Real-world Imatinib Mesylate Treatment in Patients with Chronic Myeloid Leukemia: The Importance of Molecular Monitoring and the Early Molecular Response.

INTRODUCTION: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome. After the introduction of imatinib mesylate (IM) in 2000, the natural history of the disease changed. Data on the treatment of CML with IM are from randomized clinical trials. Establishing whether these results can be reproduced or if caution is needed when extrapolating data to the general population with CML is essential. OBJECTIVES: To evaluate the molecular response (MR) in patients with chronic-phase CML (CML-CP) not included in clinical studies and correlate them with the responses obtained in clinical trials. METHODS: Between January 2007 and January 2017, 227 patients newly diagnosed with CML-CP treated with IM as first-line treatment were included. This study is an observational, retrospective, and single-center study. RESULTS: At a median follow-up time of 7.3 years, 60.3% of the 227 patients who started IM were still on IM. Early molecular response (EMR) at 3 and 6 months was achieved by 74.2% and 65%, respectively. The median time to a MMR was nine months. The MR4.0 and MR4.5 were 67.2% and 51.1%, respectively. The overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of the patients who exclusively used IM were 91%, 91%, and 85.1%, respectively. CONCLUSION: The results presented are similar to those described in prospective and randomized trials, demonstrating that the outcomes are reproducible in the real world. EMR at 3 and 6 months reflects better long-term responses, including higher rates of deeper molecular responses. Considering treatment costs, the absence of literature evidence of an impact on overall survival demonstrated by first-line second-generation tyrosine kinase inhibitors (TKIs), and the global OS of 85.8%, imatinib mesylate (IM) is still an excellent therapeutic option.

Pro-adherence complementary audiovisual educational intervention model for chronic myeloid leukemia patients treated with imatinib mesylate.

BACKGROUND: Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. OBJECTIVE: To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. METHODS: Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. RESULTS: Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. CONCLUSION: Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence.

Reacción adversa a medicamento con signos cutáneos (erupción liquenoide) atribuibles a imatinib, y respuesta favorable al tratamiento con fototerapia UVB de banda angosta / Adverse drug reaction with skin signs (lichenoid rash) attributable to imatinib, and favorable response to treatment with narrowband UVB phototherapy

Resumen El imatinib es un agente antineoplásico que actúa como inhibidor de la tirosina-cinasa. Los efectos adversos cutáneos son, en general, leves y autolimitados. Dentro de estos, la erupción liquenoide es infrecuente y suele mejorar sólo con tratamiento tópico. Presentamos el caso de una paciente con erupción liquenoide por imatinib refractaria al tratamiento con corticoides tópicos, con respuesta favorable a terapia de luz ultravioleta B de banda estrecha. No existen casos publicados a la fecha en la literatura de erupción liquenoide por imatinib tratada con fototerapia.

Abstract Imatinib is an antineoplastic agent that acts as a tyrosine kinase inhibitor. Cutaneous adverse effects are generally mild and self-limited. The lichenoid eruption due to imatinib is rare. It usually improves just with topical treatment. We present the case of a patient with a lichenoid reaction due to imatinib, refractory to treatment with topical corticosteroids, with a favorable response to narrow-band ultraviolet B phototherapy. There are no published cases to date in the literature of lichenoid eruption due to imatinib treated with phototherapy.

Imatinib Mesylate for the Treatment of Canine Mast Cell Tumors: Assessment of the Response and Adverse Events in Comparison with the Conventional Therapy with Vinblastine and Prednisone.

Mast cell tumors (MCTs) are common neoplasms in dogs, and treatments for these diseases include surgery, polychemotherapy and targeted therapy with tyrosine kinase inhibitors. This study aimed to evaluate the response and the adverse events of treatment with imatinib mesylate (IM) compared to conventional therapy using vinblastine and prednisolone (VP) in canine cutaneous MCTs. Twenty-four dogs were included in the study; 13 animals were treated with IM and 11 with VP. Tumor tissue samples were submitted for histological diagnosis, grading and KIT immunostaining. The response to treatment was assessed by tomographic measurements according to VCOG criteria. Adverse events were classified according to VCOG-CTCAE criteria. The IM and VP groups had dogs with similar breeds, gender, ages, MCT localization, WHO stages and lymph node metastasis profiles. Most MCTs were grade 2/low and had KIT- patterns 2 and 3. The objective response rate (ORR) was significantly higher (30.79%) in the IM group then in VP group (9.09%). Adverse events (AE) in IM group were all grade 1, significantly different from VP. In conclusion, IM presented better ORR and less severe adverse events when compared to VP, representing a suitable option for the treatment of low-grade canine MCTs.

