Correlative Study on the Expression of p53 and DNA Ploidy in Acute Nonlymphocytic Leukemia

We used the flow cytometric immunoassay to study the correlation between the tumor-suppressor gene product p53- and the DNA ploidy in 30 de novo cases of acute nonlymphocytic leukemia (ANLL).The results showed that 15 cases were negative and the other 15 cases were positive expression for p53. As compared with p53 negative (p53) cases, the patients with positive p53 (p53+) had higher percentage of bone marrow blasts and lower peripheral leukocyte and platelet counts,which had no influence on the complete remission rate. Before treatment, DNA diploidy was seen in 18 cases including 12 p53- cases, and DNA aneuploidy in 12 cases including 9 p53+. After therapy, aneuploidy could be transformed into diploidy.Patients with P53+ or having aneuploidy in complete remission were at risk for early relapse. We believe that p53 may be involved in the process of leukemogenesis and progression of ANLL.

A Chromosome Study on 97 Cases of Acute Nonlymphocytic Leukemia M2

Chromosomal studies were performed in the same laboratory on 97 untreated cases of de novo acute nonlymphocytic leukemia M2.The overall incidence of chromosomal abnormality was 70.1% (68 out of 97 cases),which was higher in children(84. 2% )than in edults (61%).The male to female chromosomal abnormality ratio was nearly the same(male 71% and female 68. 4% .P>0.05).Hypodiploidy was the most common numerical abnormality(39%)and t (8;21) was the most common structural abnormality (48.1%) It the patients with t (8;21),64 5%(2) out of 31cases) male lost chromosome Y (-Y) and 33%(5 out of 15 cases)female lost one chromosomeX(-X).

The Morphological Studies on M2/t(8;21)Acute Nonlymphocytic Leukemia

Bone marrow studies including morphological,morphometrical and ultrastructural aspects were performed in 35 patients with M2/t(8;21)and and 23 patients with M2/NN.It was found that M2/t(8;21)patients had higher cellularity in bone marrow.Type(Ⅱ)myeloblast cells were predominant among myeoloblasts.Deformation of nuclei,nucleocytoplasmic asynchronism and dysmegakaryctytopoiesis were more evident n M2/t (8;21) than in M2/NN patients.

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.

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.

Study on the Clinical Efficacy of Megestrol Acetate Dispersible Tablets in Adjuvant Treatment of Acute Leukemia

Objective:To analyze the clinical efficacy of megestrol acetate dispersible tablets in the adjuvant treatment of acute leukemia.Methods:80 patients with acute leukemia admitted from December 2021 to December 2022 were randomly divided into two groups.The control group underwent chemotherapy,and the observation group took megestrol acetate dispersible tablets and underwent chemotherapy.The effect of the treatments were evaluated by analyzing the albumin(Alb)and prealbumin(Palb)indicators,and the adverse reactions were observed.Results:There was no significant difference in Alb and Palb indexes between the two groups before treatment(P>0.05).After treatment,Alb and Palb indexes in the observation group were greater than those in the control group(P<0.05).The incidence of adverse reactions in the control group was 20.00%,which was significantly higher than the observation group(5.00%),with P<0.05.Conclusion:The combination of megestrol acetate dispersible tablets and chemotherapy is more effective in treating patients with acute leukemia,and the Alb and Palb indexes can be optimized.Besides,there are fewer adverse reactions,which means that the treatment is relatively safe.

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.

Synchronous diagnosis and treatment of acute myeloid leukemia and chronic lymphocytic leukemia:Two case reports

BACKGROUND The concurrence of acute myeloid leukemia(AML)and chronic lymphocytic leukemia(CLL)is rare.Previous reports of such cases have focused mainly on clinical diagnosis and characteristics,so the mechanism remains unclear,and therapy options have been poorly explored.CASE SUMMARY Here,we report two cases of synchronous AML and CLL.Flow cytometry revealed two distinct abnormal cell populations(myeloblasts and lymphoid cells)according to scatter characteristics.CD5-positive B cell lymphoma with myeloid leukemia invasion was observed on lymph node biopsy.Chemotherapy regimens indicated for both AML and CLL were used in our patients,and our patients achieved complete response after chemotherapy.Next-generation sequencing of 88 genes was performed.CONCLUSION We conclude that early mutation and dysregulation at the hematopoietic stem cell stage and the accumulation of multiple rearrangements may cause the concurrence of CLL and AML.The treatment of infection and combination therapy aimed at the CLL component are significant in the management of patients with concurrent CLL and AML.

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.

