗ALK融合阳性晚期NSCLC患者的疗效及安全性：一项随机、开放标签、III期临床研究 5%左右的晚期NSCLC患者携带ALK基因融合，目前，包括克唑替尼、阿来替尼、布格替尼、恩沙替尼、赛瑞替尼、伊鲁阿克、洛拉替尼等药物均已经被批准在这部分患者的一线应用。SAF-189s是一款新型下一代TKI类药物，本研究旨在探索该药与克唑替尼相比的疗效及安全性。 研究纳入局部晚期或转移性NSCLC患者，按1:1的比例随机分为克唑替尼250mg，口服，每日两次或研究药物160mg，口服，每日一次，治疗主要研究终点为独立评审委员会评估的PFS。最终，SAF-189s组和克唑替尼组分别入组139例和136例患者。两组基线特点均衡可比。基线时，两组分别有28.8%和27.2%的患者有脑转移，中位PFS分别为未达到和13.93个月，HR=0.23。中位至颅内进展时间分别为未达到和19.32个月，HR=0.04。两组中位OS分别为未达到和24.94个月，HR=0.6，P=0.0723，两组ORR分别为92.8%和80.9%，中位响应持续时间分别为未达到和15.93个月，颅内ORR分别为100%和50%。3级以上治疗相关不良反应发生率分别为37.7%和55.6%，严重不良反应发生率分别为15.9%和11.9%，因不良反应而导致治疗中断的患者占比分别为26.8%和35.6%，剂量降低的患者占比分别为23.9%和37.8%，并分别有3.6%和2.2%的患者因不良反应而导致永久性终止治疗。 两组的中位PFS 这项研究显示，针对ALK融合阳性的晚期NSCLC患者，一线给予SAF-189s相较于克唑替尼具有更好的疗效。 08 Rilvegostomig——一款针对PD-1和TIGIT的双特异性抗体，在初治且PD-L1表达1-49%或≥50%的晚期NSCLC患者中疗效及安全性 Rilvegostomig是一款针对PD-1和TIGIT的双抗，在体外研究中观察到了抗肿瘤活性，本研究旨在探索该药在初治、PD-L1≥1%的晚期NSCLC患者的疗效及安全性。研究纳入的患者允许接受最多一线化疗药物治疗，但不允许接受靶向治疗，符合入组标准的患者按1:1的比例，随机分为750mg，每三周一次或1500mg，每三周一次。两组均入组31例患者，主要研究终点为ORR。最终，两组分别有9.7%和6.5%的患者既往接受过化疗，脑转移患者占比分别为29.0%和22.6%。接受750mg，每三周一次治疗的患者，PD-L1表达为1~49%和≥50%的患者的ORR分别为29.0%和61.8%，中位PFS分别为6.0个月和10.2个月；接受1500mg，每三周治疗一次且PD-L1≥50%的患者，ORR为36.7%。没有4级及以上治疗相关不良反应出现，3级以上免疫相关不良反应发生率为2.1%。 09 Prolgolimab联合化疗一线治疗晚期非鳞、NSCLC患者的疗效及安全性 Prolgolimab是一款针对PD-1的免疫检查点抑制剂，本研究旨在探索该药联合化疗在驱动基因突变阴性晚期NSCLC患者中的疗效及安全性。研究纳入非鳞NSCLC患者且至少有一个远处转移病灶，驱动基因突变阴性，符合入组标准的患者按1:1的比例随机接受培美曲塞联合铂类，或在此基础上联合Prolgolimab治疗(3mg/kg)，主要研究终点为OS。 最终，两组分别入组143例和149例患者，基线分别有10.5%和15.4%的患者有脑转移。PD-L1≥1%的患者占比分别为60.1%和59.7%，两组中位OS分别为未达到和14.8个月，HR=0.48，P=0.001；PD-L1≥1%的患者，两组中位OS分别为未达到和15.7个月，HR=0.49；PD-L1表达1~49%的患者，两组中位OS分别为未达到和24.1个月，HR=0.58；PD-L1＜1%的患者，两组中位OS分别为未达到和14.6个月，HR=0.53；PD-L1≥50%的患者，两组中位OS分别为未达到和9.6个月，HR=0.31。两组中位PFS分别为7.7个月和5.5个月，HR=0.65，P=0.004；PD-L1≥50%的患者，两组中位PFS分别为8.9个月和5.5个月，HR=0.35，PD-L1＜1%的患者，两组中位PFS分别为5.6个月和4.4个月HR=0.73；PD-L1在1~49%的患者，两组中位PFS分别为10.0个月和5.8个月，HR=0.65。 两组中位OS 两组免疫相关3级及以上不良反应发生率分别为8.4%和2.7%。 10 西米普利单抗单药一线治疗PD-1≥50%的晚期NSCLC患者的疗效及安全性：EMPOWER-Lung-01研究5年随访数据 EMPOWER-Lung-01研究探索了西米普利单抗在驱动基因突变阴性且PD-L1≥50%的晚期NSCLC患者中的疗效及安全性。该研究中，符合入组标准的患者按1:1的比例随机分为4~6周期含铂双药化疗或西米普利单抗(350mg，静滴，每三周一次)。主要研究终点为OS。免疫治疗组疾病进展后，若研究者认为有获益，可继续接受免疫治疗，即在此基础上联合4周期化疗。最终，免疫治疗组和化疗组分别入组284例和281例患者，中位OS分别为26.1个月和13.3个月，HR=0.559，P＜0.001。 患者的OS数据 中位PFS分别为8.1个月和5.3个月，HR=0.50，P＜0.001，ORR分别为46.5%和20.6%。两组2年、3年、4年OS率分别为52.6% vs 32.1%；40.8% vs 21.5%；29.0% vs 15.0%；1年、2年、3年的PFS率分别为41.6% vs 7.2%、26.6% vs 4.7%、20.8% vs 3.1%，不同临床病理特点的亚组都可以从这一治疗中获益。中位响应持续时间分别为24.1个月和5.9个月。PD-L1表达50~60%、60~90%和≥90%的患者，化疗组的中位OS分别为14.0个月、11.2个月和13.7个月，而在免疫单药组分别为19.5个月、26.2个月和38.8个月。3级以上全因不良反应发生率分别为45.8%和51.6%，治疗相关3级以上不良反应发生率分别为18.3%和39.9%。75例患者疾病进展后接受免疫联合化疗，这部分患者自化疗开始，中位PFS和OS分别为6.5个月和15.1个月；从随机开始，中位OS为27.4个月。 （来源：《肿瘤瞭望》编辑部） 声 明 凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

LOS ANGELES--( BUSINESS WIRE )--Researchers from City of Hope ® , one of the largest and most advanced cancer research and treatment organizations in the United States, whose Los Angeles comprehensive cancer center is ranked among the nation’s top 5 cancer centers by U.S. News & World Report, presented new study results on treatment options, side effect prevention and risk prediction for blood cancer patients at this year’s ASH conference in San Diego, California, held Dec. 7 to 10. Scientists and physicians discussed outcomes for clinical trials and studies that investigated immunotherapies, like CAR T cell therapy and monoclonal antibodies, in understudied and rare blood cancer types, graft-versus-host disease, prevention strategies for donor stem cell transplant patients, a new risk assessment model for older transplant recipients and more. “The work presented by City of Hope experts at this year’s conference showcases our commitment to comprehensive, patient-centered cancer care and research that includes rare and difficult blood cancer subtypes and other patient populations that are often overlooked in clinical trials,” said Eileen Smith , M.D., City of Hope’s Francis & Kathleen McNamara Distinguished Chair in Hematology & Hematopoietic Cell Transplantation. “Studies in supportive care and better risk prediction models add depth to our groundbreaking