Feasibility of treatment-free remission with generic imatinib: Results of generic imatinib-free trial-in-chronic myeloid leukaemia chronic phase study

Background & objectives: Both innovator and generic imatinib are approved for the treatment of Chronic Myeloid Leukaemia-Chronic phase (CML-CP). Currently, there are no studies on the feasibility of treatment-free remission (TFR) with generic imatinib. This study attempted to determine the feasibility and efficacy of TFR in patients on generic Imatinib. Methods: In this single-centre prospective Generic Imatinib-Free Trial-in-CML-CP study, twenty six patients on generic imatinib for ?3 yr and in sustained deep molecular response (BCR ABLIS ?0.01% for more than two years) were included. After treatment discontinuation, patients were monitored with complete blood count and BCR ABLIS by real-time quantitative PCR monthly for one year and three monthly thereafter. Generic imatinib was restarted at single documented loss of major molecular response (BCR ABLIS>0.1%). Results: At a median follow up of 33 months (interquartile range 18.7-35), 42.3 per cent patients (n=11) continued to be in TFR. Estimated TFR at one year was 44 per cent. All patients restarted on generic imatinib regained major molecular response. On multivariate analysis, attainment of molecularly undetectable leukaemia (>MR5) prior to TFR was predictive of TFR [P=0.022, HR 0.284 (0.096-0.837)]. Interpretation & conclusions: The study adds to the growing literature that generic imatinib is effective and can be safely discontinued in CML-CP patients who are in deep molecular remission.

Comparison of Clinicopathological Parameters, and Treatment Responses in Younger and Older Chronic Myeloid Leukaemia Patients Treated with Imatinib

@#Introduction: Differences in baseline characteristics and response to treatment in different age groups of patients with chronic myeloid leukaemia (CML) in resource-limited countries have not been extensively studied. We aimed to determine the differences in clinicopathological parameters at diagnosis and response to imatinib in adult CML patients with younger (under 60 years; YCML) and older (60 years and older; OCML) age treated at our institution from March 2001 to March 2021. Methods: A retrospective analysis of consecutive adult CML patients receiving imatinib was performed. Clinicopathological parameters and treatment response were reviewed and analysed using hospital medical records and electronic data reports. Results: The median age at diagnosis was 50 years. OCML patients (n=17) had significantly more comorbidities. The YCML group (n=50) generally had a palpable spleen >5cm from the costal margin, mild anaemia, hyperleukocytosis and thrombocytosis. A starting dose of 400 mg/day was observed in 84% of YCML and in 65% of OCML. Cumulative complete cytogenetic response was 50% in YCML versus 70.6% in OCML, p=0.158. OCML tended to have a higher percentage of major molecular response (MMR) (52.9% versus 32%) and a shorter time to MMR, 22 months (range 5-70) versus 35 months (range 8-53). OCML experienced more haematological and non-haematological treatment-related adverse events after imatinib therapy. Conclusion: Although OCML patients had more comorbidities and treatment intolerances, overall long-term treatment response was comparable to YCML. In OCML, a more personalised approach to initial and subsequent dosing of imatinib may be considered.

Application of HRM Analysis in Detection of PDGFRA Exon 10 Polymorphism in CML Patients with Imatinib Resistance

@#Introduction: Imatinib mesylate has been widely used as a standard treatment for chronic myeloid leukemia (CML). It acts as a selective competitive inhibitor of the BCR-ABL tyrosine kinase. Despite the excellent efficacy on CML treatment, some patients developed resistance to the treatment. Mutation in the PDGFRA may be one of the factors involved in the mechanism of resistance that affects the response to imatinib. The mutational status of PDGFRA is highly relevant for prognosis and treatment prediction in CML patients. Thus, this study is intended to establish and validate a High Resolution Melting (HRM) analysis for PDGFRA exon 10 c.1432 T>C polymorphism in CML patients. Methods: High resolution melting (HRM) analysis was used to identify the c.1432 T > C polymorphism in PDGFRA exon 10 (n =86; response = 43; resistance = 43). The results from HRM analysis were compared and validated with Sanger sequencing. The association between the polymorphism and treatment response was assessed by statistical analysis using binomial logistic regression analysis. Results: HRM analyses showed two different melt curves. One curve followed the shape of the reference, homozygous wild type (TT) and the other curve showed a different melting profile than the reference with the TC genotype (heterozygous variant). The results revealed that heterozygous variant (TC) genotype showed a high risk of acquiring resistance with an OR of 3.795; 95% CI: 1.502-9.591, with a statistically significant association, p = 0.005. HRM analysis also showed 100% sensitivity and specificity in the detection of PDGFRA exon 10. Conclusion: The HRM analysis of PDGFRA exon 10 c.1432 T>C was successfully established. The exon 10 c.1432 T>C polymorphism shows a higher risk for the development of resistance toward imatinib treatment.

