Ponatinibe no tratamento de resgate de pacientes com leucemia mieloide crônica em que houve falha de inibidores de tirosinoquinase de segunda geração / Ponatinib in the salvage treatment of patients with chronic myeloid leukemia in whom second-generation tyrosine kinase inhibitors have failed

INTRODUÇÃO: A leucemia mieloide crônica (LMC) é uma neoplasia mieloproliferativa com incidência de 1-2 casos por 100.000 adultos, e responsável por aproximadamente 15% dos casos recém diagnosticados de leucemia em adultos. A patogênese da LMC origina-se da fusão do gene Abelson da leucemia murina (ABL), no cromossomo 9, com o ponto de interrupção do gene da região de agrupamento (BCR) no cromossomo 22, o que resulta na expressão de uma oncoproteína denominada BCR-ABL. Esta é uma tirosina quinase que promove o crescimento e a replicação celular, o que influencia a leucemogênese. De acordo com o PCDT da LMC do Adulto publicado pelo Ministério da Saúde, o imatinibe é indicado como o tratamento de 1ª linha na LMC. Na falha ou intolerância a esse tratamento, o nilotinibe e o dasatinibe são recomendados para 2ª linha. Quando o tratamento em 2ª linha falha, a terapia subsequente fica a critério de cada CACON ou UNACON. Para estes pacientes, o ponatinibe se constitui como uma opção de tratamento. PERGUNTA: O uso do ponatinibe no tratamento de pacientes adultos com L

Side effects and medication adherence of tyrosine kinase inhibitors for patients with chronic myeloid leukemia in Taiwan.

Nonadherence is common in patients with chronic myeloid leukemia (CML) and leads to treatment failure and poor outcomes. Side effects due to treatment are also common in patients with CML. However, no study has investigated the link between side effects and medication adherence for patients with CML in Taiwan. Therefore, the aim of our study was to explore the influence of side effects on medication adherence in Taiwanese patients with CML.CML in chronic-phase patients treated with breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 tyrosine kinase inhibitors were recruited. We designed a questionnaire to collect baseline patient information, medication adherence (measured using the 8-item Morisky Medication Adherence Scale), and side effects. Clinical outcomes were assessed by the 3-month early molecular response rate and the 12-month major molecular response rate. Statistical comparisons of different parameters between adherent and nonadherent groups were conducted.Fifty-eight patients were enrolled in this study, and 31% of them had poor adherence. The lack of information about treatment and medication was the major reason for poor medication adherence. Patients who were younger and unmarried were prone to poor adherence. The occurrence of side effects carried no statistically significant influence on adherence. Poor adherence resulted in a poor treatment response (lower 3-month early molecular response rate and lower 12-month major molecular response rate).Poor adherence is common in Taiwanese patients with CML. The main reason for a decrease in the adherence rate is the lack of comprehensive information about treatment and medication, particularly in young and single population. The next urgent step is to educate patients about their treatment and management of side effects to improve adherence and treatment outcome for patients with CML in Taiwan.

Cardiovascular Events After Exposure to Nilotinib in Chronic Myeloid Leukemia: Long-term Follow-up.

INTRODUCTION: Nilotinib is a highly effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML). However, reports of cardiovascular toxicities caused by nilotinib have recently raised critical concerns. The aim of the present study was to evaluate the incidence of cardiovascular events (CVEs) and frequency of asymptomatic peripheral arterial disease (PAD) after long-term exposure to nilotinib. PATIENTS AND METHODS: In the present retrospective cohort, we evaluated the incidence of CVEs in 63 CML patients treated with nilotinib. The results of Doppler ultrasound examination of the carotid and vertebral and lower extremity arteries with ankle-brachial index measurements were collected in asymptomatic patients. The clinical outcome was a composite endpoint of PAD, acute coronary events, stroke, heart failure, and cardiovascular death. RESULTS: Sixty-three patients with a median age of 60 years were followed up for a median duration of 63 months. After a median nilotinib exposure of 49.30 months (range, 7.00-117.95 months), for a total exposure of 178.7 patient-years, 6 patients (9%) had experienced the clinical outcome. Four patients (8%) had abnormal arterial leg Doppler ultrasound findings. No significant lesions were reported in carotid/vertebral artery ultrasound examinations. Together, hypertension and low-density lipoprotein cholesterol > 2 mmol/L significantly increased the risk of CVEs or abnormal ultrasound findings (odds ratio, 37.65; 95% confidence interval, 4.06-348.9). CONCLUSION: The incidence of CVEs and the frequency of asymptomatic PAD in this population was low, and CVEs were associated with cardiovascular risk factors. Aggressive risk factor modification and applying standard definitions for measuring cardiovascular outcomes might have contributed to the findings. Further prospective and adequately powered studies are needed to explore the effect of the cardiovascular risk profile on CVEs in CML patients taking nilotinib.