Gastrointestinal stromal tumor: outcomes of the past decade in a reference institution in southern brazil / Tumor estromal gastrointestinal (gist): resultados da última década em uma instituição de referência no sul do brasil

ABSTRACT - BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract and has a wide variation in biological behavior; surgical resection remains the main form of treatment. AIM: This study aimed to analyze clinicopathological characteristics and survival of patients with GIST in a reference institution for oncological diseases. METHODS: An observational, longitudinal, and retrospective study of patients diagnosed with GIST from January 2011 to January 2020 was carried out by analyzing epidemiological and clinical variables, staging, surgical resection, recurrence, use of imatinib, and curves of overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 38 patients were included. The majority (58%) of patients were males and the median age was 62 years. The primary organs that were affected by this tumor were stomach (63%) and small intestine (17%). Notably, 24% of patients had metastatic disease at diagnosis; 76% of patients received surgical treatment and 13% received neoadjuvant treatment; and 47% of patients received imatinib as adjuvant or palliative therapy. Tumor recurrence was 13%, being more common in the liver. The 5-year OS was 72.5% and DFS was 47.1%. The operated ones had better OS (87.1% vs. 18.5%) and DFS (57.1% vs. 14.3%) in 5 years. Tumor size ≥5 cm had no difference in OS at 5 years, but DFS was 24.6%, when compared with 92.3% of smaller tumors. Patients who were undergoing neoadjuvant therapy and/or using imatinib did not show any significant differences. CONCLUSIONS: Surgical treatment with adequate margins allows the best gain in survival, and the use of imatinib in more advanced cases has prognostic equity with less advanced-stage tumors. Treatment of metastatic tumors seems promising, requiring further studies.

RESUMO - RACIONAL: O Tumor estromal gastrointestinal (Gastrointestinal stromal tumor - GIST) é a neoplasia mesenquimal mais comum do trato digestivo, possui comportamento biológico variado e a principal forma de tratamento é a ressecção cirúrgica. OBJETIVO: analisar as características clínico-patológicas e a sobrevida de pacientes com GIST em uma instituição de referência para doenças oncológicas. MÉTODOS: Foi realizado um estudo observacional, longitudinal e retrospectivo de pacientes com diagnóstico de GIST de janeiro de 2011 a janeiro de 2020, analisando variáveis epidemiológicas e clínicas, estadiamento, ressecção cirúrgica, recidiva, uso de imatinibe e curvas de sobrevida global (SG) e sobrevida livre de doença (SLD). RESULTADOS: foram incluídos 38 pacientes, a maioria (58%) do sexo masculino, idade mediana de 62 anos. Os principais órgãos primários foram estômago (63%) e intestino delgado (17%). 24% tinham doença metastática ao diagnóstico. 76% receberam tratamento cirúrgico e 13% tratamento neoadjuvante. 47% dos pacientes receberam Imatinib como terapia adjuvante ou paliativa. A recorrência tumoral foi de 13%, mais comum no fígado. SG de 5 anos foi de 72,5% e SLD 47,1%. Os operados tiveram melhor SG (87,1% vs. 18,5%) e SLD (57,1% vs. 14,3%) em 5 anos. O tamanho do tumor igual ou maior que 5 cm não teve diferença na SG em 5 anos, mas SLD foi de 24,6%, em comparação com 92,3% dos tumores menores. Pacientes em terapia neoadjuvante e/ou em uso de imatinibe não apresentaram diferenças significativas. CONCLUSÕES: O tratamento cirúrgico com margens adequadas permite o melhor ganho de sobrevida, e o uso de Imatinibe em casos mais avançados tem equidade prognóstica com tumores em estágio menos avançado. O tratamento de tumores metastáticos parece promissor, necessitando de mais estudos.

MiR-125a-3p and MiR-320b Differentially Expressed in Patients with Chronic Myeloid Leukemia Treated with Allogeneic Hematopoietic Stem Cell Transplantation and Imatinib Mesylate.