H396P mutation in chronic myeloid leukaemia patient on nilotinib – A case report

@#Introduction: The advent of BCR-ABL1-targeted therapy with the tyrosine kinase inhibitor (TKI), for example, imatinib and nilotinib, marked a turning point in the therapy of chronic myeloid leukaemia (CML). However, a substantial proportion of patients experience primary or secondary disease resistance to TKI. There are multifactorial causes contributing to the treatment failure of which BCR-ABL1 kinase domain mutation being the most common. Here, we describe a case of a CML patient with H396P mutation following treatment with nilotinib. Case: A 60-year-old woman presented with abdominal discomfort and hyperleukocytosis. She was diagnosed as CML in the chronic phase with positive BCR-ABL1 transcripts. Due to the failure to obtain an optimal response with imatinib treatment, it was switched to nilotinib. She responded well to nilotinib initially and achieved complete haematological and cytogenetic responses, with undetectable BCR-ABL1 transcripts. However, in 4 years she developed molecular relapse. Mutation analysis which was done 70 months after commencement of nilotinib showed the presence of BCRABL1 kinase domain mutation with nucleotide substitution at position 1187 from Histidine(H) to Proline(P) (H396P). Currently, she is on nilotinib 400mg twice daily. Her latest molecular analysis showed the presence of residual BCR-ABL1 transcripts at 0.22 %. Discussion/conclusion: This case illustrates the importance of BCR-ABL1 mutation analysis in CML patients with persistent BCR-ABL1 positivity in spite of treatment. Early detection and identification of the type of BCRABL1 mutation are important to guide appropriate treatment options as different mutation will have different sensitivity to TKI.

Uncontrolled per rectal bleeding in chronic myeloid leukaemia: a mere coincidence or a dangerous sign report of an unusual case

Bleeding haemorrhoids present commonly to surgical outpatient departments (OPDs) and sometimes in emergency. Most often conservative management suffices but infrequently the patients can land up in emergency operation theatre for uncontrolled bleeding. Some haematological disorders can also present with rectal bleeding and amongst them Chronic myeloid leukaemia (CML), a haematological malignancy, presenting as bleeding per rectum has been not been reported so far, though instances of CML with gingival bleed, epistaxis have been reported. CML per se is known to be asymptomatic (40% cases) and bleeding is rarely seen. Here we present an interesting case of an emergency hemorrhoidal bleed that was subsequently diagnosed as CML. The patient after failed conservative management for bleeding haemorrhoids was taken up for emergency haemorrhoidectomy and again a relook under general anaesthesia in the post-operative period as he continued to ooze. The total leucocyte counts which were initially high continued to rise further and the bone marrow examination was reported as chronic myeloproliferative neoplasm and the excised mass was consistent with haemorrhoids. Rectal bleeding associated with CML is so far unreported even though bleeding is seen due to platelet dysfunction from gums and nose in chronic phases of the disease. A high index of suspicion is needed particularly with deranged haematological parameters for considering a diagnosis of these rare presentations. and anaesthesia.