Nilotinib Induced Recurrent Gastric Polyps: Case Report and Review of Literature.

BACKGROUND Tyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML in 2001. Nilotinib is a second-generation TKI, approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib. Tyrosine kinase enzymes are expressed in multiple tissues and are involved in several signaling pathways; they have been shown to have several off-target side effects. CASE REPORT We report a case of an elderly male with CML and no history of gastrointestinal diseases, treated with nilotinib, and developed recurrent gastric polyps after three years of treatment. We excluded common causes of gastric polyps and therefore considered nilotinib as a probable cause of recurrent gastric polyps. CONCLUSIONS Recurrent gastric polyps could be a potential side effect of nilotinib treatment. Careful long-term monitoring of patients on TKI therapy is necessary and further long-term studies of TKI side effects are needed.

Intracranial stenting for nilotinib treatment-associated cerebrovascular stenosis in chronic myeloid leukemia.

One of the second-generation tyrosine kinase inhibitors (TKIs), nilotinib, is increasingly used for imatinib-resistant or intolerant chronic myeloid leukemia (CML). Nilotinib is considered well tolerated with few side effects including hyperglycemia, hyperbilirubinemia and elevated levels of pancreatic enzymes. However, there is growing evidence that nilotinib accelerates atherosclerosis and causes peripheral arterial occlusive disease such as stroke, transient ischemic attack (TIA) and cardiovascular diseases. Herein, we report a case of a 74-year-old male CML patient with intracranial stenosis of the internal carotid artery developed during treatment with nilotinib successfully cured by the intracranial stent, Wingspan.

Cardiovascular Events Associated With Use of Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: A Population-Based Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have increased survival dramatically for patients with chronic myeloid leukemia (CML), but continuous administration of these drugs may elicit long-term toxicity. OBJECTIVE: To investigate the incidence of vascular events in patients with CML treated with first- and second-generation TKIs. DESIGN: Retrospective cohort study using nationwide population-based registries. SETTING: Sweden. PATIENTS: All patients diagnosed with chronic-phase CML in Sweden from 2002 to 2012 and treated with a TKI, and 5 age- and sex-matched control individuals per patient. MEASUREMENTS: Relative risks, expressed as incidence rate ratios comparing patients with control individuals, were calculated. Events per 1000 person-years were assessed in interdrug comparisons. RESULTS: 896 patients, 94.4% with documented TKI treatment, were followed for a median of 4.2 years. There were 54 arterial and 20 venous events in the CML cohort, corresponding to relative risks of 1.5 (95% CI, 1.1 to 2.1) and 2.0 (CI, 1.2 to 3.3), respectively. The event rate for myocardial infarction was higher in patients treated with nilotinib or dasatinib (29 and 19 per 1000 person-years, respectively) than in those receiving imatinib (8 per 1000 person-years), although data are limited and the CIs were wide and overlapped. Among 31 patients treated with a TKI who had myocardial infarction, 26 (84%) had at least 1 major cardiac risk factor diagnosed before the event occurred. LIMITATIONS: Patients may have been exposed to multiple TKIs. Data on second- and third-generation TKIs were limited. CONCLUSION: An increased risk for arterial and venous vascular events was seen in patients with CML treated with a TKI. Further study is needed to determine whether the risk for myocardial infarction increases with second-generation drugs. PRIMARY FUNDING SOURCE: No external funding.