Chronic myeloid leukemia (CML), a hematopoietic neoplasm arising from the fusion of BCR (breakpoint cluster region) gene on chromosome 22 to the ABL (Abelson leukemia virus) gene on chromosome 9 (BCR-ABL1 oncogene), originates from a small population of leukemic stem cells with extensive capacity for self-renewal and an inflammatory microenvironment. Currently, CML treatment is based on tyrosine kinase inhibitors (TKIs). However, allogeneic hematopoietic stem cell transplantation (HSCT-allo) is currently the only effective treatment of CML. The difficulty of finding a compatible donor and high rates of morbidity and mortality limit transplantation treatment. Despite the safety and efficacy of TKIs, patients can develop resistance. Thus, microRNAs (miRNAs) play a prominent role as biomarkers and post-transcriptional regulators of gene expression. The aim of this study was to analyze the miRNA profile in CML patients who achieved cytogenetic remission after treatment with both HSCT-allo and TKI. Expression analyses of the 758 miRNAs were performed using reverse transcription quantitative polymerase chain reaction (RT-qPCR). Bioinformatics tools were used for data analysis. We detected miRNA profiles using their possible target genes and target pathways. MiR-125a-3p stood out among the downregulated miRNAs, showing an interaction network with 52 target genes. MiR-320b was the only upregulated miRNA, with an interaction network of 26 genes. The results are expected to aid future studies of miRNAs, residual leukemic cells, and prognosis in CML.

Quimioterapia intensiva asociada a imatinib en leucemia linfoblástica aguda del adulto, Philadelphia positivo. Experiencia en un hospital público / Intensive chemotherapy with tyrosine kinase inhibitors in philadelphia-positive acute lymphoblastic leukemia

Background: Before the advent of tyrosine kinase inhibitors (TKIs), patients with Philadelphia-positive Acute Lymphoblastic Leukemia (Ph+ALL) had a poor prognosis. The association of TKIs to intensive chemotherapy (CT) improved outcome. Aim: To evaluate results of an intensive CT protocol including TKI in a public hospital in Santiago, Chile. Material and Methods: All patients with Ph+ALL diagnosed between January 2010 and February 2019, and who met inclusion criteria for intensive CT, received the Ph+ALL national protocol in association with imatinib and were included in this analysis. Results: Thirty-five patients aged 15 to 59 years received treatment. Complete response (CR) was obtained in 97%. Measurable residual disease (MRD) was negative in 61% (19/31 evaluable cases) during follow-up, and 55% (16/29) were MRD (-) before three months. Relapse was observed in 13 cases. Three patients underwent allogeneic hematopoietic stem cell transplant (HSCT), two in CR1. The overall survival (OS) and event-free survival (EFS) at three years were 52 and 34%, respectively. In patients who achieved MRD negativity before three months, no statistically significant differences in OS (64 and 42% respectively, p = 0.15) or EFS (35 and 32% respectively, p = 0.37) were observed. Conclusions: The prognosis of Ph+ALL improved with the association of imatinib to intensive CT. MRD-negative status before three months in this series was not significantly associated with better outcomes. Our series suggests that the Ph+ALL national protocol associated to TKI is a therapeutic alternative with high CR and aceptable MRD (-) rates.

Combined Therapy of ATRA and Imatinib Mesylate Decreases BCR-ABL and ABCB1/MDR1 Expression Through Cellular Differentiation in a Chronic Myeloid Leukemia Model.

BACKGROUND/AIM: Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disease, and a major challenge for the eradication of CML is to understand the cause of the permanence of minimal residual disease (DRM). This work aimed to induce the maturation of leukemic stem cells with All-trans-retinoic acid (ATRA), making them sensitive to treatment with Imatinib (IM). MATERIALS AND METHODS: K562 cells were treated with IM and with the combined therapy of ATRA together with IM for 48 and 72 h. The expression of BCR-ABL gene and multidrug resistance gene ABCB1 were evaluated using RT-qPCR. RESULTS: The combined ATRA and IM therapy showed a discreet cell differentiation pattern, evidenced by the panoptic morphology analysis at 48 and 72 h of treatment. The BCR-ABL expression showed no statistical difference when treated alone with IM, however in combination with ATRA, the expression was statistically significant in 48 and 72 h (p≤0.0001) and when the treatment groups were compared to each other (p≤0.001). The ABCB1 gene expression showed a decrease in isolated IM therapy (p≤0.05) and in the combination in 48 and 72 h (p≤0.0001). CONCLUSION: Combined ATRA and IM therapy was shown to be effective in decreasing BCR-ABL and ABCB1 genes, possibly through the differentiation of blast cells, demonstrating that the therapy could be potentially effective in the blast crisis of the disease and for those patients who develop resistance to available CML treatments.

