Observation on the Clinical Effect of Applying Venetoclax Combined with Demethylation Drug Therapy in Patients with Acute Myeloid Leukemia

Objective: To investigate the therapeutic effect of applying venetoclax combined with demethylating drugs in treating patients with acute myeloid leukemia (AML). Methods: Eighty cases of AML patients treated with venetoclax combined with demethylating drugs in our hospital were selected from March 2021 to March 2024, including 40 cases of primary treatment patients and 40 cases of relapsed and refractory patients. The efficacy and safety of the combined drug therapy was analyzed. Results: The primary treatment group was presented with a complete remission (CR) rate of 40.5%, partial remission (PR) rate of 47.50%, no response (NR) rate of 12.50%, and a remission rate of 87.50%. The relapsed- refractory group was presented with a CR rate of 37.50%, PR rate of 42.50%, NR rate of 17.50%, and a remission rate of 87.50%. There was no statistical significance between the groups (P > 0.05). The hematological adverse reactions of the combined treatment for AML were leukopenia and the non-hematological adverse reactions were mainly infections, with an incidence rate of 87.50%. Conclusion: The efficacy of venetoclax combined with demethylating drugs in AML was remarkable and the treatment regimen can be adjusted according to the treatment-resistant response.

Empathetic nursing with mindful cognitive therapy for fatigue,depression,and negative emotions in leukemia patients undergoing long-term chemotherapy

BACKGROUND Leukemia is a broad term for blood cell cancer.Leukemia is divided into acute or chronic,depending on cell differentiation.Leukemia patients are prone to adverse reactions during chemotherapy,such as anxiety,depression,and even suicide,affecting prognosis.As a nursing model developed by three well-known cognitive psychologists,empathetic nursing with mindfulness cognitive therapy(ENMCT)can effectively reduce anxiety and depression and improve the quality of life in patients with chronic disease.AIM To explore the effect of ENMCT on cancer-induced fatigue,hope level,and negative emotions in patients with long-term leukemia chemotherapy.METHODS A total of 103 patients with long-term leukemia chemotherapy diagnosed and treated in our hospital from July 2017 to October 2019 were enrolled and randomly assigned to observation and control groups using the random number table approach.Fifty-one patients in the control group received routine nursing,while 52 patients in the observation group received empathic nursing with mindfulness cognitive therapy.After three months of nursing care,cancerinduced fatigue was measured with the Piper Fatigue Scale(PFS),hope level with the Herth Hope Index(HHI),and negative emotion with the Hamilton Anxiety Scale(HAMA)/Hamilton Depression Scale(HAMD).Self-management(Chinese Strategies Used by People to Promote Health)was also recorded.RESULTS The observation group’s total scores in behavior,cognition,emotion,feeling,and PFS were lower than the control group after the intervention(P<0.05).Keeping close contact with others,the attitude of taking positive actions,the attitude toward reality and future,and the total HHI score were higher in the observation group than the control group(P<0.05).The observation group’s HAMA and HAMD scores were lower than the control group(P<0.05).The observation group’s positive attitude,self-decision,and self-relief scores were greater than the control group(P<0.05).CONCLUSION Empathetic nursing with cognitive mindfulness therapy is beneficial in improving cancer-related fatigue,negative emotions,expectation level,and self-management ability in patients with longterm leukemia chemotherapy.

Therapy-Related Acute Myeloid Leukemia in A Primary Pulmonary Leiomyosarcoma Patient with Skin Metastasis

Primary pulmonary leiomyosarcoma （LMS） is a very unusual tumor.Although LMS has well-known metastatic potential,cutaneous metastasis is a remarkably uncommon.Exposure to cytotoxic agents could lead to ＂therapy-related myeloid neoplasm＂ （t-MN）.Starting from 2008,the World Health Organization （WHO） has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia （t-AML）,therapy-related myelodysplastic syndrome （t-MDS） and therapy-related myelodysplastic/myelo-proliferative neoplasm （t-MDS/MPN）.We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis.This patient achieved complete remission （CR） after three courses of IA regimen chemotherapy （idarubicin 5 mg/d,d 1-3;cytarabine 100 mg/d,d 1-5） and 1 course of HA chemotherapy regimen （homoharringtonine 3 mg/d,d 1-3;cytarabine 100 mg/d,d 1-7）.This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.

