ImmunoPET imaging of hematological malignancies: From preclinical promise to clinical reality

Immuno-positron emission tomography (immunoPET) imaging is a paradigm-shifting imaging technique for whole-body and all-lesion tumor detection, based on the combined specificity of tumor-targeting vectors [e.g., monoclonal antibodies (mAbs), nanobodies, and bispecific antibodies] and the sensitivity of PET imaging. By noninvasively, comprehensively, and serially revealing heterogeneous tumor antigen expression, immunoPET imaging is gradually improving the theranostic prospects for hematological malignancies. In this review, we summarize the available literature regarding immunoPET in imaging hematological malignancies. We also highlight the pros and cons of current conjugation strategies, and modular chemistry that can be leveraged to develop novel immunoPET probes for hematological malignancies. Lastly, we discuss the use of immunoPET imaging in guiding antibody drug development.     

Clinical Benefit-Risk Profile of Lenalidomide in Patients With Lower-risk Myelodysplastic Syndromes Without del(5q): Results of a Phase III Trial

BackgroundIn the phase III MDS-005 study of patients with lower-risk, non-del(5q) myelodysplastic syndromes, lenalidomide was associated with a higher rate of ≥ 8 weeks red blood cell transfusion independence (RBC-TI) compared with placebo, but also with a higher risk of hematologic adverse events (AEs).Patients and MethodsThis analysis evaluated the ratio of clinical benefit-risk in patients treated with lenalidomide or placebo, and assessed the effect of lenalidomide dose reductions on response. Clinical benefit was a composite endpoint defined as RBC-TI, transfusion reduction ≥ 4 units packed red blood cells, hemoglobin increase ≥ 1.5 g/dL, or cytogenetic response.ResultsThe rate of clinical benefit was higher with lenalidomide than with placebo (31.9% vs. 3.8%). The ratio of response (RBC-TI and clinical benefit) to risk (hematologic AEs) favored lenalidomide over placebo. Patients who underwent ≥ 1 lenalidomide dose reduction had a longer duration of treatment, received a higher cumulative dose, and were more likely to experience clinical benefit versus patients without dose reductions.ConclusionDespite the occurrence of hematologic AEs, the overall benefit-risk profile supported lenalidomide treatment. Appropriate management of hematologic AEs by dose reductions may help patients with myelodysplastic syndromes to remain on treatment and achieve clinical benefit.     

Analyzing Survival Rate of Leukemia Patients Applying Long Term Exponential Model

Background: Making progressin treatment of all branches of cancers has increasedthe percent of patients that never experience the event of interest. These cases are called immune or cure and models for handling the data included cure fraction rate, are referred to as cure model or long-term survival models. Methods:The data for this historical cohort study, were collected from leukemia patients diagnosed between 2007 to 2014 and followed up until 2016 in Taleghani hospital and received BMT (Bone Marrow Transplant). Some data had to be excluded because of incomplete information. Using recorded files mostly and phone calls rarely, were made to confirm whether the patients were still alive or not. Death due to leukemia was regarded as interested event. Analysis were performed by R version 3.4.1and Stata version 14. Results: Number of recurrents after receiving BMT, pre-transplant Hb and age at diagnosis were found as significant prognostics of survival time. HD patients had the highest 5-years overall survival in category of diagnosis type with 81.3%. Cure fraction was estimated to be 64.1%. Conclusion: According to high percentage of censoring, using long-term model had better fit.     

应用维奈克拉桥接清髓性预处理方案的挽救性异基因造血干细胞移植治疗原发诱导治疗失败的急性髓系白血病一例

目的:探讨维奈克拉在难治急性髓系白血病（AML）患者移植中的应用。方法:回顾性分析2020年3月苏州大学附属第一医院收治的1例诱导治疗失败后使用维奈克拉和去甲基化药物桥接清髓性预处理方案后行异基因造血干细胞移植（allo-HSCT）的难治AML患者诊治过程。结果:患者，女性，28岁，诊断为难治AML。初始给予IA（去甲氧柔红霉素+阿糖胞苷）（3+7）方案诱导化疗未缓解，CLAG（克拉屈滨+阿糖胞苷+粒细胞集落刺激因子）方案再诱导化疗未缓解，使用维奈克拉与去甲基化药物桥接清髓性预处理方案化疗后，进行挽救性单倍体allo-HSCT。复查骨髓缓解，植入成功，随访100 d，持续缓解，无移植并发症发生。结论:对于原发诱导治疗失败的难治AML，使用维奈克拉与去甲基化药物桥接清髓性预处理可作为挽救性allo-HSCT的优选方案。     

