Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

An Analysis of Dasatinib Treatment Patterns in Patients with Chronic Myeloid Leukemia after Experiencing Pleural Effusion during Dasatinib Therapy.

INTRODUCTION: Treatment with dasatinib for chronic myeloid leukemia (CML) has been associated with development of pleural effusion; however, data regarding its optimal management are limited. We examined treatment patterns and healthcare resource utilization (HCRU) and costs among patients with CML treated with dasatinib who experienced a subsequent pleural effusion. METHODS: Adults with CML and ≥1 pharmacy claim for dasatinib in 2015-2018 who experienced pleural effusion after dasatinib were identified using data from claims databases. RESULTS: Overall, 123 patients were eligible. After 1 year, of the 38.2% of patients with a dose modification, 72.3% did not switch treatment; among these patients, 70.6% continued treatment. Among patients with a stable dose after pleural effusion (61.8%), 57.9% later switched to another TKI. The mean (SD) duration of dasatinib treatment after pleural effusion was 262.0 (124.0) days for patients with a dose modification versus 149.1 (155.2) days for those with a stable dose (p < 0.001). HCRU and costs were similar between groups. CONCLUSION: Dasatinib dose modification after pleural effusion was not always required; however, patients with dose modifications continued therapy for a longer duration with a lower rate of switching to another TKI versus patients who remained on a stable dose.

Bosutinib-induced massive pleural effusion: Cross-intolerance with all tyrosine kinase inhibitors.

BACKGROUND: The discovery of tyrosine kinase inhibitors provided a breakthrough in the treatment of chronic myeloid leukemia. Nowadays, the management of tyrosine kinase inhibitor-related side effects is one of the important problems in chronic myeloid leukemia treatment. Grades 3-4 pulmonary toxicity; especially pleural effusion is mostly seen with dasatinib treatment but rarely seen with nilotinib and bosutinib. Development of cross-intolerance due to pleural effusion is not an expected situation. Pleural effusion related to tyrosine kinase inhibitors is mostly exudative in nature with abundant lymphocytes. CASE REPORT: Massive pleural effusion developed in a 59-year-old male patient with chronic myeloid leukemia, who was being treated with bosutinib. In the past, the patient had experienced massive pleural effusion also with dasatinib and nilotinib. The evaluation for differential diagnosis of pleural effusion did not reveal any additional malignancy. MANAGEMENT AND OUTCOME: After discontinuation of bosutinib and initiation of prednisolone, pleural effusion was totally resolved. Prednisolone was gradually discontinued and third-generation tyrosine kinase inhibitor ponatinib was started. After 12 months of follow-up, massive pleural effusion occurred again, leading to discontinuation of ponatinib. DISCUSSION: Cross-intolerance is an important problem in the tyrosine kinase inhibitor era. The significance of this case is the development of cross-intolerance to all second-generation tyrosine kinase inhibitors and furthermore to a third-generation tyrosine kinase inhibitor. Management strategies for pleural effusion and close follow-up are important.

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.

Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).

Differentiation syndrome with lower-intensity treatments for acute myeloid leukemia.

Differentiation Syndrome (DS) has been identified in a subset of patients undergoing treatment with novel classes of differentiating therapies for acute myeloid leukemia (AML) such as IDH and FLT3 inhibitors. While DS is a well-known treatment-related complication in acute promyelocytic leukemia (APL), efforts are still ongoing to standardize diagnostic and treatment parameters for DS in AML. Though the rates of incidence vary, many of the signs and symptoms of DS are common between APL and AML. So, DS can lead to fatal complications in AML, but prompt management is usually effective and rarely necessitates interruption or discontinuation of AML therapy.

cAMP Signaling Pathway Prevents Dasatinib-Induced Vascular Hyperpermeability.

Dasatinib is a first-line pharmacotherapeutic treatment for chronic myeloid leukemia (CML). It is more effective than traditional treatments but causes adverse effects such as pleural effusion that limits its effective treatment cycle. Since pleural effusion is caused by vascular hyperpermeability and causes discontinuation of treatment with dasatinib, it is important to explore the mechanism of pleural effusion caused by dasatinib and how to prevent it. In this study, we investigated how dasatinib increase vascular permeability, and how it can be prevented. Cytotoxicity was observed in vascular endothelial cells or epithelial cells were exposed to high concentrations of dasatinib. Thus, it was observed in vascular endothelial cells such as human umbilical vascular endothelial cell (HUVEC). Vascular endothelial (VE)-cadherin is one of the important factors that control vascular permeability. When VE-cadherin expression decreases, vascular permeability increases, but it did not change with tyrosine kinase inhibitor exposure. Monolayer permeability significantly increased only with high concentration of dasatinib, but this increase was prevented by cAMP activation. Furthermore, dasatinib affects the cell morphology of HUVEC, with increased inter celluar space compared to control and bosutinib, which were also attenuated by cAMP activation. Dasatinib significantly affected permeability control of vascular endothelial cells compared to bosutinib and imatinib. These results indicated that the cAMP signaling pathway may be involved in the pleural effusion caused by dasatinib in CML patients.

