Management of Acute Myeloblastic Leukaemia (AML) Treated with Intensive Chemotherapy: Experience in a Single Centre

Introduction: Acute myeloblastic leukaemia (AML) is a haematological malignancy with a poor prognosis, despite significant therapeutic progress. This study presents the results of AML management in Mali according to GFAOP recommendations. Methodology: This was a retrospective, cross-sectional study. It included patients aged 0 - 15 years treated in the paediatric oncology unit for AML and followed up between January 2016 and December 2020. Results: During the study period, 85 cases of acute leukaemia were diagnosed in the paediatric oncology unit (including 51 cases of ALL), of which 34 cases of AML were included in this study. The majority were boys (59%). The mean age was 8 years, with extremes of 18 months and 15 years. The mean time to diagnosis was 68 days. In 79% of cases, patients were referred by 1st or 2nd level hospitals. Anaemia was observed in 91% of cases, an infectious syndrome in 68%, haemorrhage in 56% and a tumour syndrome in 85%. The haemogram showed hyperleukocytosis in 15% of cases, thrombocytosis in 22% and severe anaemia in 73%. Death occurred in 85% of cases, most often in the context of sepsis or haemorrhage. Conclusion: AML is probably underestimated in Mali and diagnosis delayed, which may be explained by patient-related factors (lack of knowledge, financial constraints) and a cumbersome referral system. These results suggest the need to implement an appropriate diagnostic and therapeutic strategy, with strong involvement of the political authorities.

Miller Fisher Syndrome Induced by Chemotherapy in Known Case of Acute Lymphocytic Leukaemia: A Case Report

Introduction: Guillain-Barre Syndrome (GBS) is an acute-onset autoimmune-mediated neuropathy. Guillain-Barre Syndrome can be divided into three subtypes: acute inflammatory demyelinating poly-radiculo-neuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor sensory axonal neuropathy (AMSAN). About 20% of patients with GBS develop respiratory failure and require mechanical ventilation. We are presenting a variant of GBS (Miller Fisher Syndrome, or MFS), which has been confirmed by nerve conduction studies along with the triad of ophthalmoplegia, ataxia, and areflexia. The objective of this study is to present a rare case of chemotherapy-induced GBS. Important clinic findings: A 25-year-old gentleman with acute lymphocytic leukemia on active chemotherapy treatment presented with lower limb weakness. This weakness started after his fifth chemotherapy session. After the sixth chemotherapy, he developed complete paralysis of the left lower limb. Later, he developed right lower limb paralysis. He was also complaining of eye dryness and incomplete closure of both eyes. While inpatient, he developed upper-limb weakness. His chemotherapy consisted of MESNA, cyclophosphamide, doxorubicin, vincristine, cyorabine, and methotrexate. He had ptosis and ophthalmoplegia in the left abducent and right oculomotor regions. He had bilateral facial nerve palsy. He was hypotonic with power grade 3 in the upper limbs and grade 0 in the lower limbs with areflexia. His sensation was intact in the upper limbs but lost in the lower limbs. His planter reflexes were mute. Diagnoses and Management: Intravenous immunoglobulins were given for 5 days. A nerve conduction study showed severe demyelinating sensorimotor polyradoculoneuropathy with secondary axonal loss. The triad of ataxia, ophthalmoplegia, and areflexia was consistent with MFS. The patient improved over the course of the hospital stay but did not reach full recovery. Conclusion: Although GBS is uncommon, it must be taken into account when making a differential diagnosis for any patient presenting with progressive weakness. Drug history is important in all GBS cases.

Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukaemia: a case–control study

The aim of this study was to evaluate the efficacy of palifermin, an N-terminal truncated version of endogenous keratinocyte growth factor, in the control of oral mucositis during antiblastic therapy. Twenty patients undergoing allogeneic stem-cell transplantation for acute lymphoblastic leukaemia were treated with palifermin, and compared to a control group with the same number of subjects and similar inclusion criteria. Statistical analysis were performed to compare the outcomes in the treatment vs. control groups. In the treatment group, we found a statistically significant reduction in the duration of parenteral nutrition （P=0.002）, duration of mucositis （P= 0.003） and the average grade of mucositis （P= 0.03）. The statistical analysis showed that the drug was able to decrease the severity of mucositis. These data, although preliminary, suggest that palifermin could be a valid therapeutic adjuvant to improve the quality of life of patients suffering： from leukaemia.

