LONG-TERM EFFECT OF HOMOHARRINGTONINE ON CHRONIC GRANULOCYTIC LEUKEMIA

Objective: To observe the long-term effect of homoharringtonine (HHT) on chronic granulocytic leukemia (CGL) and its pharmacological mechanism. Methods: 76 patients with newly diagnosed early chronic phase CGL received treatment of merely 1.5 mg/m2 daily HHT for induction remission and long-term maintenance treatment. The apoptosis rate of bone marrow CD34+ cells induced by HHT was assayed with flow cytometer. Results: 86.8% patients achieved CHR, 13.2% patients PHR and 31.8% patients got cytogenetic response in HHT treatment group, which was longer than 31 (8-54) months in hydroxyurea (HU) group (P<0.05). The effect of apoptosis induction HHT was stronger on CGL-CP patients bone marrow CD34+ cells than on normal person bone marrow CD34+ cells. Conclusion: HHT is a very effective drug for remission induction and long-term maintenance treatment in early chronic phase CGL patients.

Effect of Homoharringtonine on Bone Morrow CD34^+CD7^+ Cells in Chronic Granulocytic Leukemia

Objective： To explore the effect of homoharringtonine （HHT） on bone morrow CD34^＋CD7^＋ cells in chronic granulocytic leukemia （CGL）. Methods： The changes of bone morrow CD34^＋CD7^＋ cells were observed after the treatment of HHT in 23 cases with CGL. The proliferation and apoptosis of CD34^＋CD7^＋ cells treated with HHT in vitro were studied. Results： The proportion of CD34^＋CD7^＋ cells in CGL （0.145±0.021） was higher than that of normal control （0.052±0.013）. The proportion of CD34^＋CD7^＋ cells in patients who got cytogenetic responses to HHT （0.072±0.020） decreased remarkably, but not in those patients who did not got cytogenetic responses to HHT, （0.137±0.023）. the proliferation of CD34^＋ cells was inhibited and the proportion of CD34^＋CD7^＋ cells decreased after cultured with HHT （0.134 in 24 h, 0.126 in 48 h and 0.102 in 72）. The apoptosis rate of CD34^＋CD7^＋ cells was higher than that in CD34^＋CDT cells （35.39%±4.39% versus 24.57%±4.01%, P〈0.05） 72 h after culture with HHT. Conclusion： The proportion of CD34^＋CD7^＋ cells in CGL was higher than that of normal control and HHT may inhibit the proliferation and induce apoptosis of bone marrow CD34^＋CD7^＋ cells.

Suspected coexistence of perianal necrotizing sweet syndrome in chronic myelomonocytic leukemia:A case report

BACKGROUND Chronic myelomonocytic leukemia(CMML)complicated with Sweet syndrome(SS)is a rare hematological neoplasm.However,cases of concomitant development of perianal necrotizing SS(NSS)have not been reported.CASE SUMMARY We report a case of a 49-year-old male patient who underwent sequential procedures for hemorrhoids and perianal abscess.He developed postoperative incision infection and was referred to the department where the authors work.Initially,perianal necrotizing fasciitis secondary to incision infection after perianal abscess surgery was suspected.Despite receiving antibiotic therapy and undergoing surgical debridement,deeper necrotic areas formed in the patient’s perianal wounds,accompanied by persistent high fever.Blood and fungal cultures yielded negative results.The final diagnosis was corrected to be CMML with suspected concomitant perianal NSS.CONCLUSION CMML with perianal NSS is a rare condition,often misdiagnosed as perianal abscess or perianal necrotizing fasciitis.Conventional antibiotic therapy and surgical debridement are ineffective in managing this condition.

Network pharmacology to decipher the mechanism of Danggui Longhui Wan against chronic myeloid leukemia

Chronic myeloid leukemia(CML)is a hematopoietic myeloproliferative disorder.The Chinese prescription Danggui Longhui Wan(DGLHW)has been utilized in CML treatment,but its underlying mechanisms remain unclear.In this study,we gathered 794 constituents,1249 drug targets,1654 disease genes and 129 intersection genes.GO and KEGG were used to analyze the function of these genes.Compatibility of prescription study showed that monarch drug,minister drug,assistant and guide drug played a synergistic role in the treatment of CML.In addition,we obtained 20 hub genes and 12 key components.Molecular docking indicated that the main compounds and core proteins had good binding ability.The results of this study also showed that DGLHW might play a role in the treatment of CML by affecting MAPK,PI3K/AKT,FoxO and p53 signaling pathways.

