Long-term pattern of pleural effusion from chronic myeloid leukemia patients in second-line dasatinib therapy

Dasatinib is a potent second-generation tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia after imatinib failure. However, some patients treated with dasatinib experience pleural effusions (PEs). The determinants of pleural effusion in long-term dasatinib treatment (median 35 months, range 1–55) were investigated in single-center data of 65 patients enrolled in global phase 2 and phase 3 trials. Of the 65 patients, 35 (54%) developed dasatinib-induced pleural effusion (a median onset time, 20 months; range 0.2–54). The first pleural effusion developed in 15 (43%) patients within 12 months of dasatinib therapy. Disease phase (P = 0.02), dose schedule (P = 0.002) and actual daily mean dose (P = 0.0002) were significantly associated with an increased risk of pleural effusion. Twice-daily administration of dasatinib resulted in significantly more patients developing pleural effusions compared with the once-daily dosing schedule, particularly in advanced disease. In addition, a strong correlation was found between actual daily mean dose and time to onset of pleural effusions in patients treated with a daily mean dose >100 mg/day of dasatinib (P = 0.01). These data emphasize the need for dasatinib dose and schedule optimization and long-term monitoring of dasatinib-treated patients to prevent the negative clinical implications of pleural effusion.     

Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia and are increasingly used for other indications. Fluid retention, however, including pleural effusions, are a significant side effect of imatinib, the first-line treatment for chronic myeloid leukemia. We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment.     

Charlson comorbidity index and adult comorbidity evaluation-27 scores might predict treatment compliance and development of pleural effusions in elderly patients with chronic myeloid leukemia treated with second-line dasatinib

Background

Comorbidities may affect survival and choice of treatment among cancer patients. In fact, comorbidities have been identified as significant determinants of response to therapy in older patients with acute myeloid leukemia, breast cancer, head and neck cancer, and lung cancer. The Charlson comorbidity index and adult comorbidity evaluation-27 are lists of comorbidities with a weight assigned from 1 to 6 for the former and from 0 to 3 for the latter score, derived from relative risk estimates of a proportional hazard regression model using clinical data.

Design and Methods

We retrospectively evaluated the Charlson index and adult comorbidity evaluation-27 score in a cohort of 125 elderly (> 60 years) patients with chronic phase chronic myeloid leukemia who received dasatinib after showing resistance or intolerance to imatinib with the aim of establishing associations between comorbidities and the development of pleural effusions or compliance with the drug treatment.

Results

We found a significant association between the Charlson index as well as the adult comorbidity evaluation-27 score and the rate of drug reduction or suspension: with regards to the Charlson index, 49% of score 0 patients had a dose reduction compared to 63% of patients with score 1, 74% of those with score 2 and 100% of patients with score 3–5 (P=0.03); with regards to the adult comorbidity evaluation-27 score, 45% of patients had score 0–1 and 69% of patients with score 2–3 had a dose reduction. Of the 65 patients with Charlson score 0, 29% had at least one suspension of treatment (79% for hematologic and 21% for non-hematologic toxicity), compared to 46% of patients with score 1 (37% for hematologic and 69% for non-hematologic toxicity), 58% of patients with score 2 (36% for hematologic and 64% for non-hematologic toxicity) and 100% of patients with score 3 or 4 (all patients for both types of toxicity). High adult comorbidity index-27 scores identified patients at high risk of grade 3/4 hematologic toxicity. Forty-one patients (32.8%) experienced pleural effusion during treatment: the highest scores for both indices were associated with an increased risk of pleural effusions.

Conclusions

In elderly patients with chronic myeloid leukemia treated with dasatinib, the rate of drug reduction or suspension and the incidence of pleural effusions seem to be associated with the presence of comorbidities: stratification according to the Charlson index and adult comorbidity evaluation-27 score before dasatinib therapy may enable the identification of patients at risk of major toxicities.     

Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib

Background

Dasatinib 100 mg once daily achieves intermittent BCR-ABL kinase inhibition and is approved for chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib. To better assess durability of response to and tolerability of dasatinib, data from a 2-year minimum follow-up for a dose-optimization study in chronic-phase chronic myeloid leukemia are reported here.

Design and Methods

In a phase 3 study, 670 chronic-phase chronic myeloid leukemia patients with resistance, intolerance, or suboptimal response to imatinib were randomized to dasatinib 100 mg once-daily, 50 mg twice-daily, 140 mg once-daily, or 70 mg twice-daily.