CYP3A4*18 and CYP3A5*3 Polymorphisms in Modulating Susceptibility Risk in Malaysian Chronic Myeloid Leukaemia Patients

@#CYP3A4 and CYP3A5 are metabolizing enzymes abundantly expressed in liver and involved in the metabolism of xenobiotics as well as clinically used drugs. Genetic polymorphisms in CYP3A4 and CYP3A5 may alter the metabolic ability of individuals. Thus, CYP3A4 and CYP3A5 might play an important role in the aetiology of chronic myeloid leukaemia (CML) and as modulators of cancer therapy response. In this study, the impact of two single nucleotide polymorphisms (SNPs) CYP3A4*18 (878T>C) and CYP3A5*3 (6986A>G) on CML susceptibility risk was investigated. This case-control study involved a total of 520 study subjects comprising 270 CML patients and 250 normal healthy controls. Genotyping of CYP3A4*18 and CYP3A5*3 was performed by polymerase chain reaction – restriction fragment length polymorphism (PCR-RFLP) technique. The association between allelic variants and CML susceptibility risk was assessed by logistic regression analysis, deriving odds ratio (OR) with 95% confident intervals. The results showed that heterozygous (*1/*1*8) genotype of CYP3A4*18 was significantly associated with CML susceptibility risk (OR 3.387; 95% CI: 1.433–8.007, p = 0.005). No homozygous variant (*18/*18) genotype was detected in this study. On the contrary, homozygous variant (*3/*3) and heterozygous (*1/*3) genotypes of CYP3A5*3 were associated with significantly lower risk for CML susceptibility (OR 0.140; 95% CI: 0.079–0.246’ p < 0.001 and OR 0.310; 95% CI: 0.180–0.535, p < 0.001, respectively). The results prompt us to conclude that genetic variation in CYP3A4*18 may contribute to a higher risk whereas CYP3A5*3 polymorphism confers a lower susceptibility risk in Malaysian CML patients.

Paediatric chronic myeloid leukaemia: Is it really a different disease?

Paediatric chronic myeloid leukaemia (CML) has biological and clinical differences from adult CML. Management of paediatric CML presents unique challenges in growing children, and there are no specific guidelines for paediatric CML. This review focusses on the clinical characteristics, diagnostic issues and management of paediatric CML. Major studies that provide the basis of managing paediatric CML are summerized here. Studies conducted on adult CML patients were used to guide the management of places where studies were lacking in paediatric CML. Recently, dasatinib and nilotinib have been approved for treatment of paediatric CML, and their role has been discussed in the current management perspective. Allogeneic transplant, fertility and vaccination in paediatric CML, have also been discussed.

Extramedullary hematopoiesis in ovary: a rare presentation of CML

Extramedullary hematopoiesis (EMH) is a rare phenomenon, and represents infiltration and proliferation of myeloid, erythroid, and megakaryocytic cells in non-bone marrow sites. Extramedullary hematopoiesis (EMH) is normal during fetal life, but after birth, the presence of EMH is considered to be abnormal.  EMH has been associated with CML (chronic myeloid leukaemia). Lymph node is the most common site of involvement, other sites being the abdomen (liver, spleen) and thorax (bone, mediastinum) but very rarely in the gynecological tract. Here authors report a case of a 20-year young female, a known case of CML who presented with abdominal pain with hemoperitonium, with negative urine pregnancy test. Initially hemorrhagic corpus luteal cyst was thought to be the cause of hemoperitonium and patient was taken for surgery wherein histopathology confirmed the diagnosis of extra medullary hematopoiesis of ovary. Women with CML when presents with hemoperitoneum, extramedullary hematopoiesis should be a differential diagnosis apart from rupture ectopic and other causes of spontaneous hemoperitoneum.  Patient was started on imatinib after diagnosis and is doing well.