Survivin Antisense Oligodeoxy-Nucleotid Induces Apoptosis in Leukaemia Cell Line K562

OBJECTIVE To investigate the effects of survivin antisense oligodeoxy-nucleotid (ASODN) on proliferation and apoptosis in the chronic myeloid leukemia cell line K562. METHODS Different concentrations of an antisense oligodeoxy-nucleotid and control sequence (scrambled ODN) targeting the survivin gene were transferred into K562 by a lipofectin reagent. The MTT assay was used to measure the growth inhibitory rate, IC50, and to observe the cytotoxicity of survivin ASODN in the K562 cells. The morphologic changes in the nucleus and the apoptotic rate were observed by Hoechst33342/PI staining. Caspase-3 activity was evaluated by a kinase activity assay. The changes of survivin protein expression after transfection were detected by Western blots. RESULTS Eight hours after transfection, fluorescence in the K562 cells was well distributed. Treatment of the cells for 44 h with different concentrations of survivin ASODN produced a IC50 of 800 nmol/L. The growth inhibitory rate with 200, 400, 600 and 1000 nmol/L of survivin ASODN was 15.8±1.6%, 23.8±5.9%, 37.1±5.6% and 77.3±2.5% respectively. After 36 h of of survivin ASODN treatment, distinct morphologic changes characteristic of cell apoptosis such as karyopyknosis and conglomeration were observed by Hoechst33342/PI staining. Caspase-3 activity increased significantly after treatment of the cells with different concentrations of survivin ASODN(P<0.01)and following treatment with 800 nmol/L survivin ASODN, survivin expression decreased significantly. CONCLUSION Survivin ASODN exerts an anti-cancer effect by inducing apoptosis in K562 leukaemia cells. Up-regulated expression of caspase-3 may play a role in this process.

Association between Childhood Leukaemia and Exposure to Power-frequency Magnetic Fields in Middle Europe

Abstract Objective Higher levels of exposure to extremely low-frequency magnetic fields （ELF-MF） are associated with a slightly increased risk of childhood leukaemia. Compared with more-developed Western countries, higher exposure levels are evident in the Czech Republic, probably because of the different types of housing. In light of this, we aimed to examine the association between ELF-MF exposure and childhood leukaemia in the Czech Republic. Methods We conducted a paired case-control study. The cases （children with leukaemia） were age- sex- and permanent residence-matched to controls （children without leukaemia）. Although this limited potential bias and confounding, it also limited our number of participants. Results The matched analyses included 79 case-control pairs. No significant association between ELF-MF exposure and childhood leukaemia was observed for exposures over 0.2 μT （odds ratio [0R]=0.93, confidence interval [Cl]=0.45-1.93）, 0.3 μT （0R=0.77, Cl=0.34-1.75）, or 0.4 μT （OR=0.9, Cl=0.37-2.22）. Conclusion Despite higher levels of exposure in Middle and Eastern Europe, no indication of an association between ELF-MF exposure and childhood leukaemia was determined. This in contrast to the findings of previous studies conducted in different countries.

Probability Prediction in Multistate Survival Models for Patients with Chronic Myeloid Leukaemia

In order to find an appropriate model suitable for a multistate survival experiment, 634 patients with chronic myeloid leukaemia (CML) were selected to illustrate the method of analysis. After transplantation, there were 4 possible situations for a patient: disease free, relapse but still alive, death before relapse, and death after relapse. The last 3 events were considered as treatment failure. The results showed that the risk of death before relapse was higher than that of the relapse, especially in the first year after transplantation with competing-risk method. The result of patients with relapse time less than 12 months was much poor by the Kaplan-Meier method. And the multistate survival models were developed, which were detailed and informative based on the analysis of competing risks and Kaplan-Meier analysis. With the multistate survival models, a further analysis on conditional probability was made for patients who were disease free and still alive at month 12 after transplantation. It was concluded that it was possible for an individual patient to predict the 4 possible probabilities at any time. Also the prognoses for relapse either death or not and death either before or after relapse may be given. Furthermore, the conditional probabilities for patients who were disease free and still alive in a given time after transplantation can be predicted.