translational work in new treatment options.” Highlighting City of Hope’s leadership in treatment and research of blood cancers and related diseases, its experts will present or contribute to more than 104 sessions, including 35 oral sessions, 56 poster sessions, 13 scientific symposia, scientific workshops and educational programs. Highlights of their novel work include: Updating results for revumenib study in acute leukemias Roughly 10% of patients with acute leukemias have a certain mutation known as rearrangement in the lysine methyltransferase 2A (KMT2Ar) gene. This change in the gene is associated with a poor prognosis. Ibrahim Aldoss , M.D., City of Hope associate professor in the Division of Leukemia, reported on findings from a phase 2 study aimed at targeting a protein interaction with a therapy called revumenib for the treatment of patients with relapsed and therapy-resistant KMT2Ar acute leukemia. “In this updated pivotal phase 2 analysis, revumenib continues to consistently provide clinically meaningful responses in heavily pretreated patients with relapsed or refractory KMT2Ar acute leukemias, including high rates of complete remission and the ability to proceed to blood stem cell transplants,” said Dr. Aldoss. Previously reported interim data from the clinical trial, one of the most significant abstracts presented at the ASH conference in 2023, had shown that revumenib — a potent oral therapy that inhibits a scaffolding protein called menin, which plays a key role in the development of leukemia — had a tolerable safety profile and a high rate of complete remission. Dr. Aldoss’s 2024 ASH presentation included results from a longer follow-up timeline and a larger data set. The trial enrolled 116 heavily pretreated patients, representing the largest evaluation of menin inhibition in people with relapsed or resistant KMT2Ar acute leukemia, including the largest pediatric menin inhibitor cohort to date. The safety arm of the trial included all participants and showed that revumenib is manageable. For the efficacy cohort, including 97 patients, 62 (64%) responded with 22 (23%) attaining complete or complete remission with partial hematologic recovery (CR+CRh). At the time of the interim analysis, 13 patients had achieved CR+CRh, and with seven additional months of follow-up, the updated median duration of CR+CRh in these responders was 13 months. “Our study led to the recent FDA approval for patients with relapsed or refractory KMT2Ar acute leukemia,” said Dr.. Aldoss. “We are thrilled that our work means these high-risk patients now have access to an effective therapeutic option.” Early application of CAR T cell therapy as a curative treatment in older adults with B-ALL Dr. Aldoss also reported on preliminary results of a trial investigating the use of CD19 CAR T cell therapy in older patients with B cell acute lymphoblastic leukemia (B-ALL), a fast-growing and aggressive cancer. People 55 years or older who develop B-ALL often have poor outcomes due to both the disease’s propensity to come back or be therapy-resistant and limited tolerability of curative modalities, like stem cell transplants. To see if a City of Hope-developed CD19 CAR T cell therapy could offer a curative option for older B-ALL patients who had achieved a complete response to a frontline therapy but remained at-risk for relapse due to the biology of the disease, Dr. Aldoss and a study team have treated 13 patients with CD19 CAR T cells in a pilot, nonrandomized trial . They hypothesize that administering of single infusion of CAR T during remission could result in low rates of toxicity and offer potential cure without the need for additional cycles of therapy. So far, their hypothesis has held true, according to Dr. Aldoss. The therapy was shown to be tolerable and safe, and the patients have maintained their walking speed and cognitive function post-infusion, and returned back to their regular lifestyle early. CD19CAR T cells expanded adequately and persisted for up to nine months post-infusion. These preliminary results indicate a durable remission