FISH versus real-time quantitative PCR for monitoring of minimal residual disease in chronic myeloid leukaemia patients on tyrosine kinase inhibitor therapy

@#Introduction: BCR-ABL fusion gene, the oncogenic driver of CML, results from a translocation between short arms of chromosome 9 and 22. Monitoring of CML patients during treatment is essential, not only for tailoring the treatment but also to detect early relapse to enable timely intervention. Commonly used methods for detection of residual disease are conventional karyotyping, FISH and molecular methods. In this study, we compared FISH with QRT-PCR for detection of residual disease in CML. Materials and Methods: CML patients on tyrosine kinase inhibitor (TKI) therapy and on regular follow up at University Kebangsaan Malaysia Medical Center (UKMMC) were selected. A comparative study was conducted between FISH and QRT-PCR for BCR-ABL transcripts at diagnosis and during follow-up. Results: There was good correlation between FISH and QRT-PCR for BCR-ABL. At 6th month of follow-up post diagnosis, FISH had a sensitivity of 83.3% and specificity of 65.2% (k >0.339, p<0.033). At 12th month, the sensitivity of FISH was 83% and the specificity was 59.1% (k >0.286, p <0.065). Similarly, at the 24th month, FISH had a sensitivity of 100% and specificity of 68.8% (k >0.642, p<0.000). Discussion: Early achievement of major molecular response (MMR) and complete cytogenetic remission (CCyR) were reliable predictors of long-term maintenance of molecular remission.

Hematoma intraparenquimatoso del sistema nervioso central asociado con dasatinib en el tratamiento de leucemia mieloide crónica en fase acelerada. Presentación de dos casos y revisión de la literatura / Intraparenchymal haematoma of the central nervous system associated with Dasatinib in the treatment of chronic myeloid leukaemia in accelerated phase. Presentation of two cases and review of literature

Resumen Se presentan dos casos clínicos de pacientes con leucemia mieloide crónica en fase acelerada, hospitalizados para inicio de terapia dirigida con inhibidores de tirosina cinasa (dasatinib). Posteriormente se determina la presencia de sangrado intraparenquimatoso a sistema nervioso central. Para finalizar, se revisa la literatura disponible a cerca de eventos adversos tipo sangrado asociados a dasatinib y los posibles condicionantes de este desenlace.

Abstract Two clinical cases are presented on patients with chronic myeloid leukaemia in accelerated phase, who were admitted to hospital for initiation of targeted therapy with tyrosine kinase inhibitors (Dasatinib). Intraparenchymal bleeding in the central nervous system was subsequently observed. A review was also made on the available literature on bleeding-related adverse events associated with Dasatinib and the possible determining factors of this outcome.

Detección de mutaciones en el dominio tirosina quinasa de BCR-ABL1 en pacientes colombianos con leucemia mieloide crónica LMC, resistentes al imatinib / Detection of BCR-ABL1 tyrosine kinase domain mutations in chronic myeloid leukaemia patients with Imatinib resistance in Colombia

Resumen Introducción: Las mutaciones en el dominio BCR-ABL1, tirosina quinasa (TK) son mecanismos importantes de resistencia de los inhibidores de la tirosina quinasa (ITK) en pacientes con leucemia mieloide crónica (LMC). Objetivo: Determinar el tipo y la frecuencia de las mutaciones en el dominio tirosina quinasa del gen BCR-ABL1, asociadas con falla en la respuesta al tratamiento con imatinib en pacientes con LMC y correlacionar el perfil de mutaciones con los hallazgos clínicos, demográficos, respuesta citogenética y respuesta molecular. Materiales y métodos: Se realizó un estudio descriptivo de tipo prospectivo en pacientes con LMC en tratamiento con IMATINIB a quienes se les realizó cariotipo y análisis de mutaciones del dominio BCR-ABL1 mediante la técnica de PCR anidada. Resultados: De los 23 pacientes estudiados en cuatro se encontraron mutaciones: dos presentaron la mutación E255K, uno presentó la mutación H396P y otro presentó doble mutación L387L y T389P. Las mutaciones E255K que se ubican en la región P-loop y H396P en A-loop se asocian con mal pronóstico. La mutación T389P localizada en la región A-loop no está informada en algunas bases de datos. Conclusiones: En este estudio encontramos cuatro mutaciones en el dominio tirosina quinasa (E255K, H396P, L387L y T389P) que podrían aportar información valiosa y guiar las decisiones de tratamiento. Es importante destacar que esta investigación de análisis mutacional del dominio BCR-ABL es la primera que se realiza en el país con la particularidad adicional de cubrir una población triétnica.