Dasatinib-induced chylothorax: report of a case and review of the literature.

Dasatinib is a tyrosine kinase inhibitor for the treatment of BCR-ABL-positive chronic myeloid leukaemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukaemia (ALL). Although fluid retention is a common adverse event associated with dasatinib, chylothorax is exceptionally rare. The pathological mechanism, clinical manifestation and management of dasatinib-induced chylothorax are completely unclear. A 71-year-old man treated with dasatinib for CML was admitted for progressive dyspnea. Computed tomography (CT) showed a pleural effusion that was more prominent on the right thoracic cavity. Thoracentesis showed thick milky pleural fluid, which was then confirmed as chylothorax by chylum qualitative tests and triglyceride measurements. Radionuclide lymphoscintigraphy yielded an obstruction at the end segment of the thoracic duct, but no leakage points were found. After excluding common causes, drug-induced chylothorax was presumed. Then, dasatinib was withdrawn, and 1 week later, chylothorax resolved. To further elucidate the relationship between the medication and chylothorax, dasatinib was resumed tentatively for 2 days. As expected, pleural effusion recurred soon. Based on these clinical manifestations, the diagnosis of dasatinib-induced chylothorax was identified. The patient was suggested to stop dasatinib and use an alternative drug as recommended by the haematologist. Pleural effusion is the common adverse reaction of dasatinib, but chylothorax is rare. Only six cases of dasatinib-induced chylothorax have been reported, and our patient is the seventh case. Once a patient with dasatinib treatment develops chylothorax, dasatinib should be considered one of the possible causes. If no other definitive aetiological factor is identified, dasatinib discontinuation might be the optimum scheme.

Understanding, recognizing, and managing toxicities of targeted anticancer therapies.

Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed.

Lupus-like symptoms with anti-RNP/Sm and anti-nuclear antibodies positivity: An extremely rare adverse event of dasatinib.

INTRODUCTION: Dasatinib is a potent tyrosine-kinase inhibitor which is used for chronic myeloid leukemia treatment. Pleural effusion is a frequent side effect in patients during dasatinib treatment. Pulmonary arterial hypertension is a rare and life-threatening adverse event of dasatinib. The relationship between dasatinib and autoimmune disorders is unclear, but there are reports of possible mechanisms that have triggered autoimmunity by dasatinib. CASE REPORT: A 53-year-old male was diagnosed with chronic myeloid leukemia and initiated imatinib mesylate as a treatment. Imatinib was changed to dasatinib as the patient was unresponsive in the first year of treatment. In the fourth year of dasatinib when chronic myeloid leukemia was in both hematological and cytogenetical remission, the patient presented with bilateral massive exudative pleural effusion. Echocardiography was consistent with pericardial effusion with right ventricle enlargement and normal left-side cardiac function. Pulmonary arterial hypertension was diagnosed with high systolic pulmonary arterial pressure. When he had fever and arthralgia, further investigation showed positivity of anti-nuclear antibodies (1/160 titer) and anti-RNP/Sm, which have high specificity for the diagnosis of Systemic Lupus Erythematosus (SLE). MANAGEMENT AND OUTCOME: Dasatinib was discontinued and nilotinib was initiated. As the pleural effusion persisted despite diuretics and methylprednisolone, mycophenolate mofetil was initiated as a steroid-sparing immune-suppressive agent. The lupus-like symptoms disappeared, and antibodies became undetectable after dasatinib discontinuation. Pericardial effusion improved and pleural effusion did not relapse. DISCUSSION: Screening for auto-antibodies may be recommended for patients with a history or symptoms of autoimmune disease before starting dasatinib. All patients who develop pleural effusion while on dasatinib treatment should be investigated for antibodies for lupus.

Valproic acid associated pleuropericardial effusion: case report.