for patients after receiving an infusion. “Once our favorable results are validated in a larger confirmatory study this may change the treatment paradigm of older adults with B-ALL who otherwise do poorly with current therapeutic strategies,” said Dr. Aldoss. Evaluating CAR T cell therapy for a high-risk non-Hodgkin lymphoma Patients with transformed indolent non-Hodgkin lymphoma (tiNHL) are a high-risk patient population historically associated with poor outcomes when using conventional therapies. Now, a multicenter retrospective study led by Swetha Kambhampati Thiruvengadam , M.D, assistant professor in the Division of Lymphoma, has evaluated the real-world use of a chimeric antigen receptor (CAR) T cell therapy for this group of patients. CD19 chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment landscape of B cell lymphoma. By genetically altering patients’ T cells in the lab, scientists can program the immune cells to seek and destroy cancer cells with the CD19 antigen, which is found on B cell lymphomas, including tiNHL. The treatment is approved for people with tiNHL, but they were underrepresented in pivotal clinical trials that established CD19 CAR T cell therapy as an effective treatment for B cell cancers. “This is the largest study to our knowledge evaluating outcomes of CD19 CAR T for transformed indolent non-Hodgkin lymphoma patients compared to de novo aggressive large B cell lymphoma in the real-world setting,” said Dr. Thiruvengadam. The multicenter, retrospective study included 1,182 patients who had received CD19 CAR T cell therapies for two types of cancer: 338 tiNHL patients and 884 patients in the de novo aggressive large B cell lymphoma (aLBCL) comparison group. The results demonstrated that patients with tiNHL have higher complete response rates and may have lower risk of death or relapse/progression than those with de novo aLBCL. Patients in the tiNHL cohort also had a more favorable toxicity profile compared to de novo aLBCL. “Our study suggests CD19 CAR T is a highly effective and safe treatment option for patients with tiNHL and may overcome the historically poor prognosis in this population,” said Dr. Thiruvengadam. “It also suggests that these patients would be good candidates for clinical trials that move CAR T cell therapy to earlier lines of therapy, both because of poor expected outcomes with chemoimmunotherapy and because of excellent outcomes with CAR T.” This study was nominated for a “Best of ASH” award, which highlights the most leading-edge science presented in oral abstracts at the conference. Finding an effective therapy for rare types of lymphoma Cytotoxic T cell lymphomas (CTL) are a group of lymphomas that are very rare and have no standard treatment of care. Due to their rarity, very few patients with cytotoxic T cell lymphomas are included in clinical trials, meaning very little data exists regarding the efficacy of known T cell lymphoma therapies for this population. But a recently launched clinical trial led by Jasmine Zain , M.D., director of the T Cell Lymphoma Program and professor of hematology and hematopoietic stem cell transplantation, puts these CTL patients — for which there are five subtypes — front and center. And results from phase 1 of the phase 1/2 study testing a novel anti-CD94 monoclonal antibody are promising. “This is a first time that there is a therapy that could be effective for these rare lymphomas and may change the treatment landscape of these diseases,” said Dr. Zain. “As investigators, we now have the space to focus on these diseases that are usually fatal for patients and for which there are currently no treatments.” CD94 is a molecule that arises from cytotoxic T cells and is expressed on rare T cell lymphomas. The clinical trial tested the safety and efficacy of a next-generation therapeutic antibody called DR-01 that targets CD94. When the antibody binds to CD94 on the cancer cells, it engages natural killer cells to destroy the lymphoma. In the safety cohort of 39 CTL patients, there were no dose-limiting toxicities, and the only significant