Abstract Mutations in the BCR-ABL1 tyrosine kinase domain mutations, are one of the principal mechanisms associated with tyrosine kinase inhibitors (TKI) resistance in patients with chronic myeloid leukaemia (CML). Objectives: To determine the type and frequency of mutations in the tyrosine kinase domain of the BCR-ABL1 gene associated with failure to respond to treatment with Imatinib and Imatinib in patients with CMK, and to correlate the mutation profile with the clinical and demographic variables, as well as the cytogenetic and molecular response. Materials and methods: A descriptive prospective study was carried out on patients with CML treated with Imatinib. Karyotyping and analysis of the BCR-ABL1 domain mutations were performed on the patients using nested PCR. Results: Four types of mutations were found in the 23 patients studied, of which two of them were the E225 mutation, one with the H396P mutation, another with a double mutation L387L and T389P. Both the E255K mutation located in the P-loop region, and H396P mutation in the A-loop region, are associated with a poor prognosis. The T389P mutation located within A-loop region has not been reported in any of the databases. Conclusions: Four mutations were found in the tyrosine kinase domain (E255K, H396P, L387L and T389P) were found in this study. These findings provide valuable information and as a guideline to help make treatment decisions. It is important to point out that this analytical study on mutations of the BCR-ABL domain is the first one carried out in the country and, specifically, in a tri-ethnic population.

The predictive value of early molecular response in chronic myeloid leukaemia patients treated with imatinib in a single real-world medical centre in a developing country

<p><b>INTRODUCTION</b>The prognosis of patients with chronic myeloid leukaemia (CML) has improved since the introduction of imatinib. However, patients who do not achieve complete cytogenetic response (CCyR) and major molecular response (MMR) have poorer prognosis. Recent clinical trials have demonstrated that early and deeper cytogenetic and molecular responses predict a better long-term outcome. This study aimed to analyse the relationship between early molecular response and clinical outcome in a real-life setting.</p><p><b>METHODS</b>This retrospective study included all patients with CML, in chronic or accelerated phase, who were treated with imatinib at University of Malaya Medical Centre, Malaysia.</p><p><b>RESULTS</b>A total of 70 patients were analysed. The median follow-up duration was 74 months, and the cumulative percentages of patients with CCyR and MMR were 80.0% and 65.7%, respectively. Overall survival (OS) and event-free survival (EFS) at ten years were 94.3% and 92.9%, respectively. Patients who achieved CCyR and MMR had significantly better OS and EFS than those who did not. At six months, patients who had a BCR-ABL level ≤ 10% had significantly better OS and EFS than those who had a BCR-ABL level > 10%. The target milestone of CCyR at 12 months and MMR at 18 months showed no survival advantage in our patients.</p><p><b>CONCLUSION</b>Our data showed that imatinib is still useful as first-line therapy. However, vigilant monitoring of patients who have a BCR-ABL level > 10% at six months of treatment should be implemented so that prompt action can be taken to provide the best outcome for these patients.</p>

Hyperpigmentation of the hard palate mucosa in a patient with chronic myeloid leukaemia taking imatinib / 대한악안면성형재건외과학회지

BACKGROUND: Imatinib mesylate is an inhibitor of the tyrosine kinase Bcr–Abl and a first-line treatment for Philadelphia chromosome-positive chronic myeloid leukaemia (CML). Dermatological side effects include superficial oedema, pustular eruption, lichenoid reactions, erythroderma, and skin rash. Depigmentation of the skin and/or mucosa is uncommon, and hyperpigmentation is rare. CASE PRESENTATION: We present the case of a 63-year-old Caucasian male with widespread hyperpigmentation of the hard palate associated with a 9-year history of imatinib therapy to treat CML. He did not complain of any symptoms. Clinical examination did not reveal any abnormal pigmentation of the skin or other region of the oral mucosa. He did not smoke cigarettes or drink alcohol. His medication regimen was a proton pump inhibitor, a beta-blocker, cardioaspirin, atorvastatin, and imatinib 400 mg/day. Histopathologically, melanin and haemosiderin deposits were evident in the lamina propria. The lesion persisted, with no clinical change, through several follow-ups. We reviewed the literature to explore the possible relationship between oral hyperpigmentation and long-term imatinib mesylate treatment. CONCLUSIONS: We diagnosed oral pigmentation associated with imatinib intake based on the medical history and clinical features of the pigmented macules. Oral pigmentation may have a variety of causes, and differential diagnosis requires nodal analysis. Clinicians should be aware of possible oral mucosal hyperpigmentation in patients taking imatinib mesylate. Such pigmentation is benign and no treatment is needed, but surveillance is advisable.