Detection of Telomerase Activity and the Expression of Telomerase Subunits in the Patients with Acute Myelogenous Leukaemia

Telomerase activity and the expression of telomerase subunits (for example, telomerase reverse transcriptase and telomerase associated protein 1 and telomerase RNA component) of peripheral white blood cells were detected in the patients with acute myelogenous leukaemia (AML) and the correlation between telomerase activity and the expression of telomerase subunits was observed. In 94 peripheral white blood cells from 18 healthy volunteers and 76 patients with AML, including 31 AML at initial presentation, 24 at relapse and 21 at complete remission, the telomerase activity and telomerase subunits mRNA or RNA were detected by PCR ELISA and RT PCR respectively. The results showed that the positive rate of telomerase from patients with AML at initial presentation, at relapse and at complete remission was 74.1 %, 79.2 % and 4.8 % respectively. The positive rate of telomerase reverse transcriptase mRNA from healthy volunteers, AML at initial presentation, AML at relapse and AML at complete remission was 5.6 %, 80.6 %, 83.3 % and 9.5 % respectively. The positive rate of telomerase associated protein 1 mRNA and telomerase RNA component in all samples were 100 %. It was suggested that the up regulation of telomerase activity and the expression of telomerase reverse transcriptase is correlated closely with the occurrence and relapse of AML, so telomerase activity and the expression of telomerase reverse transcriptase may be used to estimate the curative effect and predict relapse of AML. Moreover, the up regulation of telomerase activity is correlated with the expression of telomerase reverse transcriptase significantly.

Automatic Leukaemia Segmentation Approach for Blood Cancer Classification Using Microscopic Images

Leukaemia is a type of blood cancer that is caused by undeveloped White Blood Cells(WBC),and it is also called a blast blood cell.In the marrow of human bones,leukaemia is developed and is responsible for blood cell generation with leukocytes and WBC,and if any cell gets blasted,then it may become a cause of death.Therefore,the diagnosis of leukaemia in its early stages helps greatly in the treatment along with saving human lives.Subsequently,in terms of detection,image segmentation techniques play a vital role,and they turn out to be the important image processing steps for the extraction of feature patterns from the Acute Lymphoblastic Leukaemia(ALL)type of blood cancer.Moreover,the image segmentation technique focuses on the division of cells by segmenting a microscopic image into background and cancer blood cell nucleus,which is well-known as the Region Of Interest(ROI).As a result,in this article,we attempt to build a segmentation technique capable of solving blood cell nucleus segmentation issues using four distinct scenarios,including K-means,FCM(Fuzzy Cmeans),K-means with FFA(Firefly Algorithm),and FCM with FFA.Also,we determine the most effective method of blood cell nucleus segmentation,which we subsequently use for the Leukaemia classification model.Finally,using the Convolution Neural Network(CNN)as a classifier,we developed a leukaemia cancer classification model from the microscopic images.The proposed system’s classification accuracy is tested using the CNN to test the model on the ALL-IDB dataset and equate it to the current state of the art.In terms of experimental analysis,we observed that the accuracy of the model is near to 99%,and it is far better than other existing models that are designed to segment and classify the types of leukaemia cancer in terms of ALL.

Atypical Chronic Myeloid Leukaemia with Trisomy 13: a Case Report

ATYPICAL chronic myeloid leukaemia （aCML）, which shows both myeloproliferative and mye- Iodysplastic features, is a type of myeloprolif- erative/myelodysplastic disease as defined bythe World Health Organisation （WHO） classification of the myeloid neoplasms. Because of the presence of neutrophilic leukocytosis, aCML may resemble chronic myeIogenous leukemia （CML）. However, in contrast with CML, aCML does not have the Philadelphia chromosome or the bcr/abl fusion gene.