Results

Data from a 2-year minimum follow-up demonstrate that dasatinib 100 mg once daily achieves major cytogenetic response and complete cytogenetic response rates comparable to those in the other treatment arms, and reduces the frequency of key side effects. Comparable 2-year progression-free survival and overall survival rates were observed (80% and 91%, respectively, for 100 mg once daily, and 75%–76% and 88%–94%, respectively, in other arms). Complete cytogenetic responses were achieved rapidly, typically by 6 months. In patients treated with dasatinib 100 mg once daily for 6 months without complete cytogenetic response, the likelihood of achieving such a response by 2 years was 50% for patients who had achieved a partial cytogenetic response, and only 8% or less for patients with minor, minimal, or no cytogenetic response. Less than 3% of patients suffered disease transformation to accelerated or blast phase.

Conclusions

Intermittent kinase inhibition can achieve rapid and durable responses, indistinguishable from those achieved with more continuous inhibition.     

Pericardial effusions in patients with end-stage renal disease.

Echocardiography has greatly increased the accurate recognition of pericardial effusion. Echocardiograms were performed prospectively on the total group of 35 stable asymptomatic patients on chronic haemodialysis to determine the incidence of pericardial effusion. Effusions were shown in 11 per cent (4/35); only 6 per cent (2/35) were estimated as greater than 100 ml. For comparison, records were reviewed retrospectively from 41 haemodialysis patients referred during a 27-month period for echocardiographic assessment of suspected pericardial effusion. These 41 patients came from a total group of 108 patients treated with chronic dialysis over this interval. Of 41 examined, 21 (51%) or 21 of 108 (19%) of the population at risk had an effusion. Of 21 with echocardiographic effusions, 15 (71%), or 15 of 41 (37%) of those with clinically suspected effusion, had more than 100 ml fluid. Gross (greater than 100 ml) pericardial effusions are infrequent in stable, asymptomatic patients with end-stage renal disease. When clinical findings suggest pericardial disease, the echocardiographic demonstration of over 100 ml pericardial fluid is indicative of new effusion, rather than coincidental pre-existing effusion.     

Pericardial effusions in patients with end-stage renal disease

Echocardiography has greatly increased the accurate recognition of pericardial effusion. Echocardiograms were performed prospectively on the total group of 35 stable asymptomatic patients on chronic haemodialysis to determine the incidence of pericardial effusion. Effusions were shown in 11 per cent (4/35); only 6 per cent (2/35) were estimated as greater than 100 ml. For comparison, records were reviewed retrospectively from 41 haemodialysis patients referred during a 27-month period for echocardiographic assessment of suspected pericardial effusion. These 41 patients came from a total group of 108 patients treated with chronic dialysis over this interval. Of 41 examined, 21 (51%) or 21 of 108 (19%) of the population at risk had an effusion. Of 21 with echocardiographic effusions, 15 (71%), or 15 of 41 (37%) of those with clinically suspected effusion, had more than 100 ml fluid. Gross (greater than 100 ml) pericardial effusions are infrequent in stable, asymptomatic patients with end-stage renal disease. When clinical findings suggest pericardial disease, the echocardiographic demonstration of over 100 ml pericardial fluid is indicative of new effusion, rather than coincidental pre-existing effusion.     

Dasatinib in imatinib‐resistant or ‐intolerant chronic‐phase,chronic myeloid leukemia patients: 7‐year follow‐up of study CA180‐034

Dasatinib was approved at 100 mg once daily for imatinib‐resistant or ‐intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180‐034 (NCT00123474) study. Here we present the final 7‐year analysis of this pivotal study, the longest follow‐up to date of any second‐generation BCR–ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib‐resistant or ‐intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven‐year rates for major molecular response (MMR), progression‐free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR–ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug‐related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug‐related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long‐term efficacy and well‐established safety profile of dasatinib for patients with imatinib‐resistant or ‐intolerant CML in chronic phase. Am. J. Hematol. 91:869–874, 2016. © 2016 Wiley Periodicals, Inc.     

Lack of non-hematological cross intolerance of dasatinib to imatinib in imatinib-intolerant patients with Philadelphia chromosome positive chronic myeloid leukemia or acute lymphatic leukemia: a retrospective safety analysis

The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.     

Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph‐positive acute lymphoblastic leukemia who failed imatinib: Results from a phase 3 study

Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL) intolerant or resistant to imatinib. In patients with chronic‐phase chronic myelogenous leukemia, once‐daily dosing has similar efficacy with improved safety, compared with twice‐daily dosing. A phase 3 study (n = 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg twice‐daily in patients with advanced phase chronic myelogenous leukemia or Ph+ ALL resistant or intolerant to imatinib. Here, results from the Ph+ ALL subset (n = 84) with a 2‐year follow‐up are reported. Patients were randomly assigned to receive dasatinib either 140 mg once daily (n = 40) or 70 mg twice daily (n = 44). The rate of confirmed major hematologic response with once‐daily dosing (38%) was similar to that with twice‐daily dosing (32%). The rate of major cytogenetic response with once‐daily dosing (70%) was higher than that with twice‐daily dosing (52%). Compared with the twice‐daily schedule, the once‐daily schedule had longer progression‐free survival (median, 3.0 months versus 4.0 months, respectively) and shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once‐daily dosing than with twice‐daily dosing (all grades, 18% versus 32%). Notably, none of the differences between the two schedules was statistically significant. Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib‐resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487). Am. J. Hematol. 2010. © 2009 Wiley‐Liss, Inc.     