Dual transcripts of BCR-ABL & different polymorphisms in chronic myeloid leukaemia patients.

Background & objectives: Chronic myeloid leukaemia is (CML) characterized by the presence of a hallmark chromosomal translocation, the Philadelphia chromosome. Although there are many reports available regarding the different variants of BCR-ABL in CML, we studied the co-expression of e13a2 and e14a2 transcripts and a few polymorphisms in CML patients. Methods: Molecular genetics approach was adapted to screen for polymorphisms, mutation and translocation in BCR, ABL kinase domain and BCR-ABL breakpoint region in 73 CML patients. Results: All eight patients with dual transcripts were found to harbour an exonic polymorphism (c.2700 T>C) and an intronic polymorphism (g.109366A>G) that were earlier reported to be associated with co-expression of both the transcripts. We also observed c.763G>A mutation in ABL kinase domain and two polymorphisms, c.2387 A>G and c.2736A>G in the BCR gene. Interpretation & conclusions: Though our data support the previous findings that co-expression of BCR-ABL transcripts is due to the occurrence of exonic and intronic polymorphisms in the BCR gene, it also shows that the intronic polymorphism can arise without the linked exonic polymorphism. The occurrence of ABL kinase domain mutation is less frequent in Indian population.

Queratosis pilar simil asociado a uso de nilotinib / Keratosis pilaris associated with nilotinib use

Nilotinib es un inhibidor altamente selectivo de BCR-ABL tirosina kinasa usado para el tratamiento de Leucemia mieloide crónica. Las reacciones cutáneas fueron uno de los efectos adversos no hematológicos más frecuentemente reportados en relación al uso de esta droga. El presente artículo documenta el caso una paciente femenina de 17 años de edad diagnosticada con Leucemia mieloide crónica que había estado en tratamiento con Nilotinib por 5 meses desarrollando una reacción tipo queratosis pilar. La paciente fue tratada con medidas generales, Urea 15% y antihistamínicos, con cese del prurito. Es importante reconocer las reacciones cutáneas asociadas al uso de Nilotinib para así otorgar alivio oportuno de los síntomas con el fin de lograr una mejor adherencia al tratamiento de la Leucemia mieloide crónica y mejorar la calidad de vida del paciente.

Nilotinib is a highly selective inhibitor of BCR-ABL tyrosine kinase. It is used as a treatment for chronic myelogenous leukemia (CML). Cutaneous reactions are one of the most common non-hematologic reported adverse effects. The present article documents the case of a 17-year-old female patient diagnosed with CML. She was treated with nilotinib for 5 months and developed a keratosis pilaris-like reaction. The patient was treated with general measures, topical 15%-urea and antihistamines with improvement and cessation of pruritus. It is imperative to recognize the cutaneous adverse effects associated with the use of new oncologic treatments such as nilotinib.