Introduction - Valproic acid is an effective antiepileptic and mood stabilizer used in the treatment of many neurological and psychiatric disorders. Although there are frequently seen side effects, effusions between layers of pleural and pericardial membranes are rare to be seen. Case - Pleuropericardial effusion was detected in a 23 years old woman who was under valproic acid treatment because of epileptic seizure. After 1 year of valproic acid treatment, patient complained of dyspnea. As all the researches intended on etiology were usual, valproic acid has been thought to be responsible for the matter. Control examination after 1.5 months regarding the end of treatment revealed complete recovery of pleuropericardial effusion. Discussion - Pleural and pericardial effusions are rarely seen complications related to the use of valproic acid. It must also be kept in mind that valproic acid causes a potential for such side effects which can be blamed etiologically when the other possibilities for patients are excluded.

Azacitidine-associated pleuropericardial effusion in myelodysplastic syndrome: A case report.

Azacitidine, a deoxyribonucleic acid hypomethylating agent, is used in the treatment of myelodysplastic syndrome. Common adverse effects of azacitidine include bone marrow suppression, injection site reactions, nausea, vomiting, diarrhea, and fatigue. This report focuses on pleuropericardial effusions, an infrequently reported and potentially reversible adverse effect of azacitidine. In this case report, pleuropericardial effusion manifested as the sole radiographic finding in the evaluation of cough occurring during the eighth cycle of treatment with azacitidine. Symptoms and radiographic abnormalities resolved with corticosteroids and diuretics, and the patient could continue with therapy.

Docetaxel-induced cardiac-respiratory arrest in a patient with chronic atrial fibrillation.

Docetaxel has been approved by the Food and Drug Administration for the treatment of many cancer types, including breast cancer, head and neck cancer, lung cancer, and prostate cancer. Many severe to life-threatening side effects (Grades 3-5) of docetaxel have been reported in clinical trials, case reports, and Food and Drug Administration Adverse Events Reporting System. These include anaphylactic reactions, febrile neutropenia, fluid retention, acute respiratory distress, pleural effusion, pneumonia, and peripheral neuropathy. There were fewer cardiac toxicities reported for docetaxel as compared to paclitaxel, which were less severe. In this report, we present a clinical case of docetaxel-induced cardiac-respiratory arrest in a 62-year-old Hispanic male patient with stable chronic atrial fibrillation, who has been recently diagnosed with metastatic prostate cancer. The cardiac event developed within 15 min of docetaxel infusion during the second cycle of chemotherapy despite using recommended premedication with corticosteroids.

Safety and Efficacy of Granulocyte Colony-Stimulating Factor Monotherapy for Peripheral Blood Stem Cell Collection in POEMS Syndrome.

Although autologous stem cell transplantation can achieve excellent responses in patients with POEMS syndrome, the optimal regimen for peripheral blood stem cell (PBSC) collection is still controversial. We retrospectively investigated the safety and efficacy of 41 PBSC collecting procedures in 37 patients with POEMS syndrome. PBSC mobilization was performed using cyclophosphamide + granulocyte colony-stimulating factor (G-CSF) (CG, n = 14) or G-CSF alone (G, n = 27). Twelve (85.7%) patients in the CG group and all (100%) patients in the G group received induction chemotherapy before PBSC collection. The proportions of good mobilizers (≥2.0 × 106 CD34+ cells/kg) were comparable between the 2 groups (CG versus G: 78.6% versus 70.4%, P = .71). Two (14.3%) patients in the CG group developed severe capillary leak symptoms during the PBSC mobilization period, whereas no patient in the G group experienced severe adverse events. Appropriate induction therapies followed by the G-CSF monotherapy compose an optimal strategy for PBSC collection.

Late-onset pericardial tamponade, bilateral pleural effusions and recurrent immune monoarthritis induced by ipilimumab use for metastatic melanoma.

While an important agent in the contemporary anti-melanoma armamentarium, ipilimumab is associated with serious immune reactions including late immune-mediated side effects. Recently, a case of late-onset acute pericarditis with tamponade was reported at 12 weeks after the last dose of ipilimumab. While polyarthralgia rheumatica has been previously documented with ipilimumab, we were not able to find any reports of recurrent monoarthritis with the use of this agent. Therefore, we present herein a unique case featuring a patient with late-onset autoimmune pleuropericarditis leading to cardiac tamponade at 24 weeks post-ipilimumab and recurrent late immune knee arthritis at 8 and 32 weeks, respectively. Furthermore, this late-onset toxicity seen with ipilimumab might also be expected with the PD1 inhibitors currently in clinical use. Timely diagnosis and prompt steroid use are crucial to ensure favorable clinical outcomes in these patients.