Focal lymphoblastic transformation of chronic myelogenous leukemia develops into erythroid leukemia:A case report

BACKGROUND We present a case of focal lymphoblastic transformation to erythroid leukemia following acute myeloblastic transformation in a patient with chronic myelogenous leukemia(CML)and discuss its mechanism of occurrence and development.CASE SUMMARY The presence of the Philadelphia(Ph)chromosome was identified through karyotype analysis,while the BCR-ABL fusion gene was detected using quantitative real-time polymerase chain reaction of the peripheral blood sample.Fluorescence in situ hybridization was used to detect the expression of the BCRABL gene in the lymphoma.Antigen expression and gene mutations in the primitive cells were detected by flow cytometry.The analysis confirmed the presence of CML along with focal lymphoblastic transformation to erythroid leukemia.Additionally,the patient was found to have secondary erythroid leukemia,along with multiple new gene mutations and abnormalities in complex karyotypes of chromosomes.CONCLUSION Our findings suggest a possible molecular basis for the focal lymphoblastic transformation secondary to myeloblastic transformation in patients with CML.

A Rare Entity of Accelerated Chronic Lymphocytic Leukemia: A Report of Two Cases and Review of Literature

Background: Accelerated-chronic lymphocytic leukemia (A-CLL) is a rare disease entity as it represents less than 1% of all reported cases of chronic lymphoid leukemia (CLL). Moreover, it is most likely an under diagnosed entity due to its rarity and the non-standardized practice of lymph node biopsy in CLL. Purpose: The aims of our work are to establish the diagnosis of A-CLL and to study the prognosis and treatment of this rare entity. Method: here, we report the clinical presentation and the follow up of two cases of A-CLL. Results: Distinguishing Richter transformation (RT) from A-CLL is important as it may result in a major change in disease management. The prognosis of A-CLL is intermediate between CLL and RT. The prognosis is mainly poor due to a predominance of poor prognostic markers including an increasing number of p53-positive cases. Conclusion: To this date, no prospective study has been led to define the best treatment for A-CLL. The shorter survival of A-CLL when compared to typical CLL implies the need of a more aggressive treatment.

Co-existing squamous cell carcinoma and chronic myelomonocytic leukemia with ASXL1 and EZH2 gene mutations:A case report

BACKGROUND Chronic myelomonocytic leukemia(CMML),a rare clonal hematopoietic stem cell disorder characterized by myelodysplastic syndrome and myeloproliferative neoplasms,has a generally poor prognosis,and easily progresses to acute myeloid leukemia.The simultaneous incidence of hematologic malignancies and solid tumors is extremely low,and CMML coinciding with lung malignancies is even rarer.Here,we report a case of CMML,with ASXL1 and EZH2 gene mutations,combined with non-small cell lung cancer(lung squamous cell carcinoma).CASE SUMMARY A 63-year-old male,suffering from toothache accompanied by coughing,sputum,and bloody sputum for three months,was given a blood test after experiencing continuous bleeding resulting from a tooth extraction at a local hospital.Based on morphological results,the patient was diagnosed with CMML and bronchoscopy was performed in situ to confirm the diagnosis of squamous cell carcinoma in the lower lobe of the lung.After receiving azacitidine,programmed cell death protein 1,and platinum-based chemotherapy drugs,the patient developed severe myelosuppression and eventually fatal leukocyte stasis and dyspnea.CONCLUSION During the treatment and observation of CMML and be vigilant of the growth of multiple primary malignant tumors.