Clinical effect of low-dose homoharringtonine and cytarbine with long-course in treating atypical chronic myeloid leukaemia / 中国综合临床

Objective To investigate the therapeutic effect of low-dose and long-course homoharringtonine and cytarbine (HA) in treating atypical chronic myeloid leukaemia (aCML).Methods Twenty-seven patients diagnosed atypical chronic myeloid leukaemia(aCML) from Oct.2003 to May 2014.in the Affiliated Hospital of Logistics University of People's Armed Police Force were divided into treatment and control groups.Fourteen cases in the treatment group were given the chemotherapy of HA (H:1.5 mg/(m2 · d),A:100 mg/(m2· d) for two weeks,and 13 cases in the control group were given the combined therapy of Hydroxycarbamide(1-3 g/d) and recombined human interferon α-2b(3×106U by intramuscular injection every other day) for four weeks.The haemoglobin (Hb) level,the numbers of white blood cell count (WBC) and platelet count(PLT) were measured.Moreover,the clinical effects were evaluated through measured hemogram and myelogram at 4 weeks after treatment.Results The levels of Hb,the numbers of WBC and PLT at before and 1 and 2 weeks in treatment group were as same as those in control group(P＞0.05).While,the numbers of WBC and PLT at 2 weeks,as well as Hb and the numbers of WBC and PLT in 3 weeks,4 weeks in treatment group were significantly different from those in control group (P ＜ 0.05).Furthermore,repeated measurement ANOVA showed that the levels of WBC,Hb,PLT between two groups were significant (F between groups =833.16,145.59,143.11;P＜0.05),and there were significant differences at different time (F between groups =443.92,17.41,149.11;P ＜ 0.05),meanwhile with interaction (F across group =69.77,43.26,75.25;P ＜0.05).In treatment group,there was 8 cases were complete remission,2 cases were partial remission and 4 cases were not released,and the total effective rate 71.4％.While in control group,there were no one was complete remission,2 cases were partial remission and 4 cases were not released,and the total effective rate was 15.4％.And the different was significant (x2 =11.25,P＜ 0.05).Conclusion The therapeutic effect of lowdose and long-course HA in treating atypical chronic myeloid leukaemia is more efficient and practical than traditional treatment.And its side effects are tolerable.

Visual and Auditory Complications of Chronic Myeloid Leukemia: A Case Report.

Hearing loss and visual impairment are not common presentations of Chronic Myeloid Leukemia (CML). We report such a case who presented in the chronic phase with profound hearing loss, visual impairment, progressively enlarging spleen, anaemia, and weight loss. Laboratory evaluation showed Packed Cell Volume – 10%, Total White Cell Count – 1,343 x 109/ L, Platelets – 589 x 109/ L. Blood chemistry showed Uric Acid level of 530mmol/L. Karyotyping showed the Philadelphia chromosome. Chemotherapy was instituted and she improved remarkably with minimal improvement in perception of sound.

Five-year follow-up of patients treated with imatinib mesylate for chronic myeloid leukaemia in Trinidad and Tobago / Pacientes con cinco años de seguimiento tratados con imatinib mesilato por leucemia mieloide crónica en Trinidad y Tobago

OBJECTIVE: Data on the use of Imatinib (IM) in developing countries remain limited. A retrospective study was done to assess the efficacy and toxicity of IM in treating chronic myeloid leukaemia (CML) in Trinidad and Tobago. METHODS: Patients in all phases of CML who started IM therapy between February 2001 and February 2004 were included. All had received other previous therapy. They were assessed for haematological, cytogenetic and molecular response, overall survival (OS), event free survival (EFS) and adverse effects (AE). RESULTS: Twenty-five patients were followed-up for a median 61 months. At initiation ofIM, 18 were in the chronic phase (CP), 3 in accelerated phase (AP), 3 in blast crisis (BC) and one in myelofibrotic transformation (MF). Overall, 96% of patients achieved complete haematological remission (CHR). Among CP patients, 67% attained a major cytogenetic response (MCR) and 44% a complete cyto genetic response (CCR). Overall survival and event free survival in the CP group were 82% and 76% respectively. Overall survival for advanced phase patients was 14% at 61 months The adverse effects of IM were the same as previously described and generally tolerable. No patient opted to discontinue IM because ofside effects. CONCLUSION: After 5 years of follow-up, IM was found to induce favourable and durable survival responses with an acceptable side effect profile in CP-CML patients who had received prior treatment with alternative agents.