Resistance to FLT3 inhibitors in acute myeloid leukemia: Molecular mechanisms and resensitizing strategies

FMS-like tyrosine kinase 3(FLT3) is classified as a type Ⅲ receptor tyrosine kinase, which exerts a key role in regulation of normal hematopoiesis. FLT3 mutation is the most common genetic mutation in acute myeloid leukemia(AML) and represents an attractive therapeutic target. Targeted therapy with FLT3 inhibitors in AML shows modest promising results in current ongoing clinical trials suggesting the complexity of FLT3 targeting in therapeutics. Importantly, resistance to FLT3 inhibitors may explain the lack of overwhelming response and could obstruct the successful treatment for AML. Here, we summarize the molecular mechanisms of primary resistance and acquired resistance to FLT3 inhibitors and discuss the strategies to circumvent the emergency of drug resistance and to develop novel treatment intervention.

Current assessment and management of measurable residual disease in patients with acute lymphoblastic leukemia in the setting of CAR-T-cell therapy

Chimeric antigen receptor(CAR)-modified T-cell therapy has achieved remarkable success in the treatment of acute lymphoblastic leukemia(ALL).Measurable/minimal residual disease(MRD)monitoring plays a significant role in the prognostication and management of patients undergoing CAR-T-cell therapy.Common MRD detection methods include flow cytometry(FCM),polymerase chain reaction(PCR),and next-generation sequencing(NGS),and each method has advantages and limitations.It has been well documented that MRD positivity predicts a poor prognosis and even disease relapse.Thus,how to perform prognostic evaluations,stratify risk based on MRD status,and apply MRD monitoring to guide individual therapeutic decisions have important implications in clinical practice.This review assesses the common and novel MRD assessment methods.In addition,we emphasize the critical role of MRD as a prognostic biomarker and summarize the latest studies regarding MRD-directed combination therapy with CAR-T-cell therapy and allogeneic hematopoietic stem cell transplantation(allo-HSCT),as well as other therapeutic strategies to improve treatment effect.Furthermore,this review discusses current challenges and strategies for MRD detection in the setting of disease relapse after targeted therapy.

Immune therapy:a new therapy for acute myeloid leukemia

Although complete remission could be achieved in about 60%–70%of acute myeloid leukemia(AML)patients after conventional chemotherapy,relapse and the state of being refractory to treatment remain the main cause of death.In addition,there is a great need for less intensive regimens for all medically frail patients(both due to age/comorbidity and treatment-related).Immune therapy anticipates improved prognosis and reduced toxicities,which may offer novel therapeutic rationales.However,one of the major difficulties in developing immune therapies against AML is that the target antigens are also significantly expressed on healthy hematopoietic stem cells;B-cell malignancies are different because CD20/CD19/healthy B-cells are readily replaceable.Only the anti-CD33 antibody-drug conjugate gemtuzumab-ozogamicin is approved by the FDA for AML.Thus,drug development remains extremely active,although it is still in its infancy.This review summarizes the clinical results of immune therapeutic agents for AML,such as antibody-based drugs,chimeric antigen receptor therapy,checkpoint inhibitors,and vaccines.

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.

A novel mesenchymal stem cell-based regimen for acute myeloid leukemia differentiation therapy

Currently the main treatment of acute myeloid leukemia(AML)is chemotherapy combining hematopoietic stem cell transplantation.However,the unbearable side effect of chemotherapy and the high risk of life-threatening infections and disease relapse following hematopoietic stem cell transplantation restrict its application in clinical practice.Thus,there is an urgent need to develop alternative therapeutic tactics with significant efficacy and attenuated adverse effects.Here,we revealed that umbilical cord-derived mesenchymal stem cells(UC-MSC)efficiently induced AML cell differentiation by shuttling the neutrophil elastase(NE)-packaged extracellular vesicles(EVs)into AML cells.Interestingly,the generation and release of NE-packaged EVs could be dramatically increased by vitamin D receptor(VDR)activation in UC-MSC.Chemical activation of VDR by using its agonist 1a,25-dihydroxyvitamin D3 efficiently enhanced the pro-differentiation capacity of UC-MSC and then alleviated malignant burden in AML mouse model.Based on these discoveries,to evade the risk of hypercalcemia,we synthetized and identified sw-22,a novel non-steroidal VDR agonist,which exerted a synergistic prodifferentiation function with UC-MSC on mitigating the progress of AML.Collectively,our findings provided a non-gene editing MSC-based therapeutic regimen to overcome the differentiation blockade in AML.

Characteristics of leukemic stem cells in acute leukemia and potential targeted therapies for their specific eradication

In acute myeloid leukemia(AML),a small cell population that contains stem cell features such as lack of differentiation,self-renewal potential,and drug resistance,can be identified.These so-called leukemic stem cells(LSCs)are thought to be responsible for relapse initiation after initial treatment leading to successful eradication of the bulk AML cell population.Since many studies have aimed to characterize and eliminate LSCs to prevent relapse and increase survival rates of patients,LSCs are one of the best characterized cancer stem cells.The specific elimination of LSCs,while sparing the healthy normal hematopoietic stem cells(HSCs),is one of the major challenges in the treatment of leukemia.This review focuses on several surface markers and intracellular transcription factors that can distinguish AML LSCs from HSCs and,therefore,specifically eliminate these stem cell-like leukemic cells.Moreover,previous and ongoing clinical trials of acute leukemia patients treated with therapies targeting these markers are discussed.In contrast to knowledge on LSCs in AML,insight into LSCs in acute lymphoid leukemia(ALL)is limited.This review therefore also addresses the latest insight into LSCs in ALL.