CLAG-M chemotherapy followed by umbilical cord blood stem cell transplantation for primary refractory acute myeloid leukaemia in a child:A case report

BACKGROUND The prognosis of paediatric primary refractory/relapsed acute myeloid leukaemia(R/R AML)remains poor.Intensive therapy is typically used as salvage treatment for those with R/R AML.No data are currently available about the use of the CLAG-M protocol as salvage therapy in paediatric patients with R/R AML.CASE SUMMARY An 8-year-old patient was diagnosed with acute myeloid leukaemia by bone marrow morphology and immunophenotype.The patient showed poor response to two cycles of induction therapy with 60%blast cells in the bone marrow after the second induction cycle.The patient achieved complete remission after being treated with the CLAG-M protocol as salvage therapy before undergoing umbilical cord blood stem cell transplantation.Morphological complete remission with haematological recovery has hitherto been maintained over 4 mo.Abnormal gene mutations detected at diagnosis were undetectable after haematopoietic stem cell transplantation.CONCLUSION Here we present a paediatric patient with primary refractory acute myeloid leukaemia who was successfully treated with the CLAG-M protocol.Given the positive results of the presented patient,large-scale clinical studies are required to assess the role of the CLAG-M protocol in the salvage treatment of refractory or relapsed AML in childhood.

Mexican Guidelines for the Diagnosis and Treatment of Chronic Myeloid Leukaemia

Background: This document includes recommendations and guidelines issued by a group of Mexican researchers and specialists gathered in the First National Colloquium for the Diagnosis and Management of Chronic Myeloid Leukaemia (CML) by initiative of Instituto Nacional de Cancerología and with the support of the Leukaemia Department of the MD Anderson Cancer Center. Mexico lacks of updated information taken from its own reality on the diagnosis and treatment of CML and other haematological disorders;besides, there are no national guidelines. Aim: To publish a consensus document with guidelines for the management of CML adjusted to the national environment and overall characteristics. Method: The participants answered a DELPHI questionnaire about the overall aspects of the disease, aiming to target controversial topics, discuss them in the colloquium, and to agree on the best ones. After those meetings, a final document was drawn up. Results: The group presents recommendations for definition, diagnosis, prognosis, monitoring, and treatment of CML in Mexico. Conclusions: Having consensus guidelines for the clinical management of CML in our country will enable the consensual practice of Mexican specialists regarding the clinical approach to CML, as well as optimize the resources which allow the rational planning of the medical care strategies.

Etoposide-induced apoptosis results in chromosome breaks within the <i>AF</i>9 gene: Its implication in chromosome rearrangement in leukaemia

Treatment with etoposide (VP-16) has been associated with translocation of the mixed lineage leukaemia (MLL) gene seen in treatment-related acute myeloid leukaemia (t-AML). Among the different partner genes, AF9 is the most common partner gene of MLL. AF9 shares similar structural element with the MLL gene. Various mechanisms of translocation have been proposed for the MLL gene, including apoptosis, particularly the apoptotic nuclease. In the current study, we show that VP-16 induced cleavage of the AF9 gene in both leukaemic cells and cultured normal blood cell. All the breakpoints were mapped within the BCR1 of the AF9 gene. AF9 cleavages in leukaemic cells were abolished by pre-treatment with caspase inhibitor (Z-DEVD-FMK), suggesting the involvement of caspase-activated DNase (CAD). The absence of AF9 cleavage in K562 cells further supported the involvement of apoptosis. However, AF9 cleavages in cultured normal blood cell were not eliminated by caspase inhibitor. The possible role of CAD and other apoptotic nucleases/effectors that could be involved in AF9 translocation are discussed.

Chronic myeloid leukaemia presenting as acute small bowel gangrene:A case report

Rationale:Chronic myeloid leukaemia is a myeloproliferative disorder due to clonal hyperproliferation of myeloid cells within the bone marrow.It can present both pro-and anti-thrombotic states.CML has different presentations within the gastrointestinal tract.Patient’s concern:A 40-year-old non-diabetic and non-hypertensive male complained of abdominal pain with nausea and emesis for 1 day.Besides,he had a history of abdominal distension and fever for 1 day.Diagnosis:Acute small bowel gangrene due to chronic myeloid leukaemia.Intervention:A limited resection of small intestine with ileostomy and mucus fistula.Outcome:After 3 months following surgery the patient underwent stoma closure.The patient was followed up for more than 3 years postoperatively.During the follow-up,the patient was asymptomatic without any recurrence of the disease.Lesson:Chronic myeloid leukaemia should be considered as one of the causes for small intestine gangrene when there is increased leukocyte count,splenomegaly without evidence of atherosclerotic occlusion or systemic emboli from the heart.