Dasatinib,large granular lymphocytosis,and pleural effusion: Useful or adverse effect?

Dasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more potent than imatinib in the treatment of Ph+ leukemias. In the last 3 years, increases in cytotoxic T and natural-killer cells in peripheral blood samples have been reported in cases treated by dasatinib. The awareness of the clonal expansion of large granular lymphocytes and beneficial effect of these clonal cells increased the interest to dasatinib in cases receiving this drug. Clonal expansion of large granular lymphocytes is an important effect of dasatinib therapy, shown to be an off-target phenomenon associated with pleural effusion and better clinical response. The benefit of dasatinib-induced lymphocytosis and its underlying mechanism of this are important points for clinicians working in hematology and oncology.     

Improved tolerability by a modified intermittent treatment schedule of dasatinib for patients with chronic myeloid leukemia resistant or intolerant to imatinib

Intermittent dosing of dasatinib with a once daily regimen has been shown to reduce side effects while preserving clinical efficacy in early and advanced phase chronic myeloid leukemia (CML). Yet, hematologic toxicity and fluid retention demand a dose modification or treatment discontinuation in selected patients. Patients resistant or intolerant to imatinib were retrospectively evaluated based on the toxicity-guided administration of a dose-reduced dasatinib regimen. Patients were treated with an on/off regimen (3 to 5 days on, 2 to 4 days off) to allow regression of dasatinib-dependent off-target toxicity. Patients were followed up by routine hematologic and cytogenetic assessment and molecular monitoring to safeguard clinical response to the altered drug schedule. Thirty-three CML patients primarily in chronic phase with imatinib intolerance (n?=?11) or resistance (n?=?22) were investigated. Nonexclusive reasons for dose reduction were hematologic toxicity (17/33, 51 %) and pleural effusions (18/33, 55 %). On/off treatment with a weekend drug holiday significantly reduced pleural effusions and hematologic toxicity. Eighteen of 31 (58 %) patients showed effective disease control despite reduced total weekly dasatinib doses, either demonstrated by achieving an improved response level (12/31) or keeping the response level achieved by conventional continuous dosing (6/31). Of note, 10/12 patients with subsequently improved response have been treated for a minimum of 6 months with continuous dosing dasatinib regimens without having achieved the response level achieved after allowing drug holiday. Weekend treatment interruption of dasatinib allows continuation of dasatinib treatment for patients suffering from side effects. These data mandate prospective investigation of alternative intermittent targeting regimens.     

Usefulness of nuclear magnetic resonance imaging for evaluation of pericardial effusions, and comparison with two-dimensional echocardiography

Nuclear magnetic resonance (NMR) imaging clearly delineates cardiovascular structures without interference from overlying bone and lung tissue. The techniques of NMR imaging and echocardiography were compared in 26 patients with pericardial effusions, 10 of whom had associated pleural effusions. In those patients with fluid detected by both techniques, estimated size of the effusion tended to be somewhat larger by NMR. NMR imaging detected several small pericardial effusions that were not visualized by echocardiography. Both techniques demonstrated loculation well, although NMR imaging was better for detecting fluid located superiorly at the aortic pericardial reflection site, medially at the border of the right atrium and posteriorly at the left ventricular apex. In the 14 patients with documented exudative effusions (10 pericardial, 4 pleural) NMR signals of varying intensity were present in the effusion. One patient had a documented transudative effusion and no NMR signal was observed in the fluid. NMR imaging clearly distinguished pericardial from pleural effusions. NMR imaging is indicated when a suspected pericardial effusions is not detected by echocardiography or when specific localization or fluid characterization is desired.     

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.     

Pericardial effusion and cardiac tamponade in pediatric stem cell transplant recipients

Pericardial effusion and cardiac tamponade is a rarely reported complication following stem cell transplant (SCT). The incidence among pediatric SCT recipients is not well defined. To assess the frequency of clinically significant pericardial effusions, we retrospectively examined clinically significant cardiac effusions at our center. Between January of 1993 and August 2004, clinically significant pericardial effusions were identified in nine of 205 patients (4.4%). The median age at the time of transplant was 9 years (range 0.6-18 years) and seven received an allogeneic transplant. All nine had normal cardiac function prior to transplant. The effusion developed at a median of 30 days (range 18-210 days). All allogeneic recipients had acute or clinically extensive graft-versus-host disease (GVHD) at the time the effusion was diagnosed. Seven patients (78%) required pericardiocentesis or surgical creation of a pericardial window. No patient died as a complication of the effusion or the therapeutic procedures. Clinically significant pericardial effusions are more common than previously reported in pediatric SCT recipients. Acute and chronic GVHD is an associated factor.     