treatment-related adverse event observed was an infusion-related reaction that was managed with supportive measures. In the efficacy group of 21 patients, the overall response rate was 33%, with three complete responses in which two of the patients went on to receive a potentially curative stem cell transplant. “These results are very promising for patients,” said Dr. Zain. “This trial is for relapsed and refractory patients, but if it is successful, then we may be able to study it either alone or in combinations in the upfront setting and move the needle towards curing these patients.” Improving outcomes for cutaneous T cell lymphomas Cutaneous T cell lymphomas (CTCL) are rare, aggressive, incurable types of cancer that cause itchy, disfiguring skin conditions impacting patients’ quality of life. Patients with therapy-resistant or advanced CTCL have poor prognoses and few treatment options. Which is why Christiane Querfeld , M.D., Ph.D., director of the Cutaneous Lymphoma Program at City of Hope’s Toni Stevenson Lymphoma Center, is searching for new ways to treat the disease. Dr. Querfeld recently led a phase 1/2 trial investigating whether adding an immune booster called lenalidomide — typically used to treat multiple myeloma — to durvalumab, an immune checkpoint inhibitor to treat relapsed and/or resistant CTCL, would improve outcomes for CTCL patients. Findings from phase 2 of the study suggest that, when combined, the two therapies harness the body’s immune system to attack cancerous cells more potently than durvalumab alone. “This combined treatment demonstrated superiority to single-agent durvalumab and showed unparalleled responses relative to FDA-approved therapies, producing the most encouraging outcomes we have seen in our long experience of treating CTCL,” said Dr. Querfeld, who is also a professor in dermatology and dermatopathology at City of Hope. “It’s particularly exciting to note that these positive results were also seen in a subset of Black patients, who have a significantly increased risk of developing CTCL with worse outcomes.” A total of 25 patients who had failed at least two prior treatments were enrolled in the trial and randomized: 12 received durvalumab and 13 received a combination of durvalumab and lenalidomide. The overall response rate was 42% in patients who just received durvalumab and 75% in those who received the combination treatment. Similarly, progression-free survival at the one-year mark was 36% for the single agent cohort and 73% in the combination cohort. Responses were durable and ongoing, and the treatment was well tolerated. “This proposed immunotherapeutic strategy could provide CTCL patients with a more effective treatment for a disease that is currently incurable and in which standard approved treatments only achieve short durations of responses,” said Dr. Querfeld. “Furthermore, the knowledge gained from this study may be used to develop novel treatments not only for those with CTCL but for many other cancers.” Developing a new transplant risk-assessment model for older adults For many patients with high-risk blood cancers, hematopoietic cell transplantation (HCT), also known as bone marrow/blood stem cell transplants, are the only treatment options for long-term disease control. The older the patient, though, the higher the risk for transplant-related death. A team of researchers have now developed a model to better predict allogenic HCT outcomes in patients 60 years or older . “CHARM is a new score based on patient health information that predicts toxicities and degree of recovery after transplantation in older patients,” said Andrew Artz , M.D., M.S., a professor in the Division of Leukemia and senior author of a study outlining the model’s capabilities that was presented at ASH. “By using CHARM to assess risk, older patients who are likely to have fewer complications and better function after transplant will be more likely to be offered a potentially curative transplant.” CHARM assigns a total score for seven health variables: increasing age, lower albumin, higher