Early Recognition and Management of Posterior Reversible Encephalopathy Syndrome: A Newly Recognized Complication in Patients Receiving Tyrosine Kinase Inhibitors.

BACKGROUND: Adult patients with cancer receiving antineoplastic, targeted, and other immunosuppressive therapies are at risk for severe side effects. Studies link posterior reversible encephalopathy syndrome (PRES) with immunosuppressants used for patients undergoing transplantation, as well as select tyrosine kinase inhibitors (TKIs) and other targeted therapies used in patients with cancer. PRES is a reversible condition with early recognition and management; however, permanent neurologic toxicities have been reported. OBJECTIVES: This article aims to educate oncology nurses on signs, symptoms, and management of PRES in patients receiving TKIs. METHODS: The literature was reviewed to develop an educational session about causes, manifestations, pathophysiology, and management of PRES. Using a case study and flipped classroom model, staff participated in an online lecture and concept engagement exercise. Education for nurses included frequent neurologic and mental status assessments, blood pressure monitoring with mean arterial blood pressure goal, and seizure precautions. Nursing knowledge was evaluated with pre- and post-testing. FINDINGS: Evaluation revealed improved knowledge in recognizing and managing patients with PRES related to TKIs. The flipped classroom approach was perceived as a valuable tool for busy staff nurses.

Toxicidad asociada a la inhibición de EGFR: Revisión y aspectos clave del manejo de afatinib / Toxicity associated with EGRF inhibition: review and key aspects in the management of afatinib

Afatinib es un inhibidor irreversible de la tirosincinasa de la familia ErbB, aprobado para el tratamiento de pacientes con cáncer de pulmón no microcítico y mutaciones sensibilizadoras del gen EGFR. Como otros inhibidores de EGFR, afatinib puede provocar efectos adversos de clase como la diarrea, el exantema, la paroniquia o la mucositis. El manejo adecuado de estos efectos adversos es clave para mantener la calidad de vida de los pacientes y obtener el máximo beneficio del tratamiento con afatinib. El objetivo de este trabajo es revisar la toxicidad y resumir las recomendaciones de prevención y tratamiento de los efectos adversos más significativos de afatinib (AU)

Afatinib is an irreversible tyrosine kinase inhibitor of the ErbB family, approved for the treatment of patients with non-small cell lung cancer with EGFR-sensitizing mutations. Like other EGFR inhibitors, afatinib can provoke adverse events such as diarrhoea, rash, paronychia or mucositis. The correct management of these adverse events is essential to maintain quality of life in these patients and obtain the maximum benefit from afatinib therapy. This study aimed to review the toxicity of the drug and summarize recommendations for the prevention and treatment of the most significant adverse events associated with afatinib (AU)

Ocular Toxicity of Tyrosine Kinase Inhibitors.

PURPOSE/OBJECTIVES: To review common tyrosine kinase inhibitors, as well as their ocular side effects and management.
. DATA SOURCES: A comprehensive literature search was conducted using CINAHL®, PubMed, and Cochrane databases for articles published since 2004 with the following search terms. DATA SYNTHESIS: Tyrosine kinase inhibitors can cause significant eye toxicity.
. CONCLUSIONS: Given the prevalence of new tyrosine kinase inhibitor therapies and the complexity of possible pathogenesis of ocular pathology, oncology nurses can appreciate the occurrence of ocular toxicities and the role of nursing in the management of these problems.
. IMPLICATIONS FOR NURSING: Knowledge of the risk factors and etiology of ocular toxicity of targeted cancer therapies can guide nursing assessment, enhance patient education, and improve care management. Including a review of eye symptoms and vision issues in nursing assessment can enhance early detection and treatment of ocular toxicity.

Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results.

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for ≥2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade ≥3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade ≥3 bleeding events in ≥2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391.

Adverse skin effects of imatinib, a tyrosine kinase inhibitor.