Disseminated Intravascular Coagulation at Diagnosis in Acute Myeloblastic Leukaemia

Background: Disseminated Intravascular Coagulation (DIC) is a life threatening complication frequently observed in acute leukemia. Among the morphological varieties of Acute Myeloid Leukaemia (AML), Acute Promyelocytic Leukaemia (APL) is well established to cause DIC. But there have been reports noted that abnormal DIC parameters also commonly observed in the patients with non-APL AML. This study evaluated the DIC parameters & DIC score according to International Society of Thrombosis and Haemostasis (ISTH) in newly diagnosed non-APL AML patients. Materials and Methods: This cross-sectional observational study was conducted in the Department of Haematology, BSMMU, Dhaka, Bangladesh. 48 newly diagnosed non-APL AML patients were enrolled. Platelets count was measured by auto analyzer (Sysmax XT 2000i/Pentra ABX-120DX) as well as checked manually. Prothrombin time, fibrinogen, D-Dimer were measured using STAGO Coagulation analyzer. The ISTH-DIC scoring system was used to calculate DIC score. The statistical analysis was carried out using the Statistical Package for Social Sciences version 24.0 for Windows. Chi-Square test & Fisher exact test was used for categorical variables. Unpaired t-test was used to compare mean between groups. For all statistical tests, p-value less than 0.05 was considered as statistically significant. Results: By analyzing 48 newly diagnosed patients with non-APL AML, found that DIC developed in 14.6% patients at presentation. Among the DIC parameters, PT and D-dimer were significantly higher in patients presented with DIC. Patients with DIC exhibit lower expression of CD117, CD34, HLA-DR and statistically significant association with negative expression of HLA-DR (p-value 0.034). No significant association was found between presence of DIC and age, gender, bleeding at presentation, morphological type, WBC count or peripheral blast percentage. Conclusion: Abnormalities of DIC parameters in common in patients with AML. A significant portion of patients with DIC have no apparent symptom or bleeding. So, routine screening of DIC parameter at presentation is recommended for early diagnosis & effective management of DIC.

Similarity of regulatory network between leukaemia stem cells and normal hemopoietic stem cells

Few studies have deeply compared the expression profiles between normal hematopoietic cells and acute myeloid leukaemia(AML) blasts. To reveal the biology of AML, we compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts(LBs) from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells, unselected bone marrows(BMs), and unselected peripheral bloods(PBs). Gene expression profile of normal hematopoietic cells from healthy donors and LBs from AML patients were compared to identify differentially expressed genes(DEGs). We defined the comparison of LB and unselected BM as experiment 1, LB and CD34+ isolated from BM as experiment 2, LB and unselected PB as experiment 3, as well as LB and CD34+ isolated from PB as experimen4. Then, protein-protein interaction(PPI) network of DEGs was constructed to identify critical genes. Regulatory impac factors(RIF) was used to identify critical transcription factors(TFs) from the differential co-expression network constructed via re-analyzing the microarray profile from the perspective of differential co-expression. GO(Gene Ontology) enrichmen was performed to extract biological meaning. The comparison among the number of DEGs obtained in the four experiments showed LB cells did not tend to differentiation and CD34+ was more similar to cancer stem cells. Based on the results of PP network, CREBBP, F2 RL1, MCM2 and TP53 were respectively the key genes in experiment 1, 2, 3, and 4. For GO analysis, we found that immune response was the common one in these four stages. Our results might provide a platform for determining the pathology and therapy of AML.