Renal tuberculosis in an imatinib-treated chronic myeloid leukemia / Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

[Jejunal gastrointestinal stromal tumor (GIST): clinical case]. / Tumor del estroma gastrointestinal (GIST) de yeyuno: caso clínico.

Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. It is exposed a clinical case of jejunal GIST from a second-level hospital in Mexico. Clinical case: Female patient of 76 years, with history of tobacco use (two cigarettes per day for 25 years), that is referred to General Surgery due to a four month evolution of symptoms, characterized by abdominal pain, hyporexia and urinary symptomatology. Physical examination revealed a non-pulsatile, solid, non-mobile, non-painful mass in the hypogastrium and right iliac fossa of approximately 15 cm in length. Ovarian tumor was ruled out, since CEA and CA-125 tumor markers were negative. Abdominopelvic ultrasound was performed and reported a solid tumor with cystic spaces inside. CT reported a solid tumor of 9.5 x 2.5 x 8.3 cm, with defined edges, multilobed, presence of some calcifications in its wall that did not show enhancement with the use of contrast media. Patient underwent exploratory laparotomy and it was found a jejunal tumor, 210 cm from the ligament of Treitz. Immunohistochemistry reported positivity to KIT and DOG1, confirming the diagnosis of GIST. Conclusion: GISTs are uncommon entities. Their clinical presentation is insidious and the preoperative diagnosis is complex due to the need for biopsy. The treatment is surgery, but tyrosine kinase inhibitors should be administered. Even in patients with response to treatment, follow-up is mandatory due to the risk of recurrence.

Introducción: los tumores del estroma gastrointestinal (GIST) son los tumores mesenquimatosos más comunes del tracto gastrointestinal. Se expone un caso clínico de GIST en yeyuno que se presentó en un hospital de segundo nivel en México. Caso clínico: femenino de 76 años, con antecedente de tabaquismo (dos cigarros diarios durante 25 años), referida a Cirugía General por cuadro de cuatro meses de evolución (dolor abdominal tipo cólico en hipogastrio, hiporexia y sintomatología urinaria). A la exploración física, se le detectó tumor no pulsátil, sólido, no móvil, no doloroso, adherido a planos profundos en hipogastrio y fosa ilíaca derecha de aprox. 15 cm de longitud. Se descartó tumor ovárico al resultar negativos los marcadores tumorales ACE y CA-125. Se realizó ultrasonido abdominopélvico que reportó imagen de tumoración sólida con zonas quísticas en su interior. La TC reportó tumoración sólida, de bordes definidos, multilobulada con algunas calcificaciones milimétricas en su pared de 9.5 x 2.5 x 8.3 cm y sin realce al administrar medio de contraste. La paciente se sometió a laparotomía exploradora y se encontró tumoración adherida a yeyuno a 210 cm del ligamento de Treitz. El tumor fue positivo a KIT y DOG1, lo que confirmó el diagnóstico de GIST de patrón fusiforme. Conclusión: los GIST son poco frecuentes. Su presentación clínica es insidiosa y el diagnóstico preoperatorio es complejo debido a la toma de biopsia. El tratamiento continúa siendo la cirugía, pero se deben administrar inhibidores de la tirosina cinasa. Incluso en pacientes con respuesta favorable al tratamiento, se recomienda seguimiento por riesgo de recidiva.

Hipofosfatemia inducida por drogas: fierro carboximaltosa e imatinib. Casos clínicos / Hypophosphatemia induced by carboxymaltose iron and imatinib. Report of two cases

Hypophosphatemia is a relatively frequent and a potentially serious adverse drug effect. Clinically it is characterized by bone pain and muscle weakness. There are several mechanisms by which a drug can induce hypophosphatemia and they can be classified according to whether or not they are mediated by an excess of Fibroblast Growth Factor 23 (FGF23). We report two patients with the condition: (i) A 49-year-old woman with Chronic Myeloid Leukemia (CML) and gastric sleeve surgery at 46 years of age. After receiving intravenous carboxymaltose iron in one occasion due to refractory anemia, she developed symptomatic hypophosphatemia. Urinary phosphate losses associated with high FGF23 levels were confirmed. Plasma phosphate returned to normal values 90 days after the iron administration. (ii) A 40-year-old man with a history of CML in whom imatinib was started. He developed symptomatic hypophosphatemia due to non FGF23-mediated hyperphosphaturia. As treatment with imatinib could not be interrupted, hypophosphatemia and its symptoms resolved with oral phosphate intake. These cases illustrate the importance of recognizing and treating drug-induced hypophosphatemia in a timely manner, and thus avoid the morbidity associated with this entity.