Imatinib-induced pleural effusion: A case report.

Imatinib is a tyrosine kinase inhibitor and has rarely been reported to cause pleural effusion. We report the case of an 88-year-old male, known case of gastrointestinal stromal tumor on treatment with imatinib, who presented with a 2-week history of cough and dyspnea. He was diagnosed to have a right-sided pleural effusion and thoracentesis of the fluid revealed an exudate with low adenosine deaminase and negative cytology. Withdrawal of the drug lead to resolution of symptoms. We report this case to highlight the side effect profile of imatinib and warn physicians regarding this potential adverse effect which may be mistaken for metastasis or infection.

Dobutamine aggravates haemodynamic deterioration induced by pleural effusion: A randomised controlled porcine study.

BACKGROUND: Pleural effusion is a common finding in critically ill patients and may contribute to circulatory instability and the need for inotropic support. OBJECTIVE: We hypothesised that dobutamine would affect the physiological determinants preload, afterload, contractility and changes of inferior vena cava characteristics during experimental pleural effusion. DESIGN: A randomised, controlled laboratory study. SETTING: Animal laboratory, conducted from March 2013 to May 2013. ANIMALS: Twenty-four Landrace and Yorkshire female piglets (21.3 ±â€Š1.7 kg). INTERVENTION: Twenty piglets were included in the analyses. After inducing bilateral pleural effusion (30 ml kg), the piglets were block randomised to either incremental dobutamine infusion (n = 10) or control (n = 10). MAIN OUTCOME MEASURES: Ultrasonographic measures of left ventricular end-diastolic area, left ventricular afterload, left ventricular fractional area change and inferior vena cava diameter and distensibility were used to assess the basic physiological effect of incremental dobutamine administration during experimental pleural effusion. RESULTS: In the dobutamine group, preload, measured as left ventricular end-diastolic area, decreased from 11.3 ±â€Š2.0 cm after creation of the pleural effusion to 8.1 ±â€Š1.5 cm at a dobutamine infusion rate of 20 µg kg min (P < 0.001). In the same period, central venous pressure and the expiratory diameter of the inferior vena cava decreased from 9 ±â€Š3 to 7 ±â€Š4 mmHg (P < 0.001) and from 1.1 ±â€Š0.2 to 0.9 ±â€Š0.1 cm (P = 0.008), respectively. CONCLUSION: In a porcine model of pleural effusion, dobutamine affected basic haemodynamic determinants substantially by decreasing left ventricular preload. Changes in central venous pressure and inferior vena cava characteristics were minimal, discouraging their use as indices of preload. This study underlines the significance of evaluating basic haemodynamic determinants to avoid inappropriate, potentially harmful treatment.

Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: Effects on response and toxicity.

BACKGROUND: The proliferation of clonal cytotoxic T-cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML). METHODS: The incidence of lymphocytosis and its association with response, survival, and side effects were assessed in patients from 3 large clinical trials. Overall, 1402 dasatinib-treated patients with newly diagnosed CML in chronic phase (CML-CP), CML-CP refractory/intolerant to imatinib, or with CML in accelerated or myeloid-blast phase were analyzed. RESULTS: Lymphocytosis developed in 32% to 35% of patients and persisted for >12 months. This was not observed in the patients who received treatment with imatinib. Dasatinib-treated patients in all stages of CML who developed lymphocytosis were more likely to achieve a complete cytogenetic response, and patients who had CML-CP with lymphocytosis were more likely to achieve major and deep molecular responses. Progression-free and overall survival rates were significantly longer in patients with CML-CP who were refractory to or intolerant of imatinib and had lymphocytosis. Pleural effusions developed more commonly in patients with lymphocytosis. CONCLUSIONS: Overall, lymphocytosis occurred and persisted in many dasatinib-treated patients in all phases of CML. Its presence was associated with higher response rates, significantly longer response durations, and increased overall survival, suggesting an immunomodulatory effect. Prospective studies are warranted to characterize the functional activity of these cells and to assess whether an immunologic effect against CML is detectable. Cancer 2016;122:1398-1407. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Sirolimus in Advanced Epithelioid Hemangioendothelioma: A Retrospective Case-Series Analysis from the Italian Rare Cancer Network Database.

BACKGROUND: The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network ("Rete Tumori Rari"; RTR). METHODS: We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15-20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RESULTS: Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic; WWTR1 rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1-45), with four patients progression-free at 24 months. The clinical benefit (complete response [CR] + PR + SD >6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1-8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients. CONCLUSIONS: A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.