The Influence of IFN-α on Blood Plasmacytoid Dendritic Cell in Chronic Myeloid Leukaemia

OBJECTIVE To study the mechanism of IFN on CML.METHODS Samples of 15 CML patients and 10 healthy controlswere studied. The flow cytometry was performed to identifycirculating pDCs. The concentration of IFN-α in serum and that inthe supernatant of peripheral blood mononuclear cells (PBMCs)cultured after stimulation with CpG ODN2216 were examinedboth in CML patients and in the healthy controlsRESULTS There was significant reduction in the numberof circulating pDCs, serum concentration of IFN-α and thecapacity of IFN-α producing PBMCs in CML patients comparedwith those in healthy control individuals (P < 0.001). After theactive treatment with IFN-α and hydroxyurea, the quantity andfunction of pDCs were increased in stabilized patients, especiallythe function of pDCs in 2 patients achieving major cytogeneticresponse (MCR). The proportion and function of pDCs and theserum levels of IFN were inversely correlated with both WBC andage of the patients with CML, and positively correlated with thestate of the illness.CONCLUSION CML patients had a reduced number anddysfunction of circulating pDCs. The active treatment with IFN inCML patients may be related to the restoration of pDCs.

Successful Treatment of Spontaneous Rupture of the Spleen by Embolization of Splenic Artery in a Patient with Acute Promyelocytic Leukaemia and COVID-19 Infection

Spontaneous rupture of the spleen (SRS) is a rare clinical entity with a potentially poor medical outcome. In most cases, SRS is caused by neoplastic disorder. Acute promyelocytic leukaemia is a rare but important cause of SRS that physicians are required to assess for. We present a 28-year-old woman with APL and COVID-19 pneumonia, who successfully underwent embolisation of the splenic artery for spontaneously occurring splenic rupture during induction chemotherapy. After the intervention the patient completed induction chemotherapy and achieved complete remission. Our case demonstrates that emergent transcatheter arterial embolisation can be lifesaving even in the unfavourable condition of a patient with severe immune deficiency.

Pulmonary Lymphangioleiomyomatosis on a Post-Menopausal Woman with Chronic Lymphocytic Leukaemia

A 62 years old, post-menopausal female was admitted to the Internal Medicine Ward due to dyspnoea, cough and sputum of at least 2 months. Shortness of breath, cough and hypoxaemia persisted and the patient was submitted to a pulmonary angiogram ct which revealed numerous thin-walled air cysts affecting upper and medial zones of both lungs, typical images of pulmonary lymphangioleiomyomatosis. After discharge to Internal Medicine Consultation Service with Metilprednisolone, the patient was no longer hypoxaemic and remained asymptomatic, even after withdrawal of oral corticosteroid to inhalatory formulation. Further surveillance in short time was scheduled in order to implement rapid imunossupressive treatment when necessary.

Cytogenetic Response in Chronic Myeloid Leukaemia Patients Treated with Imatinib Mesylate Homolog-Drugs:6 Year’s Transitional Study

Background: Treatment for Chronic Myeloid Leukaemia (CML) is mainly imatinib mesylate (IM) from original-brand, Glivec? or generic-type homologs, Imatib?. Materials and Methods: A collection of 149 CML patients was treated over a period of 6 years at Hiwa hospital. These patients were clustered into three groups: Group A was treated with Imatib for more than one year. All survivors of group A patients were switched to Glivec, classified as group B. Group C received only Glivec after June 2011. Imatib and Glivec are administered at doses 400-, 600- and 800-mg according to the CML stage. Results: Among group A patients, 68 (60%) were in complete haematological response (CHR), 32 (28.3%) developed acceleration and 13 (11.5%) patients were deceased. After switching to Glivec (group B), 69 (69%) patients remained in CHR, 10 (10%) patients weredeceased and 21 (21%) patients remained in acceleration. Of the 36 patients in group C, 33 (91.7%) were in CHR, 1 (2.8%) were in acceleration and 2 (5.5%) deceased. Those patients with CHR were tested randomly for BCR/ABL by FISH, and only 1/25 (4%) patients were found with complete cytogenetic response (CCyR) in group A, while 31/42 (73.8%) and 13/17 (76.5%) have CCyR in group B and C, respectively. Conclusions: Our results demonstrate a less cytogenetic response to treatment in patients of CML, who received the Imatib therapy, while a significant cytogenetic remission was found in patients with CHR after they switched to Glivec.