Imatinib mesylate affects extracellular ATP catabolism and expression of NTPDases in a chronic myeloid leukemia cell line.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the occurrence of the t(9;22)(q34;q11) translocation. First-line therapy for CML consists of treatment with imatinib mesylate, which selectively inhibits the BCR-ABL protein by competing for its ATP-binding site. Adenine nucleotide signaling is modulated by the ectonucleotidases and this pathway is related to tumorigenic processes. Considering the relationship between ATP and cancer, we aimed to evaluate the influence of imatinib mesylate on the expressions and functions of the NTPDase and ecto-5'-nucleotidase (CD73) enzymes in imatinib-sensitive and -resistant K-562 cell lines. mRNA analysis showed that K-562 cells express all ENTPDs and NT5E. However, when treated with imatinib mesylate for 24 h, the expression of ENTPD1, -2, -3 and -5 increased, leading to a higher nucleotides hydrolysis rate. HPLC analysis identified increased ATP degradation in cells after 24 h of treatment, with consequent ADP and AMP formation, corroborating the increase in gene and protein expression of ectonucleotidases as observed in previous results. On the other hand, we observed that imatinib-resistant K-562 cells presented a decrease in nucleotide hydrolysis and expressions of ENTPD1 and -5. These results suggest an involvement of imatinib in modulating ectonucleotidases in CML that will need further investigation. Since these ectonucleotidases have important catalytic activities in the tumor microenvironment, their modulation in CML cells may represent an important therapeutic approach to regulate levels of extracellular adenine nucleotides.

Development and validation of highly selective method for the determination of imatinib mesylate and dexketoprofen trometamol combination in three different media

Imatinib mesylate is a small molecule used in cancer therapy as a thyrosine kinase inhibitor. Dexketoprofen trometamol is a non-steroidal anti-inflammatory drug that has seen use in cancer therapy in combination with an anticancer drug to minimize tumor size and to reduce pain in patients. In the present study, imatinib mesylate and dexketoprofen trometamol were selected as potential model drugs to be used in combination. A new, simple and selective Ultra Performance Liquid Chromatography method was developed and validated to determine the drug substances in distilled water, in a pH 7.4 phosphate buffer and in Dulbecco's Modified Eagle Medium. The proposed method was developed using a BEH C-18 column with isocratic elution. A mixture of methanol:acetonitrile (80:20, v/v) and pH 9.5, 0.05 M ammonium acetate were (70:30, v/v) used as a mobile phase. Detection was carried out with a flow rate of 0.3 mL/min, a column temperature of 30°C and an injection volume of 20 µL. The method was validated considering linearity, accuracy, precision, specificity, robustness, detection limit and quantitation limit values, and was found to be linear in a range from 0.05 to 20.0 µg/mL for the three different media

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

ABSTRACT Objective: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. Methods: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. Results: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p < 0.01). Decreased overall survival was associated with advanced-phase disease (p < 0.01), failure to achieve major molecular response in first-line treatment (p < 0.01) and interruption of first-line treatment due to any reason (p = 0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. Conclusion: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

What happens to intolerant, relapsed or refractory chronic myeloid leukemia patients without access to clinical trials?

OBJECTIVE: To assess clinical outcomes of intolerant, relapsed or refractory patients who could not be treated with new tyrosine kinase inhibitors or experimental therapies. METHODS: A retrospective cohort of 90 chronic myeloid leukemia patients in all phases of the disease treated with imatinib mesylate as their first TKI therapy, and with dasatinib or nilotinib as the next line of therapy. We evaluated clinical outcomes of these patients, with special focus on the group that needed more than two therapy lines. RESULTS: Thirty-nine percent of patients were refractory or intolerant to imatinib. An 8-year overall survival rate of the patients who went through three or more lines of treatment was significantly lower, compared to those who were able to maintain imatinib as their first-line therapy (83% and 22%, respectively p<0.01). Decreased overall survival was associated with advanced-phase disease (p<0.01), failure to achieve major molecular response in first-line treatment (p<0.01) and interruption of first-line treatment due to any reason (p=0.023). Failure in achieving complete cytogenetic response and major molecular response and treatment interruption were associated with the progression to the third-line treatment. CONCLUSION: The critical outcome observed in relapsed, intolerant or refractory chronic phase CML patients reflects the unmet need for this group of patients without an alternative therapy, such as new drugs or experimental therapies in clinical trials. Broader access to newer treatment possibilities is a crucial asset to improve survival among CML patients, especially those refractory or intolerant to first-line therapies.

