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.

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.

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.

Atypical Chronic Myeloid Leukaemia with Trisomy 13: a Case Report

ATYPICAL chronic myeloid leukaemia (aCML),which shows both myeloproliferative and myeIodysplastic features,is a type of myeloproliferative/myelodysplastic disease as defined by the World Health Organisation (WHO) classification of the myeloid neoplasms.1 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.

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.

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.

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.

Gene Expression Pattern of Signal Transduction in Chronic Myeloid Leukemia

To explore the transcriptional gene expression profiles of signaling pathway in Chronic myeloid leukemia （CML）, a series of cDNA microarray chips were tested. The results showed that differentially expressed genes related to singal transduction in CML were screened out and the genes involved in Phosphoinositide 3-kinases （PI3K）, Ras-MAPK （mitogen-activated protein kinase） and other signaling pathway genes simultaneously. The results also showed that most of these genes were up-expression genes , which suggested that signal transduction be overactivated in CML. Further analysis of these differentially expressed signal transduction genes will be helpful to understand the molecular mechanism of CML and find new targets of treatment.

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.

Acute Priapism: A Revealing Inaugural Mode of Chronic Myeloid Leukemia. A Case Report and Review of the Literature

Priapism is a painful and prolonged erection occurring without any sexual stimulation and not resulting in ejaculation. It most often occurs in patients with sickle cell disease. We report here the case of acute recurrent priapism revealing inaugural mode of CML in a 22-year-old patient with no particular pathological history. The study of the onco-hematological karyotype revealed a karyotype with 46 chromosomes with a clonal chromosomal anomaly: The t (9;22) “Philadelphia chromosome”. The evolution was favorable under imatinib.

Horn of plenty:Value of the international registry for pediatric chronic myeloid leukemia

Chronic myeloid leukemia(CML)in minors is a rare disease which can be effectively treated by tyrosine kinase inhibitors(TKIs)since the year 2000.A majority of pediatricians will encounter one or two CML patients in the course of their careers and will typically have to rely on written information along with their own intuition to provide care.Knowledge of response to TKIs and of agespecific side effects has an impact on the design of pediatric CML trials in many ways aiming to contribute toward greater predictability of clinical improvements.Information from a registry on a rare disease like CML offers the enormous benefit of enabling treating physicians to interact and share their collective experience.The International Registry on Pediatric CML(IR-PCML)was founded at Poitiers/France almost 10 years ago.Since then,the number of collaboration centers and in parallel of registered patients continuously increased(>550 patients as of December 2019).Ideally,from a given treatment center in a country data are transferred to a national coordinator who interacts with the IR-PCML.In the sense of quality assurance,the registry can offer dissemination of knowledge on state-of-the-art diagnostics(including reference appraisal),optimal treatment approaches,and follow-up procedures within a network that is exerting its strength via participation.With continuous growth during the recent years,very rare subgroups of patients could be identified(e.g.,CML diagnosed at age<3 years,children presenting with specific problems at diagnosis or during course of treatment)which had not been described before.Publications coming from the IR-PCML disseminated this useful information derived from patients who robustly participate and share information about their disease,among themselves and with their caregivers and clinicians.Patient input driving the collection of data on this rare leukemia is the basis for the considerable success of bringing new therapeutics into clinical use.

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.

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.

MDR1 Haplotypes and G2677T/A Polymorphism Predict Imatinib Response in Tunisian Patients with Chronic Myeloid Leukemia

Background: The role of human multidrug resistance gene (MDR1) SNPs in the interindividual variability of imatinib mesylate (IM) response has received considerable attention. We aimed to study the association between SNPs of the MDR1 gene (C1236T, G2677T/A, C3435T) and IM response in chronic myeloid leukemia (CML) patients. Method: A retrospective case-control study was conducted on 48 patients with CML undergoing IM therapy. All patients were genotyped using PCR-RFLP method. Results: The genotype and allele frequencies of C1236T and C3435T were not significantly different between CML patients responders and non-responders to IM (p > 0.05). The frequencies of 2677T allele and 2677TT genotype were significantly increased in CML patients IM responders which as compared with IM non-responders (50% vs 26.9%, p = 0.013 and 27.3% vs 3.8%, p = 0.029 respectively). Whereas the 2677AA genotype and CAC haplotype were found only in CML patients IM non-responders (15.4%). Conclusion: Pretreatment genotyping of G2677A/T appears to be useful for predicting IM resistance, which may allow the best choice of drug treatment for CML patients.