Dasatinib-Induced Pulmonary Arterial Hypertension

A 73-year-old woman with chronic myeloid leukemia developed severe pulmonary arterial hypertension (PAH) and pleural effusions after treatment with dasatinib. During workup, partial anomalous pulmonary venous connection and a sinus venosus atrial septal defect were found; these anomalies may have predisposed her to developing this rare and life-threatening condition. Fortunately, her PAH was completely reversible by discontinuation of dasatinib. This case highlights dasatinib’s ability to cause PAH in patients predisposed to pulmonary vascular disease.     

Hepatic hydropericardium

A 41-year-old man with chronic hepatitis C and cirrhosis presented with pericardial effusion and tamponade requiring pericardiocentesis. Nine liters of pericardial fluid was drained with complete resolution of his ascites. He represented with recurrent pericardial effusions despite salt restriction and diuretic therapy. Subsequent radionuclide scans demonstrated a direct connection between the peritoneal and pericardial spaces. A pericardial window was formed but despite this there was recurrence of pericardial effusion and pleural effusion. The patient underwent orthotopic liver transplantation 7 months later and no recurrence of pleural or pericardial effusion was observed following transplantation. We believe this is the first case report of pericardial effusion secondary to cirrhotic ascites and a communication between the peritoneal and pericardial cavities.     

Phase I/II study of dasatinib in combination with decitabine in patients with accelerated or blast phase chronic myeloid leukemia

Treatment of advanced-phase chronic myeloid leukemia (CML) remains unsatisfactory. Single-agent tyrosine kinase inhibitors have modest and short-lived activity in this setting. We conducted a phase I/II study to determine safety and efficacy of the combination of dasatinib and decitabine in patients with advanced CML. Two different dose schedules were investigated with a starting decitabine dose of either 10 mg/m² or 20 mg/m² daily for 10 days plus dasatinib 100 mg daily. The target dose level was decitabine 10 mg/m² or 20 mg/m² daily for 10 days plus dasatinib 140 mg daily. Thirty patients were enrolled, including seven with accelerated-phase CML, 19 with blast-phase CML, and four with Philadelphia-chromosome positive acute myeloid leukemia. No dose-limiting toxicity was observed at the starting dose level with either schedule. Grade ≥3 treatment emergent hematological adverse events were reported in 28 patients. Thirteen patients (48%) achieved a major hematologic response and six (22%) achieved a minor hematologic response, with 44% of these patients achieving a major cytogenetic response and 33% achieving a major molecular response. Median overall survival (OS) was 13.8 months, with significantly higher OS among patients who achieved a hematologic response compared to non-responders (not reached vs 4.65 months; P < .001). Decitabine plus dasatinib is a safe and active regimen in advanced CML. Further studies using this combination are warranted.     

Deaths from Severe Megaloblastic Anaemia in Hospitalised Patients

In a series of 128 consecutive patients dying from severe megaloblastic anaemia, over half the deaths occurred within one week of hospitalisation and one third were sudden and unexpected. Congestive cardiac failure was extremely common in these patients and was often associated with pleural effusions. Just over half the patients were examined at autopsy and of these 42% had pleural effusions and 15% had pericardial effusions. The cause of the latter is unclear as is their clinical significance, nevertheless this condition has not previously been reported in the megaloblastic anaemias and may well play a part in the fatal outcome in such patients. Blood transfusion was administered to over half the patients, usually in the form of whole blood. It is recommended that transfusions be used sparingly, and consist of cells or preferably exchange transfusion, the latter being of particular value in the elderly or in those with pre-existing cardiac failure.     

A case of chronic myelomonocytic leukemia who developed pericardial effusion during stably controlled leukocytosis

We report a rare case of chronic myelomonocytic leukemia (CMML) with pericardial effusion. After receving the diagnosis of CMML, she had been successfully treated with hydroxycarbamide (HU). However, she was admitted to our hospital due to pericardial effusion. The majority of the cells in the pericardial fluid were monocytes. We made the diagnosis of pericardial involvement with CMML cells and intravenously administered etoposide (100 mg/body daily for 5 days). Although CMML cells disappeared from the peripheral blood, the pericardial effusion still persisted. This case indicates that pericardial effusion is a possible and life-threatening complication in CMML patients despite stably controlled leukocytes.