Association of oral mucosa hyperpigmentation with imatinib mesylate use: a cross-sectional study and a systematic literature review.

OBJECTIVES: To assess the association between oral mucosa hyperpigmentation in patients with leukemia and imatinib mesylate use. Additionally, we compared our data to those obtained from a systematic review. MATERIALS AND METHODS: A cross-sectional study was conducted with 74 patients undergoing treatment with imatinib mesylate. Sociodemographic characteristics, oral mucosa alterations, and medical history were evaluated. Oral hyperpigmentation was scored. The use of imatinib mesylate and hydroxyurea was evaluated. Association between oral hyperpigmentation and imatinib mesylate was assessed. A systematic review was also conducted to retrieve case reports or case series of patients with oral hyperpigmentation associated with imatinib mesylate. RESULTS: Among the 74 participants, 41 were male (55.4%) and 33 were female (44.6%). Participants' mean age was 49.3 years. Sixty-six (89.2%) patients developed hyperpigmented lesions in the hard palate mucosa. In multivariate analysis, patients who had used imatinib mesylate for > 72 months had a hyperpigmentation score 1.62 times higher than those who had used this medication during a shorter period. Patients who had used hydroxyurea for > 30 days had a hyperpigmentation score 1.43 times higher than those who had used this medication during a shorter period. The systematic review retrieved 20 clinical cases of patients undergoing imatinib mesylate treatment and exhibiting oral hyperpigmentation. CONCLUSIONS: The development of oral hyperpigmentation is associated with imatinib mesylate use. Hydroxyurea seems to increment such an association. CLINICAL RELEVANCE: To assist providers in the differential diagnosis of hyperpigmented lesions associated with imatinib mesylate, as well as in the clinical management of such lesions.

Tumores del estroma gastrointestinal / Gastrointestinal stromal tumors

Los tumores del estroma gastrointestinal (GIST) son neoplasias mesenquimales originadas en el tracto gastrointestinal. Su localización más frecuente es en estómago e intestino delgado. Pueden originarse a cualquier edad, pero más del 80% de los casos son mayores de 50 años sin predilección de sexo, aunque puede observarse en pacientes más jóvenes asociados a síndromes que predisponen el desarrollo de estos tumores. Presentan sintomatología inespecífica. La tomografía axial computarizada está recomendada para realizar el estudio de extensión y seguimiento de estos pacientes. Los marcadores inmunohistoquímicos más sensibles y específicos son el KIT y DOG1. El tratamiento en caso de lesiones primarias localizadas es la resección quirúrgica, con o sin terapia adyuvante con imatinib durante 3 años en dependencia del riesgo de recidiva. En los casos avanzados o metastásicos se recomienda terapia neoadyuvante con imatinib por tiempo indefinido; el tratamiento en casos de progresión o intolerancia a imatinib es el sunitinib.

Gastrointestinal stromal tumors (GIST) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine. GISTs can arise at any age, but more than 80% are reported in individuals older than 50 years men and women are affected at a roughly similar frequency. The few patients are who younger frequently have GIST associated with a syndrome. The clinical manifestations are non-specifics. The computer-tomography is recommended for staging and follow-up. The KIT and DOG1 are the most sensitive and specific immunohistochemistry markers. The standard treatment of localized GIST is complete surgical excision of the lesion, with or without adjuvant imatinib in dependence with the relapse risk. Neoadjuvant imatinib is the standard treatment for locally advanced and metastatic disease. In locally advanced and metastatic disease the imatinib treatment should be continued indefinitely. Following confirmed progression, or intolerance, to imatinib the standard second-line treatment is sunitinib.