Unusual presentation of extramedullary blast crisis in chronic myeloid leukemia:A case report

BACKGROUND Extramedullary blast crisis in chronic myeloid leukemia(CML)is an uncommon occurrence of leukemic blast infiltration in regions other than the bone marrow.Malignant infiltration of the serosal membranes should be considered in cases where CML presents with ascites or pleural effusion.CASE SUMMARY A 23-year-old female with CML presented with progressively worsening ascites and pleural effusion despite first-line tyrosine kinase inhibitor treatment.Her blood work indicated leukocytosis with myelocyte bulge and 2%blasts.Analysis of the patient’s bone marrow confirmed the chronic phase of CML.Abdominal ultrasound revealed hepatosplenomegaly with ascites.The fluid investigation of both ascites and pleural effusion revealed a predominance of neutrophils with exudate.However,no acid-fast bacilli or growth was observed after culturing.Although hydroxyurea reduced cell counts,there was no observed effect on ascites or pleural effusion.Repeat investigation of the ascitic and pleural fluid revealed a polymorphous myeloid cell population consisting of myelocytes,metamyelocytes,band forms,neutrophils and a few myeloblasts.Extramedullary blast crisis was suspected,and mutation analysis was performed.We switched the patient to dasatinib.The patient’s symptoms were relieved,and ascites and pleural effusion diminished.CONCLUSION Serosal membrane involvement in CML is extremely rare.In this case,the patient responded well to dasatinib treatment.

Chronic myeloid leukemia-from the Philadelphia chromosome to specific target drugs:A literature review

Chronic myeloid leukemia(CML)is a myeloproliferative neoplasm and was the first neoplastic disease associated with a well-defined genotypic anomaly―the presence of the Philadelphia chromosome.The advances in cytogenetic and molecular assays are of great importance to the diagnosis,prognosis,treatment,and monitoring of CML.The discovery of the breakpoint cluster region(BCR)-Abelson murine leukemia(ABL)1 fusion oncogene has revolutionized the treatment of CML patients by allowing the development of targeted drugs that inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein.Tyrosine kinase inhibitors(known as TKIs)are the standard therapy for CML and greatly increase the survival rates,despite adverse effects and the odds of residual disease after discontinuation of treatment.As therapeutic alternatives,the subsequent TKIs lead to faster and deeper molecular remissions;however,with the emergence of resistance to these drugs,immunotherapy appears as an alternative,which may have a cure potential in these patients.Against this background,this article aims at providing an overview on CML clinical management and a summary on the main targeted drugs available in that context.

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.

STUDIES ON THE MECHANISM OF INDIRUBIN ACTION IN THE TREATMENT OF CHRONIC GRANULOCYTIC LEUKEMIA——V.BINDING BETWEEN INDIRUBIN AND DNA AND IDENTIFICATION OF THE TYPE OF BINDING

The binding between indirubin and calf thymus DNA in vitro has been verified by meansof the isotope labelling method, spectrophotometric method and thermal denaturation meas-urements. The λ_max 207 nm of indirubin shifted toward longer wave length with decrease ofabsorbance after the incubation of indirubin with DNA. The escalation of Tm value of DNAinduced by indirubin was about 2.4°C and it was reproducible. The binding force between themwas rather weak, as indirubin molecules were easily released during the precipitation withalcohol or the gel filtration. The binding was not affected by sodium chloride even at high con-centration but greatly decreased (to 20-30% of the control) in the presence of 8 M urea.These results showed that the binding between indirubin and DNA might be of hydrogen bondrather than ionic. The amount of bound ~3H-indirubin was directly proportional to the con-centration of indirubin. However, it increased abruptly when the concentration of indirubinreached 1.5×10^(-4) M. This suggested another binding force in the latter instance. By using spectrophotometric analysis and Scatchard plot it was found that calf thymusDNA bound 46 indirubin molecules/1000 nucleotides. The association constant (K) was5.7×10~6.

Serum LDH level may predict outcome of chronic lymphocytic leukemia patients with a 17p deletion： a retrospective analysis of prognostic factors in China

Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results： The overall response rate （ORR） in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- （defined as more than 25% of cells harbouring a 17p-） had a lower ORR. The median overall survival （OS） in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality （median 162.0 months, P〈0.001）. Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase （LDH）, B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions： These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.