C-reactive protein, higher percent of weight loss over the preceding year, lower patient-reported performance status scores, lower cognitive score per Montreal Cognitive Assessment and higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores. HCT-CI summarizes comorbid conditions aside from the primary disease. Originally developed to predict risks of nonrelapse mortality, the researchers wanted to assess CHARM’s ability to predict functional trajectories and morbidity after allogenic HCT in older patients. They enrolled 1,226 HCT candidates (ages 60+) from 49 centers in the United States to take the assessment and followed up on 1,105 patients who received the transplants. Among the HCT recipients, high CHARM scores predicted worse frailty, disability, cognitive decline and serious organ toxicities, all of which are critically important to older recipients of HCT. CHARM succeeds at informing patients and clinicians of transplant morbidity risks, which are separate from risks of developing acute graft-versus-host disease, the most common complication in donor HCT recipients. According to Dr. Artz and the other researchers, the study results support adopting CHARM in practice to counsel patients, expedite HCT referrals for lower risk patients and design trials to address the needs of high-CHARM-score patients. The Aging and Blood Cancers Program facilitated the high enrollment at City of Hope as one of many initiatives to advance transplant and cellular therapy outcomes in older adults. Assessing potential for engineered T cell therapies to reduce relapse in transplant patients In preparation for a hematopoietic cell transplantation (HCT), or bone marrow transplant for blood cancers, a patient’s own bone marrow cells must be destroyed. But for many older or less healthy individuals, a treatment regimen called reduced intensity conditioning (RIC) that uses lower doses of chemotherapy or radiation to prepare a patient for a bone marrow transplant is often more appropriate. However, disease relapse affects nearly 40% of this patient population — due to residual disease that RIC doesn’t eliminate — and is the leading cause of death. To reduce relapse rates, a group of researchers led by Monzr M. Al Malki , M.D., director of the unrelated donor bone marrow transplant and haploidentical transplant programs at City of Hope, is currently testing donor-derived T cell receptor engineered T cells designed to eliminate residual disease cells after transplantation in clinical trial called ALLOHA . “Early trial results show that the treatment is safe and tolerable,” said Dr. Al Malki. “Only 8% of all participants who received the engineered T cells relapsed compared to 35% relapsing on the control arm, showing the potential of the therapy to extend lives in high-risk populations.” ALLOHA is investigating the use of TSC-100 and TSC-1001, donor-derived T cell receptor engineered T cells that target HA-1 and HA-2 antigens, respectively, which are only expressed on bone marrow stem cells of HLA-A*02:01-positive patients. By choosing donors who are negative for the same target, this therapy can eliminate residual patient stem cells post-transplant while sparing donor-derived cells, thereby preventing relapse. Developed by TScan Therapeutics, Inc., a clinical-stage biotechnology company, TSC-100 and TSC-1001 were administered to 22 patients with either acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome which are the most common indication for transplantation. A control arm of 13 patients received the standard of care RIC HCT with no follow-up treatment. No dose-limiting toxicities were reported among the group receiving treatment and side effects encountered were similar in the treatment arm and control arm indicating the safety profile. The multicenter trial is ongoing, and enrollment continues. Targeting disease-initiating cells in acute myeloid leukemia In acute myeloid leukemia (AML) cells, a protein called cytoplasmic proliferating cell nuclear antigen (PCNA) is highly expressed, especially in leukemia stem cells, where it supports