Circulating microRNAs expression profile in newly diagnosed and imatinib treated chronic phase - chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is a stem cell derived malignant disorder result of translocation t(9;22)(q34;q11) called Philadelphia chromosome (Ph+). microRNAS (miRNAs) are involved in several biological processes, altering the progression of various pathologies, including CML. This study evaluated whether circulating miRNAs display differential expression profiles in peripheral blood of CML-Chronic Phase (CML-CP) patients newly diagnosed in comparison with CML-CP treated with imatinib. We obtained peripheral blood samples from CML-CP Ph+ patients divided among group 1 (untreated newly diagnosed) and group 2 (treated with imatinib). A pool of total leukocytes from healthy donors was considered as control group. Expression analyses were performed for 768 miRNAs by RT-qPCR array. Bioinformatic tools were used to identify significant pathways and interaction networks. We found 80 deregulated miRNAs between the groups and, according to bioinformatic analysis, they are involved in different pathways, including molecular mechanisms of cancer. The study allows better understanding of disease molecular behavior, and it is useful for possible monitoring CML treatment and prognostic biomarkers identification.

Associação entre a hiperpigmentação da mucosa oral com o uso de mesilato de imatinibe: estudo transversal e revisão sistemática da literatura / Association of oral mucosa hyperpigmentation with imatinib mesylate use: a cross-sectional study and a systematic literature review

As lesões hiperpigmentadas são comumente observadas em mucosa oral. Apesar de, frequentemente, apresentarem características clínicas semelhantes, essas lesões apresentam etiopatogenias e diagnósticos distintos. Dessa forma, para o diagnóstico correto, é necessária a investigação sobre o histórico médico do paciente, uso de fármacos, além de exame clínico e eventualmente biópsia. Uma série de medicamentos podem causar pigmentações na mucosa oral. A patogênese dessa pigmentação pode variar dependendo do agente causal. Quimioterápicos como o Mesilato de Imatinibe, empregado no tratamento da leucemia mieloide crônica e da leucemia linfoblástica aguda pH+, pode estar associado ao desenvolvimento de lesões orais hiperpigmentadas principalmente em região de palato duro. O objetivo desse estudo foi avaliar a associação entre hiperpigmentação da mucosa oral em pacientes com leucemia e em uso do fármaco Mesilato de Imatinibe. Além disso, objetivamos comparar nossos dados com aqueles obtidos de uma revisão sistemática da literatura. O estudo foi aprovado pelo Comitê de Ética em Pesquisa da Universidade Federal de Minas Gerais sob CAAE número 48317515.6.0000.5149. Um estudo transversal foi conduzido com 74 pacientes submetidos ao tratamento com o Mesilato de Imatinibe. As características sociodemográficas, história clínica dos pacientes e dados a respeito do uso dos fármacos adotados durante o tratamento da leucemia foram coletados. Além disso, foi realizado um exame clínico intra-oral e registro fotográfico da região de palato duro. A associação entre o uso do Mesilato de Imatinibe e a presença de lesões orais hiperpigmentadas foi investigada. Análise descritiva, análise bivariada e análise multivariada (regressão de Poisson) foram realizadas. Na regressão de Poisson, intervalos de confiança (IC) foram fornecidos. Uma revisão sistemática da literatura foi conduzida nas principais bases de dados com o objetivo de recuperar relatos de casos ou séries de casos de pacientes em uso do Mesilato de Imatinibe e que desenvolveram lesões hiperpigmentadas em mucosa oral. Entre os 74 participantes, 41 eram do sexo masculino (55,4%) e 33 do sexo feminino (44,6%). A idade média dos indivíduos foi de 49,3 anos. Sessenta e seis (89,2%) pacientes desenvolveram lesões hiperpigmentadas em mucosa oral. Na análise multivariada em que foi empregada a regressão de Poisson, os pacientes que usaram o Mesilato de Imatinibe por mais de 72 meses tiveram um escore de hiperpigmentação 1,62 (1.12 ­ 2.33 95% IC) vezes maior do que aqueles que usaram este medicamento durante um período mais curto. Pacientes que usaram Mesilato de Imatinibe associado à Hidroxiuréia por um período superior a 30 dias tiveram um escore de hiperpigmentação 1,43 (1.02 ­ 2.01 95% IC) vezes maior do que aqueles que usaram este medicamento durante um período inferior. A revisão sistemática da literatura recuperou 20 casos clínicos de pacientes submetidos ao tratamento com Mesilato de Imatinibe e exibindo lesões hiperpigmentadas na mucosa bucal. Com base na análise desses dados foi possível concluir que o desenvolvimento de lesões orais hiperpigmentadas está associado ao uso do Mesilato de Imatinibe e que a Hidroxiuréia parece incrementar tal associação. (AU)