Time-limited,Combined Regimen in Chronic Lymphocytic Leukemia:A Promising Strategy to Achieve a Drug Holiday

Chemoimmunotherapy(CIT)is defined as standard first line treatment for chronic lymphocytic leukemia(CLL)patients while patients with unfavorable biological characteristics such as unmutated immunoglobulin heavy chain(UM-IGHV)and TP53 aberration failed to benefit from it.The emergency of the small molecular targeted agents including Bruton’s tyrosine kinase(BTK)inhibitor(BTKi)leads to a brand-new era,from a CIT to a chemo-free era in CLL.However,the treatment of target agents is not enough to attain a deep remission and high rate of complete remission(CR),especially in patients with high risks.The long duration brought about problems,such as cost,drug resistance and toxicity.To benefit CLL in progression free survival(PFS)and long-term remission,exploration of time-limited therapies,mainly with BTKi plus CIT and BCL2i based combination therapy has become a mainstream in clinical trials.The time-limited combination therapy shed light on the promising potentiality to attain sustainable deep remission and partly overcame the risk factors,although long term follow-up is required to consolidate the conclusion.In this review,we intend to introduce key results of clinical trials with combination therapy,discuss the achievements and limitations and put forward future direction for clinical trial design in this field.

Concomitant Chronic Lymphocytic Leukemia and Multiple Myeloma: Proof of Common Clonal Origin

We describe a patient with concomitant B-cell chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). CLL- and MM-cell were separated by preparative flourescence-activated cell sorting (FACS). DNA sequence analysis of the complementarity-determinining region III (CDR III) of the immunoglobulin heavy chain genes showed identical gene rearrangements in the CLL- and the MM-cell population. Our findings prove a common clonal tumor origin of both B-cell diseases in this patient.

Combination of Rapamycin and Imatinib in Treating Refractory Chronic Myeloid Leukemia Myeloid Blast Crisis:a Case Report

HRONIC myeloid leukemia （CML） is characterized by the presence of the BCR/ABL fusion gene, which is the result of a reciprocal translo cation between chromosomes 9 and 22, calledPhiladelphia （Ph） chromosome. Imatinib mesylate （imatinib）, a specific small molecular inhibitor of BCR/ABL, could improve the prognosis of CML and is now the standard drug applied in all phases of this disease} Despite the efficacy of imatinib, the development of resistance and the persistence of minimal residual disease have seriously impaired the efficiency of this medicine. Resistance may develop through several different mechanisms, such as mutations in the Abl kinase domain, BCR/ABL overexpression, or compensatory phosphatidylinositol 3 kinase （PI3K）/Akt/ mammalian target of rapamycin （mTOR） activation.2,3 Rapamycin, with mTOR as a potential therapeutic target, has been studied in patients with hematologic malignancies. Here we report a case of refractory CML myeloid blast crisissuccessfully treated by the combination of rapamycin and imatinib.

Chronic myelomonocytic leukemia-associated pulmonary alveolar proteinosis:A case report and review of literature

BACKGROUND Pulmonary alveolar proteinosis(PAP)is a rare condition that can cause progressive symptoms including dyspnea,cough and respiratory insufficiency.Secondary PAP is generally associated with hematological malignancies including chronic myelomonocytic leukemia(CMML).To the best of our knowledge,this is the first reported case of PAP occurring secondary to CMML.CASE SUMMARY We report the case of a 63-year-old male who presented with a recurrent cough and gradually progressive dyspnea in the absence of fever.Based upon clinical symptoms,computed tomography findings,bone marrow aspiration,flow cytometry studies and cytogenetic analyses,the patient was diagnosed with PAP secondary to CMML.He underwent whole lung lavage in March 2016 to alleviate his dyspnea,after which he began combined chemotherapeutic treatment with decitabine and cytarabine.The patient died in January 2020 as a consequence of severe pulmonary infection.CONCLUSION This case offers insight regarding the mechanistic basis for PAP secondary to CMML and highlights potential risk factors.