Imatinib mesylate is a tyrosine kinase inhibitor that targets the BCR-ABL, c-kit, and PDGF (platelet-derived growth factor) receptors. Imatinib is mainly indicated for chronic myeloid leukemia and gastrointestinal stromal tumors but is also prescribed by dermatologists for dermatofibrosarcoma protuberans, systemic sclerosis, and systemic mastocytosis, among other conditions. Most adverse effects are mild or moderate and therapy is generally well tolerated. Adverse skin effects are very common and include nonspecific manifestations such as edema and maculopapular rashes or eruptions of diverse types (lichenoid or psoriasiform lesions, acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and more). Identifying and properly treating these reactions can help optimize adherence to treatment and improve the prognosis of the underlying disease.

Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Gastric upset is a common side effect of nilotinib therapy, and calcium carbonate is frequently used concomitantly, either as antacid or as calcium supplementation. With the increasing number of oral agents in cancer therapy, oral drug-drug interactions are becoming more relevant. Nilotinib has already been shown to be absorbed to a much lesser extent when co-administered with proton pump inhibitors. Because exposure to sub-therapeutic concentrations of anticancer drugs such as nilotinib may result in selection of resistant clones and ultimately relapse, we studied the effect of a calcium carbonate supplement (Tums Ultra 1000®) on nilotinib pharmacokinetics. WHAT THIS STUDY ADDS: Calcium carbonate may be co-administered with nilotinib without significantly affecting the pharmacokinetics of nilotinib and potentially impacting efficacy. PURPOSE: Nilotinib is a second-generation oral tyrosine kinase inhibitor with superior efficacy compared with imatinib mesylate in the treatment for chronic phase chronic myelogenous leukemia. Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers. METHODS: Healthy subjects were enrolled in a two-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4,000 mg of calcium carbonate (4 X Tums Ultra 1000®) was administered p.o. 15 min prior to the nilotinib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC-MS, and data were analyzed non-compartmentally. RESULTS: Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma concentration versus time curve (18.4 µg/mL h alone vs. 16.9 µg/mL h with calcium carbonate, p = 0.83; 80 % power); maximum plasma concentration (C(max)) (0.670 µg/mL alone vs. 6.18 µg/mL with calcium carbonate, p = 0.97); or half-life (18.9 h alone vs. 17.2 h with calcium carbonate, p = 0.18). CONCLUSIONS: Our results indicate that the use of calcium carbonate does not significantly affect nilotinib pharmacokinetics.

[Hand-foot syndrome with tyrosine kinase inhibitor therapy: treatment recommendations]. / Hand-Fuss-Syndrom bei Tyrosinkinaseinhibitortherapie: Empfehlungen für die Praxis.

A significant component of advanced renal cell carcinoma therapy is treatment with tyrosine kinase inhibitors. Hand-foot syndrome is a frequent adverse reaction and the quality of life of patients can be considerably affected depending on the severity. Effective treatment options are, therefore, essential and standardization of treatment recommendations is desirable. In this article practical and standardized recommendations for the treatment of outpatients with hand-foot syndrome are introduced and several strategies for prophylaxis and therapy are discussed.

Nilotinib exacerbates diabetes mellitus by decreasing secretion of endogenous insulin.

We report a 74-year-old female with chronic myelogenous leukemia (CML) in accelerated phase with pre-existing severe type 2 diabetes (T2D) and hemorrhagic gastric ulcers who was successfully treated with nilotinib. We first considered second-generation tyrosine kinase inhibitors for the treatment of this patient, as they elicit a superior response compared with imatinib. We next selected nilotinib, rather than dasatinib, since the increased risk of bleeding associated with dasatinib represented a greater risk of fatality than aggravation of T2D with nilotinib. After improvement of hemorrhagic gastric ulcers and T2D with exogenous insulin therapy, we began nilotinib administration; insulin dose was increased to maintain her glucose levels whereas urine C-peptide level decreased. Conversely, when nilotinib was discontinued due to liver dysfunction, the dosage of injected insulin was decreased and urine C-peptide levels increased. After re-starting nilotinib, the required dose of insulin gradually increased again, and urine C-peptide level decreased, indicating that nilotinib may have impaired secretion of endogenous insulin. The patient obtained a complete cytogenetic response after 3 months of nilotinib treatment. Her T2D has since been well controlled by insulin therapy. To our knowledge, this is the first report that nilotinib treatment for patients with severe T2D may induce a reversible decrease in endogenous insulin secretion, although the precise underlying mechanisms remain unknown. We highly recommend sufficient screening and early intervention with exogenous insulin therapy for diabetic CML patients who receive nilotinib.

Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial.

PURPOSE: Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). PATIENTS AND METHODS: A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. RESULTS: The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. CONCLUSION: This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile.

[Chronic myeloid leukemia. Diagnostics, therapy and future strategy]. / Chronische myeloische Leukämie. Diagnostik, Therapie und Zukunftsstrategie.

Survival of patients with chronic myeloid leukemia (CML) has dramatically improved with the introduction of the BCR-ABL-specific tyrosine kinase inhibitor imatinib. As a rule patients on therapy with imatinib achieve permanent complete cytogenetic and molecular remission. Patients who are primarily refractive to imatinib or lose remission achieved using imatinib are in the minority. This group has a poor prognosis. This article gives a transparent review of the diagnostics necessary when CML is primarily diagnosed and for assessment of the response during the course of the therapy. The guidelines developed for this procedure by the European leukemia network on the type and frequency of surveillance controls as well as the diagnostic criteria for imatinib resistance or suboptimal response will be presented. The indications for allogenic stem cell transplantation and the administration of second generation BCR-ABL inhibitors will be discussed as therapeutic alternatives in cases of imatinib failure in a stage-specific manner. Finally a view on therapy targets and forms of future first-line therapy of CML will be given.

Management of sorafenib, sunitinib, and temsirolimus toxicity in metastatic renal cell carcinoma.

PURPOSE OF REVIEW: To review the common and serious toxicities associated with the use of tyrosine kinase inhibitors such as sorafenib and sunitinib and mTOR inhibitor temsirolimus, and to outline the most recent toxicity management guidelines. RECENT FINDINGS: Common grade 3 or 4 side effects with sorafenib include lymphopenia (13%), hypophosphatemia (13%), elevated lipase (12%), hand-foot syndrome (6%), and mucositis/stomatitis (6%). Common grade 3 or 4 side effects with suntinib elevated lipase (16%), neutropenia (12%), lymphopenia (12%), hypertension (8%), and fatigue/asthenia (7%). As for temsirolimus, common grade 3 or 4 side effects consist of anemia (20%), hyperglycemia (11%), fatigue/asthenia (11%), dyspnea (9%), and hypophosphatemia (5%). Intracranial hemorrhage (ICH) is rare but occurred in sorafenib-exposed and sunitinb-exposed patients. Cardiovascular morbidity may also be observed in sorafenib-exposed and sunitinib-exposed patients. SUMMARY: Through preventive and therapeutic measures, these side effects can be effectively managed, without reducing the dose and, therefore, affecting the efficacy of the treatment.

[New drugs in oncology and skin toxicity]. / Effets cutanés des nouvelles molécules utilisées en cancérologie.

The targeted agents have considerably modified the therapeutic approach of cancer over the last few years. The use of these new agents has been associated with the occurrence of new side-effects among which cutaneous side-effects are the most prominent. Although they rarely compromise the vital prognosis, these cutaneous side-effects must be taken into consideration in order to improve treatment compliance and to maintain an acceptable quality of life. Accurate identification of these cutaneous side-effects is therefore critical to improve the management of these patients. A better understanding of the mechanisms underlying cutaneous signs is also an important issue as it gives us the opportunity to increase our knowledge of the skin pathophysiology. Furthermore, the cutaneous manifestations could sometimes be associated to the antitumor response. The skin is an easily accessible interface, allowing addressing the complexity of the targeted therapies effect on tissues.