Targeting leukemia stem cells:The new goal of therapy in adult acute myeloid leukemia

The most popular view of hematopoietic cell lineage organization is that of complex reactive or adaptative systems.Leukemia contains a subpopulation of cells that display characteristics of stem cells.These cells maintain tumor growth.The properties of leukemia stem cells indicate that current conventional chemotherapy, directed against the bulk of the tumor,will not be effective.Leukemia stem cells are quiescent and do not respond to cell cycle-specific cytotoxic agents used to treat leukemia and thus contribute to treatment failure. New strategies are required that specifically target this malignant stem cell population.

Breathing adapted radiation therapy for leukemia relapse in the breast: A case report

BACKGROUND Infiltration of the breast by leukemic cells is uncommon but may manifest as an oncological emergency requiring prompt management.Extramedullary relapse of T-cell acute lymphoblastic leukemia(T-ALL)within the breast is exceedingly rare and there is paucity of data in the literature regarding this entity.No consensus exists on management of isolated extramedullary breast relapses of T-ALL.Herein,we report a case of isolated extramedullary breast relapse of T-ALL treated with breathing adapted radiation therapy(BART)using the active breathing control(ABC)system.CASE SUMMARY The patient was a 33-year-old female with diagnosis of T-ALL.She received intensive systemic chemotherapy that resulted in complete remission of her disease,and then underwent allogeneic hematopoietic stem cell transplantation.After a 15 mo period without symptoms and signs of progression,the patient presented with palpable masses in both breasts.She complained from severe pain and swelling of the breasts.Imaging workup showed bilateral breast lesions,and diagnosis of breast infiltration by leukemic cells was confirmed after immunohistopathological evaluation.The patient suffering from severe pain,discomfort,and swelling of both breasts due to leukemic infiltration was referred to the Radiation Oncology Department for symptomatic palliation.Whole breast irradiation was delivered to both breasts of the patient with BART using the ABC system.The patient had complete resolution of her symptoms after treatment with BART.CONCLUSION BART with the ABC system resulted in complete resolution of the patient’s symptoms due to leukemic infiltration of both breasts with T-ALL.This contemporary treatment technique should be preferred for radiotherapeutic management of patients with leukemic infiltration of the breasts to achieve effective symptomatic palliation.

OPTIMIZATIONS FOR 5-AMINOLEVULINIC ACID BASED PHOTODYNAMIC THERAPY IN PURGING LEUKEMIA CELL HL60

Objective To optimize experimental parameters for the photosensitization of 5-aminolevulinic acid (ALA) in promyelocytic leukemia cell HL60 and compare them with normal human peripheral blood mononuclear cell (PBMC). Methods ALA incubation time, wavelength applied to irradiate, concentration of ALA incubated, irradiation fluence may modulate the effect of 5-aminolevulinic acid based Photodynamic Therapy (ALA-PDT).The high-pressure mercury lamps of 400W served as light source, the interference filter of 410nm, 432nm, 545nm, 577nm were used to select the specific wavelength. Fluorescence microscope was used to detect the fluorescence intensity and location of protoporphyrin IX (PpIX) endogenously produced by ALA. MTT assay was used to measure the survival of cell. Flow cytometry with ANNEXIN V FITC kit (contains annexin V FITC, binding buffer and PI) was used to detect the mode of cell death. Results ① 1mmol/L ALA incubated 1×105/mL HL60 cell line for 4 hours, the maximum fluorescence of ALA induced PpIX was detected in cytomembrane. ② Irradiated with 410nm for 14.4J/cm2 can result in the minimum survivability of HL60 cell. ③ The main mode of HL60 cell death caused by ALA-PDT is necrosis. Conclusion ALA for 1mmol/L, 4 hours for dark incubation time, 410nm for irradiation wavelength, 14.4J/cm2 for irradiation fluence were the optimal parameters to selectively eliminate promyelocytic leukemia cell HL60 by ALA based PDT. The photosensitization of ALA based PDT caused the necrosis of HL60 cell, so it could be used for inactivation of certain leukemia cells.