Infections During Induction Therapy of Protocol CCLG-2008 in Childhood Acute Lymphoblastic Leukemia： A Single-center Experience with 256 Cases in China

Background：Infections remain a major cause of therapy-associated morbidity and mortality in children with acute lymphoblastic leukemia （ALL）.Methods：We retrospectively analyzed the medical charts of 256 children treated for ALL under the CCLG-2008 protocol in Beijing Children＇s Hospital.Results：There were 65 infectious complications in 50 patients during vincristine,daunorubicin,L-asparaginase and dexamethasone induction therapy,including microbiologically documented infections （n =12; 18.5％）,clinically documented infections （n =23; 35.3％） and fever of unknown origin （n =30; 46.2％）.Neutropenia was present in 83.1％ of the infectious episodes.In all,most infections occurred around the 15t1h day of induction treatment （n =28）,and no patients died of infection-associated complications.Conclusions：The infections in this study was independent of treatment response,minimal residual diseases at the end of induction therapy,gender,immunophenotype,infection at first visit,risk stratification at diagnosis,unfavorable karyotypes at diagnosis and morphologic type.The infection rate of CCLG-2008 induction therapy is low,and the outcome of patients is favorable.

The percentage of peripheral blood blasts on day 7 of induction chemotherapy predicts response to therapy and survival in patients with acute myeloid leukemia

Background Rapid clearance of peripheral blood blasts （PBBs） predicts complete remission （CR） and survival in patients with acute myeloid leukemia （AML）.We aimed to explore the correlation between induction therapy response,outcome,and the PBB percentage.Methods Forty-six consecutive patients with de novo AML （excluding acute promyelocytic leukemia） were enrolled in this study.Flow cytometry was performed to identify cells with a leukemia-associated aberrant immunophenotype in the initial bone marrow aspirate and in peripheral blood on day 7 of induction therapy.Results The PBB percentage on day 7 （D7PBBP） was significantly lower in patients who achieved CR （0.03% （0.0%,0.45%）） than in those who did not （10.85% （1.13%,19.38%）; u =-3.92,P 〈0.001）.The CR rate was significantly higher among patients with a D7PBBP of 〈0.945% （84.62%,22/26） than among those with a D7PBBP of 〉0.945% （25.0%,5/20;Х^2 =16.571,P 〈0.001）.D7PBBP was significantly correlated with overall survival （OS; r=-0.437,P=0.003） and relapsefree survival （RFS; r=-0.388,P=0.007）.OS and RFS were significantly higher in patients with a D7PBBP of 〈0.43% than in those with a D7PBBP of 〉0.43% （P 〈0.001 and P=0.039,respectively）.D7PBBP was also found to be an independent prognostic indicator in multivariate analysis for both OS （P=-0.036） and RFS （P=0.035）.Conclusion D7PBBP may be an important risk factor for the achievement of complete remission,for overall survival,and for relapse-free survival.

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.

Precision medicine in acute lymphoblastic leukemia

The cure rate of childhood acute lymphoblastic leukemia(ALL)has exceeded 90%in some contemporary clinical trials.However,the dose intensity of conventional chemotherapy has been pushed to its limit.Further improvement in outcome will need to rely more heavily on molecular therapeutic as well as immuno-and cellular-therapy approaches together with precise risk stratification.Children with ETV6-RUNX1 or hyperdiploid>50 ALL who achieve negative minimal residual disease during early remission induction are suitable candidates for reduction in treatment.Patients with Philadelphia chromosome(Ph)-positive or Ph-like ALL with ABL-class fusion should be treated with dasatinib.BH3 profiling and other preclinical methods have identified several high-risk subtypes,such as hypodiplod,early T-cell precursor,immature T-cell,KMT2A-rearranged,Ph-positive and TCF-HLF-positive ALL,that may respond to BCL-2 inhibitor venetoclax.There are other fusions or mutations that may serve as putative targets,but effective targeted therapy has yet to be established.For other high-risk patients or poor early treatment responders who do not have targetable genetic lesions,current approaches that offer hope include blinatumomab,inotuzumab and CAR-T cell therapy for B-ALL,and daratumumab and nelarabine for T-ALL.With the expanding therapeutic armamentarium,we should start focus on rational combinations of targeted therapy with non-overlapping toxicities.