A novel t(3;12)(q21;p13) translocation in a patient with accelerated chronic myeloid leukemia after imatinib and nilotinib therapy

The acquisition of secondary chromosomal aberrations in chronic myeloid leukemia (CML) patients with Philadelphia chromosome-positive (Ph+) karyotype signifies clonal evolution associated with the progression of the disease to its accelerated or blastic phase. Therefore, these aberrations have clinical and biological significance. T(3;12)(q26;p13), which is a recurrent chromosomal aberration observed in myeloid malignancies, is typically associated with dysplasia of megakaryocytes, multilineage involvement, short duration of any blastic phase, and extremely poor prognosis. We have identified a recurrent reciprocal translocation between chromosomes 3 and 12 with different breakpoint at bands 3q21 in the malignant cells from a 28-year-old man. The patient was initially diagnosed as having Ph+ CML in the chronic phase. The t(3;12)(q21;p13) translocation occurred 4 years after the patient was first diagnosed with CML while undergoing tyrosine kinase inhibitor therapy. We confirmed the t(3;12)(q21;p13) translocation via fluorescence in situ hybridization assay by using whole-chromosome paint probes for chromosomes 3 and 12. Our findings demonstrate that, similar to other recurrent translocations involving 3q26 such as t(3;3) and t(3;21), the t(3;12)(q21;p13) translocation is implicated not only in myelodysplastic syndrome and acute myeloid leukemia but also in the progression of CML. These findings extend the disease spectrum of this cytogenetic aberration.

Time-series Analysis in Imatinib-resistant Chronic Myeloid Leukemia K562-cells under Different Drug Treatments

Chronic myeloid leukemia（CML） is characterized by the accumulation of active BCR-ABL protein. Imatinib is the first-line treatment of CML; however, many patients are resistant to this drug. In this study, we aimed to compare the differences in expression patterns and functions of time-series genes in imatinib-resistant CML cells under different drug treatments. GSE24946 was downloaded from the GEO database, which included 17 samples of K562-r cells with（n=12） or without drug administration（n=5）. Three drug treatment groups were considered for this study： arsenic trioxide（ATO）, AMN107, and ATO＋AMN107. Each group had one sample at each time point（3, 12, 24, and 48 h）. Time-series genes with a ratio of standard deviation/average（coefficient of variation） 〉0.15 were screened, and their expression patterns were revealed based on Short Time-series Expression Miner（STEM）. Then, the functional enrichment analysis of time-series genes in each group was performed using DAVID, and the genes enriched in the top ten functional categories were extracted to detect their expression patterns. Different time-series genes were identified in the three groups, and most of them were enriched in the ribosome and oxidative phosphorylation pathways. Time-series genes in the three treatment groups had different expression patterns and functions. Time-series genes in the ATO group（e.g. CCNA2 and DAB2） were significantly associated with cell adhesion, those in the AMN107 group were related to cellular carbohydrate metabolic process, while those in the ATO＋AMN107 group（e.g. AP2M1） were significantly related to cell proliferation and antigen processing. In imatinib-resistant CML cells, ATO could influence genes related to cell adhesion, AMN107 might affect genes involved in cellular carbohydrate metabolism, and the combination therapy might regulate genes involved in cell proliferation.

Curcumin in chronic lymphocytic leukemia——A review

Curcumin is a widely researched natural product and is known to possess anticarcinogenic properties.Chronic lymphocytic leukemia is a type of leukemia that principally affects patients with age higher than 60 years.Since the toxicity of conventional drugs exceeds the benefits of treating this leukemia type,patients are treated only in the advanced symptomatic stages.The current article reviews curcumin,its general actions and targets in cancer,and specifically that of it in chronic lymphocytic leukemia.

Trisomy 12 in a Case of Multiple Cutaneous Squamous Cell Carcinoma in Association with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukaemia （CLL）, which shares clinical and morphological overlap with small lymphocytic lyjmphoma （SLL）, is a low-grade clonal B-cell lymphoproliferative disorder that accounts for 25% of all cases of leukaemia in Western countries, while it is considered rare in Oriental patients and is thought to constitute only 2% of all leukemias in these patients. CLL is associated with an increased incidence of secondary malignant neoplasms, such as brain tumors, melanomas, and gastrointestinal-tract carcinomas. However, the simulataneous occurrence of CLL and cutaneous squamous cell carcinoma （SCC） is rarely reported. We present here a case of CLL with multiple SCC on the face. Subsequent studies demonstrated the patient to have a trisomy 12 identified in bone marrow specimen.