OBJETIVO: Los datos sobre el uso de imatinib (IM) en los países en vías de desarrollo, siguen siendo limitados. Se hizo un estudio retrospectivo con el fin de evaluar la eficacia y toxicidad de IM en el tratamiento de la leucemia mieloide crónica (LMC) en Trinidad y Tobago. MÉTODOS: Se incluyeron todos los pacientes -en todas las fases de LMC - que empezaron la terapia de IM entre febrero de 2001 y febrero de 2004. Todos habían recibido otra terapia previamente. Se les evaluó con respecto a su respuesta hematológica, citogenética y molecular, supervivencia global (SG), supervivencia libre de eventos (SLE), y efectos adversos (EA). RESULTADOS: Veinticinco pacientes tuvieron seguimiento por espacio de 61 meses como promedio. En la iniciación de IM, 18 estaban en fase crónica (FC), 3 en la fase acelerada (FA), 3 en crisis blástica (CB) y uno en transformación mielofibrótica (MF). En general, 96% de los pacientes lograron la remisión hematológica completa (RHC). Entre los pacientes de CF, 67% lograron una repuesta citogénica mayor (RCM) y 44% una respuesta citogénica completa (RCC). La supervivencia global (SG) y la supervivencia libre de eventos (SLE) en el grupo FC fueron 82% y 76% respectivamente. La supervivencia global para los pacientes en fase avanzada fue de 14% en 61 meses. Los EA de IM fueron los mismos previamente descritos, y eran generalmente tolerables. Ningún paciente optó por discontinuar IM debido a efectos adversos. CONCLUSIÓN: Después de 5 años de seguimiento, se halló que IM induce respuestas de supervivencia favorables y duraderas en los pacientes de LMC-FC previamente tratados, con un perfil aceptable de efectos colaterales.

New drugs in the treatment of chronic myeloid leukaemia / Novas drogas no tratamento da leucemia mielóide crônica

The introduction of the BCR-ABL kinase inhibitor, imatinib mesylate (Gleevec®, Novartis) led to significant changes in the treatment of chronic myeloid leukaemia (CML) patients. However, despite the impressive percentage of responding patients, some CML cases, particularly those in advanced phases of the disease, show primary resistance or relapse after the initial response. The second-generation BCR-ABL inhibitors nilotinib (Tasigna®, Novartis) and dasatinib (Sprycel®, Bristol-Myers Squibb) have shown significant activity in clinical trials in patients who failed imatinib therapy, but these agents are still incapable of inhibiting the T315I mutant of Bcr-Abl and present partial activity in advanced phases of CML. The acquired biological notions of the mechanisms of tyrosine kinase inhibitor (TKI) resistance has led to the development of new compounds, some of which have shown encouraging preliminary results in clinical trials, even against T315I mutants. In this paper we discuss the new emerging therapies which may overcome TKI resistance in CML patients.

A introdução do inibidor de tirosino quinase BCR-ABL mesilato de imatinibe (Glivec®, Novartis) levou a significantes mudanças no tratamento da LMC. Entretanto, a despeito de impressionante porcentagem de pacientes que respondem, alguns casos de LMC, particularmente em fases avançadas da doença mostram resistência primaria ou recidivas após terapêutica inicial. Inibidores de tirosino quinases de segunda geração como o nilotinibe (Tasigna®, Novartis) e o dasatinibe (Sprycel®, Bristol Myers Squibb) têm mostrado significante atividade nos estudos clínicos em paciente onde o imatinibe falhou. Porém, estes agentes não são capazes de inibir a mutação T315I do Bcr-Abl e apresentam atividade parcial em fases avançadas da LMC. As noções biológicas adquiridas sobre os mecanismos de resistência aos inibidores de TK levaram ao desenvolvimento de novos compostos alguns dos quais têm resultados preliminares encorajadores incluindo a mutação T315I. Neste trabalho nós discutimos os novos agentes emergentes e qual o potencial poderão atingir para ultrapassar a resistência aos inibidores de TK em pacientes com LMC.

Probability Prediction in Multistate Survival Models for Patients with Chronic Myeloid Leukaemia / 华中科技大学学报（医学）（英德文版）

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 afterrelapse 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.