ENHANCED ANTITUMOR EFFECTS OF SUICIDE GENETHERAPY BY SIMULTANEOUS TRANSFER OF GM CSF GENE IN LEUKEMIABEARING MICE

In the present report, antitumor effect of combined transfer of suicide gene and cytokine gene was studied. Adenovirus engineered to express E. Coli. Cytosine deaminase (AdCD) and/or adenovirus engineered to express murine granulocytemacrophage colonystimulating factor (AdGMCSF) were used for the treatment of leukemiabearing mice. The mice were inoculated s.c. with FBL3 erythroleukemia cells and 3 days later received intratumoral injection of AdCD in the presence or absence of AdGMCSF followed by intraperitoneal 5fluorocytosine (5FC) treatment. The results demonstrated that mice received combined therapy of AdCD/5FC and AdGMCSF developed tumors most slowly and survived much longer when compared with mice treated with AdCD/5FC alone, AdGMCSF alone, AdlacZ/5FC or PBS. Combined transfer of CD gene and GMCSF gene achieved higher specific CTL activity than control therapies. Pathological examination illustrated that the tumor mass showed obvious necrosis and inflammatory cell infiltration in mice after combined therapy. The results demonstrated that combined transfer of suicide gene and cytokine gene could synergistically inhibit the growth of leukemia in mice and induce antitumor immunity of the host. The combination therapy might be a potential approach for cancer gene therapy.

Chidamide,Decitabine,Cytarabine,Aclarubicin,and Granulocyte Colony-stimulating Factor Therapy for Patients with Relapsed/Refractory Acute Myeloid Leukemia:A Retrospective Study from a Single-Center

Objective Preclinical evidence and clinical trials have suggested synergistic effects of epigenetic modifiers in combination with cytotoxic agents for the treatment of leukemia.However,their efficacy in patients with relapsed/refractory acute myeloid leukemia(R/R AML)remains unclear.Methods Clinical data of R/R AML patients who received a CDCAG regimen(chidamide,decitabine,cytarabine,aclarubicin,and granulocyte colony-stimulating factor)from July 1,2018 to October 31,2021 at our center were retrospectively assessed,and the safety and efficacy of the CDCAG regimen were evaluated.Patients were followed up until November 30,2021,with a median follow-up of 21.6 months(95%CI:10.0–33.2 months).Results A total of 67 patients were enrolled.Two patients died within 3 weeks after the initiation,and therefore only 65 patients underwent the assement for clinical response and survival.It was found that 56.9%patients achieved complete remission with a median overall survival(OS)of 9.6 months.The median OS of responders was 25.9 months,while that of non-responders was 5.0 months(P<0.0001).Patients with gene mutations had a superior overall response rate(ORR)(80.4%vs.45.5%,P=0.043)compared to those without gene mutations.The presence of DNA methyltransferase 3 A(DNMT3A),ten-eleven translocation-2(TET2),and isocitrate dehydrogenase 1/2(IDH1/2)mutations did not affect the response rate(88.2%vs.68.9%,P=0.220)and reflected a better OS(not attained vs.9.0 months,P=0.05).The most common non-hematologic adverse events were pulmonary infection(73.1%),followed by febrile neutropenia(23.9%)and sepsis(19.4%).Conclusions The CDCAG regimen was effective and well-tolerated in R/R AML patients,increasing the potential for allogeneic hematopoietic stem cell transplantation.Moreover,patients with DNMT3A,TET2,and IDH1/2 mutations might benefit from this regimen.

The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

For patients with chronic myeloid leukemia（CML） failing imatinib therapy,second-generation tyrosine kinase inhibitors（TKIs） are recommended.Here,we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib,but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullar/ toxicity.Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Active targeted drug delivery system constructed from functionalized pillararenes for chemo/photodynamic synergistic therapy

Nowadays,although functionalized pillararenes have been widely designed to be used in drug delivery system,targeted group modified pillararenes have been seldom reported and used in tumor multimodal therapy.Herein,a functionalized pillararene with a polyethylene glycol chain and triphenylphosphonium cation WP5-PEG-TPP was designed and synthesized.Subsequently,an active targeted drug delivery system was constructed based on its host-guest interactions with a newly designed porphyrin derivative,Py-Por.The experimental results demonstrated that this drug delivery system has exhibited excellent targeting ability against tumor cells,but interestingly it could not enter normal cells.After loading the hypoxia-activated prodrug tirapazamine,the prepared nanodrugs displayed high lethality to tumor cells due to their chemo/photodynamic synergistic therapy capability,but negligible toxicity to normal cells.Preliminary therapeutic mechanism study elucidated the synergistic therapy process.