their growth. HyunJun Kang, Ph.D., a staff scientist in the City of Hope’s Department of Hematologic Malignancies Translational Science, and his colleagues conducted the study in their lab using the novel PCNA inhibitor AOH1996 — developed by researchers in the lab of Linda Malkas, Ph.D., the M.T. & B.A. Ahmadinia Professor in Molecular Oncology — to treat AML by reducing the energy production of leukemia stem cells, effectively slowing tumor growth and diminishing their numbers. “AOH1996, the PNCA inhibitor, represents a highly selective and innovative therapeutic approach for acute myeloid leukemia,” said Dr. Kang. “Effectively reducing leukemia stem cells can eliminate the disease and prevent reoccurrence. And, importantly, AOH1996 spares normal hematopoietic stem cells, emphasizing its safety and specificity.” The research team tested AOH1996 in animal models of AML, showing that the therapy effectively inhibits cancer cell growth and induces DNA damage in multiple cancer cells with minimal toxicity. Additionally, when combined with an existing, FDA-approved cancer medication called venetoclax, AOH1996 showed enhanced efficacy and improved survival in the animal models. While AOH1996 is in clinical trials for solid tumors, the team plans to develop a clinical trial to assess the combination of AOH1996 with venetoclax in patients with AML. “By selectively targeting leukemia stem cells while sparing normal blood stem cells, AOH1996 offers a promising therapeutic option with fewer off-target effects,” said Le Xuan (Truong) Nguyen, Ph.D., an assistant professor in City of Hope’s Department of Hematology & Hematopoietic Cell Transplantation and the study’s senior author. “The demonstrated efficacy in preclinical models suggest that a combination of AOH1996 and venetoclax could provide a powerful and well-tolerated strategy for patients with relapsed or refractory AML, ultimately improving survival rates and reducing the likelihood of relapse.” Preventing graft-versus-host disease in stem cell transplant patients Graft-versus-host-disease, or GVHD, is the most common complication for patients receiving stem cell transplants from a donor for blood cancers. According to results from a clinical trial led by Haris Ali , M.D. associate professor in the Division of Leukemia, adding a potent anti-inflammatory therapy to a standard GVHD prophylaxis may improve GVHD-free, relapse-free survival for transplant recipients. GVHD develops when donated cells attack a patient’s own tissues and can cause a variety of symptoms ranging from mild to life-threatening. In a phase 2a clinical trial, Dr. Ali and his colleagues tested the efficacy of a combination of the standard therapy to prevent GVHD, immunosuppression therapies tacrolimus and sirolimus, with itacitinib, a Janus kinases-1 inhibitor, which help reduce the body’s inflammatory response. (Previously reported early results of the trial had shown the combination to be safe and tolerable.) A total of 59 patients with acute leukemias, myelodysplastic syndrome or myelofibrosis who underwent hematopoietic stem cell transplants from matched donors received the combination GVHD prophylaxis. At one- and two-years post-transplant, GVHD-free, relapse-free survival was 54% and 40%, respectively. The historical rate of GVHD-free, relapse-free survival at one year is 30%. “This novel GVHD prophylaxis markedly improves GVHD-free, relapse-free survival by significantly reducing acute GVHD, a key cause of transplant related mortality and morbidity,” said Dr. Ali. “We hope to refine tapering strategies of the combination to further increase the length of GVHD-free, relapse-free survival timelines.” About City of Hope City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the U.S., and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines , as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked top 5 in the nation for cancer care by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHope TM . For more information about City of Hope, follow us on Facebook , X , YouTube , Instagram and LinkedIn .