Priapism secondary to chronic myeloid leukemia treated by a surgical cavernosa-corpus spongiosum shunt: Case report

Priapism secondary to chronic myeloid leukemia(CML)is rarely observed in the clinic.Here,we present an 18-year-old patient with priapism for over 72 h due to hyperleukocytosis.Emergent interventions such as therapeutic aspiration and intracorporal injection of phenylephrine failed before a surgical corpora cavernosa-corpus spongiosum shunt was inserted to relieve symptoms.During hospitalization,bone marrow aspiration confirmed the diagnosis of CML.

Development of plasma cell dyscrasias in a patient with chronic myeloid leukemia:A case report

BACKGROUND Chronic myeloid leukemia(CML)is a clonal hematopoietic stem cell disorder.Plasma cell dyscrasias are a rare heterogeneous group of hematological disorders.The co-occurrence of CML and plasma cell dyscrasias in the same patient is an extremely rare incident and has been reported in several cases in the literature.CASE SUMMARY In the present report,we described a rare case of the co-occurrence of CML and plasma cell dyscrasias in a 48-year-old man,and we discussed the reason why monoclonal gammopathy of undetermined significance progressed to smoldering multiple myeloma and eventually to multiple myeloma while being treated with dasatinib for CML.The tyrosine kinase inhibitor treatment and cytogenetic change may contribute to this phenomenon,and clonal hematopoiesis of indeterminate potential may lead to both CML and multiple myeloma cells in a patient.Future studies are warranted to further explain the hidden reasons.CONCLUSION This case highlights that gene translocation may contribute to initiation and sustainability of clonal proliferation.Moreover,the treatment with tyrosine kinase inhibitor and cytogenetic change may contribute to progression from monoclonal gammopathy of undetermined significance to smoldering multiple myeloma and eventually to multiple myeloma.

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.

About a Case of Chronic Myeloid Leukemia and Pregnancy

Chronic myeloid leukemia (CML) associated with pregnancy is a very rare situation (less than one case per 100,000 pregnancies). It raises a serious ethical and therapeutic problem because chemotherapy during pregnancy can expose the fetus to various complications such as congenital malformations, abortion and intra uterine growth restriction. Inhibitors of tyrosine kinase are the most widely used molecules but without much certainly about their non-teratogenic effects. This is a report case of pregnancy occurring in a patient with Imatinib for CML replaced by Hydrea who gave birth to a healthy newborn with no congenital malformation.

Hematobiological Profile of Patients with Chronic Myeloid Leukemia at the Diagnosis in Yaoundé: A Cross-Sectional Study

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative blood neoplasia, characterized by the presence of a translocation between chromosomes 9 and 22 leading to the formation of the Philadelphia chromosome. Data on the biological profile of patients with CML at diagnosis are still lacking in sub-Saharan Africa, particularly in Cameroon. Methods: A cross-sectional study was carried out from January 2001 to July 2016 among patients recently diagnosed with CML at the Yaounde University Teaching Hospital, the Yaoundé Central Hospital and the Yaoundé General Hospital. Analyzed variables included socio-demographic, clinical presentation, the diagnosis means, biological parameters (hematological and biochemical). Sampling was consecutive. Results: We included 132 (76 males) patients with CML with a median age of 39.2 years at diagnosis. The 31 - 45 years age group was the most represented, with 40.9% of the study population. A risk factor was found in only 5 (3.8%) of patients. Clinical manifestations were recorded in only 27 (20.45%) patients, with fatigue being the commonest (10.6%). Almost all patients (128, 96.9%) have performed the karyotype while 22 (16.7%) have performed fluorescence in situ hybridization (FISH) and 4 (3.0%) the PCR. At diagnosis, 66% of the patients were in the chronic phase (CP), 11.3% in accelerated phase (AP), and 22.7% in blast crisis (BC). All patients presented hyperleukocytosis, with a white blood cell mean of 128,362/mm3. Anemia was common (77.3%), usually moderate (61.4%). Thrombocytopenia was rare (8.3%), as far as basophilia (1.2%). Among those patients, mean values of creatinine, Glutamic pyruvate transaminase (GPT) and glycemia were normal while activated partial thromboplastin time (APTT), prothrombin time (PT), plasma uric acid level, gamma glutamic transferase (GGT), lactate dehydrogenase (LDH), and inflammatory parameters (ESR and CRP) were increased. Conclusion: Patients with CML presented at their diagnosis hyperleukocytosis and anemia as hematological clues. Other biological anomalies include increased signs of cellular destruction (plasma uric acid level, LDH), coagulation perturbation and inflammatory syndrome. The chronic phase of the disease was common.