Non-canonical BRAF variants and rearrangements in hairy cell leukemia

Hairy cell leukemia(HCL)is an uncommon mature B-cell malignancy characterized by a typical morphology,immunophenotype,and clinical profile.The vast majority of HCL patients harbor the canonical BRAF V600E mutation which has become a rationalized target of the subsequently deregulated RAS-RAF-MEK-MAPK signaling pathway in HCL patients who have relapsed or who are refractory to front-line therapy.However,several HCL patients with a classical phenotype display non-canonical BRAF mutations or rearrangements.These include sequence variants within alternative exons and an oncogenic fusion with the IGH gene.Care must be taken in the molecular diagnostic work-up of patients with typical HCL but without the BRAF V600E to include investigation of these uncommon mechanisms.Identification,functional characterization,and reporting of further such patients is likely to provide insights into the pathogenesis of HCL and enable rational selection of targeted inhibitors in such patients if required.

HUMAN GENOME RESEARCH & LEUKEMIA THERAPY IN CHINA

Ⅰ. HGP AND HUMAN GENOME SCIENCE IN CHINA The HGP, standing for "human genome project," is one of the basic research programs of vital importance in life science, now underway in a worldwide scope. Its significance is never to be overestimated when we place any stress on it. As a matter of fact, it will provide an invaluable tool to reveal the essence of human life by

老年急性髓细胞性白血病个体化治疗研究进展

老年急性髓细胞性白血病(AML)是一种严重危及生命的血液系统恶性肿瘤,目前化学治疗和造血干细胞移植仍然是治疗AML的主要手段,但在老年患者中应用受限。近年来,异柠檬酸脱氢酶1/2(IDH1/2)、类猫巨噬细胞刺激蛋白酪氨酸激酶3(FLT3)抑制剂等新型分子靶向药物,以及嵌合抗原受体T细胞(CAR-T)细胞免疫疗法等个体化方案不断涌现。由于个体异质性和耐药性等因素,老年AML长期治疗效果仍然不佳,亟须开发更加安全有效的精准化个体化治疗策略。化学治疗联合新型靶向药物或免疫治疗有望为老年AML治疗带来新希望。本文对老年AML治疗的最新研究进展作一综述,为更具个体化和安全性的治疗策略提供可行性方案。

急性髓系白血病的中西医药物治疗研究进展

急性髓系白血病是当前发病率最高的白血病类型之一,且预后不良。目前,中西医治疗急性髓系白血病均取得了一定进展,但仍存在疗效不佳、不良反应大、并发症严重等缺陷。该文梳理中西医常用的治法及药物作用机制,分析二者治疗原理上的相似之处,通过案例探讨,总结归纳中西医结合治疗急性髓系白血病的优势,展望未来发展路径,为探索新疗法、研制新药物提供参考。

间充质干细胞在急性髓系白血病骨髓微环境中的研究进展

急性髓系白血病(acute myeloid leukemia, AML)是一种高度异质性、多基因突变驱动的血液肿瘤,具有发病率高、致死率高的特点。间充质干细胞(mesenchymal stem cells, MSCs)是具有自我更新、多向分化潜能的多能干细胞,是骨髓微环境中的重要细胞成分。研究表明,MSCs通过转移线粒体、传递细胞外囊泡、促进自身成脂分化、分泌促癌蛋白等多种机制促进AML的发生发展。该文就MSCs在AML骨髓微环境中的作用作一综述,为靶向MSCs治疗AML的新策略提供参考。

Identification and targeting leukemia stem cells: The path to the cure for acute myeloid leukemia

Accumulating evidence support the notion that acute myeloid leukemia(AML) is organized in a hierarchical system, originating from a special proportion of leukemia stem cells(LSC). Similar to their normal counterpart, hematopoietic stem cells(HSC), LSC possess selfrenewal capacity and are responsible for the continued growth and proliferation of the bulk of leukemia cells in the blood and bone marrow. It is believed that LSC are also the root cause for the treatment failure and relapse of AML because LSC are often resistant to chemotherapy. In the past decade, we have made significant advancement in identification and understanding the molecular biology of LSC, but it remains a daunting task to specifically targeting LSC, while sparing normalHSC. In this review, we will first provide a historical overview of the discovery of LSC, followed by a summary of identification and separation of LSC by either cell surface markers or functional assays. Next, the review will focus on the current, various strategies for eradicating LSC. Finally, we will highlight future directions and challenges ahead of our ultimate goal for the cure of AML by targeting LSC.

Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date

Chronic lymphocytic leukemia(CLL) is the most common leukemia in the western world. Despite significantadvances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor(BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents.

Bone marrow microenvironment: The guardian of leukemia stem cells

Bone marrow microenvironment (BMM) is the main sanctuary of leukemic stem cells (LSCs) and protects these cells against conventional therapies. However, it may open up an opportunity to target LSCs by breaking the close connection between LSCs and the BMM. The elimination of LSCs is of high importance, since they follow cancer stem cell theory as a part of this population. Based on cancer stem cell theory, a cell with stem cell-like features stands at the apex of the hierarchy and produces a heterogeneous population and governs the disease. Secretion of cytokines, chemokines, and extracellular vesicles, whether through autocrine or paracrine mechanisms by activation of downstream signaling pathways in LSCs, favors their persistence and makes the BMM less hospitable for normal stem cells. While all details about the interactions of the BMM and LSCs remain to be elucidated, some clinical trials have been designed to limit these reciprocal interactions to cure leukemia more effectively. In this review, we focus on chronic myeloid leukemia and acute myeloid leukemia LSCs and their milieu in the bone marrow, how to segregate them from the normal compartment, and finally the possible ways to eliminate these cells.

HIGH EFFICIENCY RETROVIRUS-MEDIATED GENE TRANSFERTO LEUKEMIA CELLS

Objective: To establish an efficient and safe gene transfer system mediated by retrovirus for gene marking and gene therapy of human leukemia. Method: The retroviral vector LXSN, containing the neomycin resistance (NeoR) gene, was transferred into amphotropic packaging cells GP+envAm12 by liposome transfection or by ecotropic retrovirus transduction. Amphotropic retrovirus in supernatants with higher titer was used to infect human leukemic cell lines NB4, U937, and THP-1. The efficiency of gene transfer was assayed on colonies formed by transduced K562 cells. Results: The titer of DOSPER directly transfected GP+envAm12 cells determined on NIH3T3 cells was 8.0×105 CFU/ml, while that of producer infected with retrovirus was 1.6×107 CFU/ml. Integration of NeoR gene into all leukemia cells was confirmed by polymerase chain reaction (PCR). Absence of replication-competent virus was proved by both nested PCR for env gene and marker gene rescue assay. Gene transfer with the efficiency as high as 93.3 to 100% in K562 cells was verified by seminested PCR for integrated NeoR gene on colonies after 7 days’ culture. Conclusion: The efficiency and safety of retrovirus mediated gene transfer system might provide an optimal system in gene therapy for leukemia or genetic diseases.

GENE THERAPY USING RETROVIRAL VECTOR OF bcr-abl SPECIFIC MULTI-UNIT RIBOZYMES COULD INHIBIT CML CELL GROWTH AND INDUCE APOPTOSIS

Objective: To investigate the in vitro cleavage ability and effects on apoptosis and cell growth of the bcr-abl fusion gene specific multi-unit ribozymes. Methods: Three fusion point specific ribozymes were designed and the multi-unit ribozymes?in vitro transcription vector and retroviral vector were constructed. The in vitro cleavage ability was tested. The retroviral vector was transfected into K562 cell and the effects on proliferation, apoptosis, cell cycle and cell structure were observed. Results: Multi-unit ribozymes had in vitro cleavage efficiency of 70.8%, which was more efficient than single-unit and double-unit ribozymes. Transfection of the retroviral vector of the ribozyme into K562 cells, induced inhibition of cell growth and apoptosis. The incorporation rate of DNA in ribozymes transfected K562 cells was greatly decreased along with time passed, with an inhibition rate of more than 50% after 96 h of transfection. Under FCM, 18.4% of the cells underwent apoptosis 72 h after transfection and more cells were blocked in G phase, with the ratio in S phase greatly decreased (41.9%). Under electron microscope, compaction of nuclear chromatin and apoptosis bodies were observed. Conclusion: Multi-unit ribozymes specific to bcr-abl fusion gene can be used to treat CML and to purge bone marrow for self-grafting.