Selective Inhibitors of Nuclear Export in the Treatment of Hematologic Malignancies

The correct localization of molecules between nucleus and cytoplasm is fundamental for cellular homeostasis and is controlled by a bidirectional transport system. Exportin 1 (XPO1) regulates the passage of numerous cancer-related proteins. In this review, we summarize the development of a novel class of antitumor agents, known as selective inhibitors of nuclear export (SINEs). We report results of preclinical studies and clinical trials, and discuss the mechanism of action of SINEs and their effects in multiple myeloma, non-Hodgkin lymphomas, lymphoblastic leukemia, and acute and chronic myeloid leukemia. In the future, the numerous experimental studies currently underway will allow us to define the role of SINEs and will possibly permit these substances to be introduced into daily clinical practice.     

依维莫司联合全反式维甲酸逆转急性早幼粒细胞白血病细胞耐药的研究

目的探讨依维莫司联合全反式维甲酸(简称维甲酸)逆转急性早幼粒细胞白血病(APL)细胞株NB4-R1耐药的作用。方法应用CD11b染色流式细胞术及硝基四唑氮蓝(NBT)还原实验检测两药联合应用对细胞分化的影响, 流式细胞术检测细胞周期情况, Annexin V/PI双染色检测细胞凋亡情况, 蛋白质印迹法检测自噬相关蛋白微管结合蛋白轻链3(LC3)、Beclin 1及早幼粒白血病-维甲酸受体融合蛋白(PML-RARα)、磷酸化核糖体S6激酶(P-P70S6K)、磷酸化4E结合蛋白1(P-4E-BP1) 等表达水平。结果与维甲酸组比较, 联用组能诱导耐药细胞株NB4-R1细胞的分化, 并将细胞增殖阻止在G ₁期而对细胞凋亡无明显影响。100 nmol/L依维莫司组、1μmol/L维甲酸组、联用组、对照组NB4-R1细胞培养48 h后分化百分率分别为(2.29±0.57)%、(17.06±2.65)%、(54.47±4.91)%、(2.54±0.53)%; 处于G ₁期的细胞百分率分别为(35.20±11.97)%、(33.54±6.25)%、(53.70±8.73)%、(27.40±6.01)%; 四组细胞凋亡细胞百分率分别为(2.30±0.14)%、(2.25±0.21)%、(2.40±0.28)%、(1.95±0.07)%。与维甲酸组比较, 联用组mTOR信号通路下游的P70S6K、4E-BP1分子磷酸化水平下降, LC3-II和Beclin 1的表达上调, 且能部分降解融合蛋白PML-RARα。 结论依维莫司联合维甲酸能诱导NB4-R1细胞分化, 且能阻滞细胞周期而不致细胞凋亡, 其机制可能与依维莫司联合维甲酸抑制mTOR信号通路激活自噬作用从而降解PML-RARα蛋白有关。     

Altitude exposure as a training & iron overload management strategy post leukemia

ObjectivesTo examine iron stores, hemoglobin mass, and performance before, during and after intermittent altitude exposure in a professional male rugby player experiencing iron overload following blood transfusions for treatment for acute myeloid leukemia.DesignLongitudinal, repeated measures, single case-study.MethodsThe player was followed prior to (control), and during (study), an in-season block of altitude training. During the control period two venesections were performed for a total of 750 mL of blood removal. Internal and external training load, match statistics, blood volume, plasma volume, haemoglobin mass, serum ferritin and reticulocyte count were monitored throughout.ResultsDuring the control period serum ferritin declined following the two venesections (∼51%) as did haemoglobin mass (∼2%), reticulocyte count remained stable. During the study period serum ferritin further declined (∼30%), however haemoglobin mass and reticulocyte count increased (∼4% and ∼14% respectively). Internal training load for the control and study period was similar, however external training load was lower in the study period. Match statistics were not favourable for the player during the control period, however they improved during the study period.ConclusionsThis case supports the theory that individuals with elevated iron availability are well placed to achieve increases in haemoglobin mass. Furthermore, although therapeutic venesections may still be required to manage iron overload, the addition of altitude exposure may be a method to assist in reducing total body iron by means of mobilising available (excessive) iron to incorporate into haemoglobin. Altitude exposure did not hinder the players’ performance. Further research is encouraged.