Hyperpigmented lesions are commonly observed in the oral mucosa. Although they often present similar clinical characteristics, these lesions present different etiopathogenesis and diagnosis. Thus, for the correct diagnosis, it is necessary to investigate the medical history of the patient, use of drugs. Clinical examination and biopsy may also be necessary. A number of medications can cause pigmentation in the oral mucosa. The pathogenesis of pigmentation may vary depending on the causative agent. Chemotherapeutic agents such as Imatinib Mesylate, used in the treatment of chronic myeloid leukemia and acute lymphoblastic leukemia pH +, may be associated with the development of hyperpigmented oral lesions in particular in the hard palate. The objective of this study was to evaluate the association between hyperpigmentation of the oral mucosa and the use of imatinib mesylate in patients with leukemia. In addition, we also aimed to compare our data with those obtained from a systematic review of the literature. The study was approved by the Research Ethics Committee of the Federal University of Minas Gerais under the protocol number 48317515.6.0000.5149. A cross-sectional study was conducted with 74 patients undergoing treatment with imatinib mesylate. The sociodemographic characteristics, clinical history of the patients and data regarding the use of drugs used during the treatment of leukemia were collected. In addition, an intra-oral clinical examination and photographic record of the hard palate region were performed. The association between the use of imatinib mesylate and the presence of hyperpigmented oral lesions was also investigated. Descriptive statistics, bivariate analysis and multivariate (Poisson regression) analysis were carried out. In the Poisson regression, confidence intervals (CI) were provided. A systematic review of the literature was conducted in the main electronic databases with the objective of retrieving case reports or case series of patients using imatinib mesylate, who developed hyperpigmented lesions in the oral mucosa. Among the 74 participants, 41 were male individuals (55.4%) and 33 were female individuals (44.6%). The mean age of the participants was 49.3 years. Sixty-six (89.2%) patients developed hyperpigmented lesions in the oral mucosa. In the multivariate analysis, in which Poisson regression was employed, patients who had used imatinib mesylate for more than 72 months had a hyperpigmentation score 1.62 (1.12 ­ 2.33 95% CI) times greater than those who had used this drug for a shorter period. Patients who had used Hydroxyurea associated Imatinib Mesylate over a period of more than 30 days had a hyperpigmentation score 1.43 (1.02 ­ 2.01 95% CI) times higher than those who had used this drug for a shorter period. The systematic review of the literature retrieved 20 clinical cases of patients submitted to treatment with imatinib mesylate and exhibiting hyperpigmented lesions in the oral mucosa. Based on the analysis of these data, it was possible to conclude that the development of hyperpigmented oral lesions was associated with the use of imatinib mesylate. The use of hydroxyurea seemed to increment this association. (AU)

Characterization of imatinib mesylate formulations distributed in South American countries: Determination of genotoxic impurities by UHPLC-MS/MS and dissolution profile.

Imatinib mesylate (IM) is an anti-neoplasic drug used for the treatment of cancer. Recent new guidelines specify daily doses and concentration limits for genotoxic impurities (GTIs) in pharmaceutical final products. Therefore, in this work an analytical method using UHPLC-MS/MS was developed, validated and applied to characterize IM tablets for two GTIs: N-(2-methyl-5-aminophenyl)-4-(3-pyridyl)-2-pyrimidine amine (Imp. 1), and N-[4-methyl-3-(4-methyl-3-yl-pyrimidin-2-ylamino)-phenyl]-4- chloromethyl benzamide (Imp. 2), simultaneously. Additionally, dissolution data of IM tablets were compared using a methodology recommended by the US Food and Drug Administration. The UHPLC method utilized an Acquity BEH C18 (150 × 2.1 mm, 1.7 µm) maintained at 40°C. The mobile phase consisted of ammonium formate 0.063% (phase A) and acetonitrile plus 0.05% formic acid (phase B) in gradient elution. A sensitive method for determination of previously mentioned GTIs in IM tablets was successfully developed and applied. Overall, the formulations analyzed in this work showed low levels of Imp. 1 and Imp. 2. However, the sample named D1 showed very high levels of Imp. 1 and failed to meet the requirements established by the US Food and Drug Administration for dissolution data. Periodic verification of GTIs in pharmaceutical formulations is important to minimize safety risks, so analytical methods to determine it need be available and implemented in routine analysis.