Dasatinib and Quercetin Senolytic Therapy - Table 2: Clinical Trials

D= 100 mg once daily

Q= 500 mg twice daily

• abdominal subcutaneous excisional adipose tissue biopsies were acquired from 9 subjects before and 11 days after completion of a 3-day course of oral D+Q
• adipose tissue p16INK4a was reduced by 35%
• p21CIP1+ decreased by 17%
• SABgal+ cells were reduced by 62%
• macrophages per adipocyte were lowered by 28%
• decreased numbers of "CLS" crown-like structures"
• increased number of primary adipocyte progenitors following treatment
• cells in the epidermal layer: p16INK4a were 20% less abundant
• SASP factors were lower: Plasma IL-1a,2,6,9.MMP-2,9,12 were lower 11 days after the last treatment
• FGF-2 and GM-CSF tended to be lower 
• no serious adverse events
• no subjects required drug discontinuation

D= 100 mg once daily

Q= 500 mg twice daily

• we reported a statistically significant decrease in skin senescent cells in the 9 subjects whose skin data were reported in the original article, however, that conclusion did not hold up upon reanalysis of the non-transformed data. 
• blood SASP factors were overall statistically significantly reduced after D+Q treatment, further supporting our finding of a senolytic effect of D+Q in humans
• the composite score of SASP factors was significantly decreased as was MMP-12, although the decreases in the other factors did not reach significance.
• no serious adverse events
• no subjects required drug discontinuation

• no results published yet

Hematopoietic Stem Cell Transplant Survivors Study (HTSS Study) (HTSS)

• no results published yet

• no results published yet

Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.

D= 100 mg once daily

Q= 1250 mg daily

• the retention rate was 100% with no DQ discontinuation
• planned clinical assessments were complete in 13/14 participants.
• physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically meaningfully improved
• pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged.
• D+Q effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and proinflammatory cytokines (23/48 markers r ≥ 0.50)
• no drug discontinuation
• one serious adverse event was reported.
• non-serious events were primarily mild-moderate, with respiratory symptoms (n = 16 total events), skin irritation/bruising (n = 14), and gastrointestinal discomfort (n = 12) being most frequent.
• adverse events were primarily consistent with the underlying diagnosis, study procedures, or known off-target effects of the study drugs (GI discomfort, headache)
• no changes in laboratory tests suggestive of hepatic or renal toxicity were found

• Onions, the most important quercetin source in the human diet, contain primarily quercetin-4’-glucoside and quercetin-3,4’-diglucoside,[14] while apples contain, among others, quercetin-3-O-glucoside, quercetin-3-O-galactoside, quercetin-3-O-rhamnoside, and quercetin-3-O-rutinoside.
• Human kinetic studies recovered primarily quercetin conjugates in blood plasma after oral intake of quercetin, while only very low levels of quercetin aglycone were found.
• In human intervention studies, pro-oxidative effects of quercetin were not found with quercetin doses at 500–1000 mg d–1 applied for 3–12 weeks (nQ = 6–333),[55–59] but it is still an open question whether quercetin may exhibit pro-oxidative effects in the human body, especially after long-term use of high quercetin doses.
• Patients with kidney dysfunction may be a potential risk group for the long-term quercetin supplementation at high doses considering the possible nephrotoxic effects of quercetin particularly on the pre-damaged kidney in rodents.
• Due to the potential tumor-promoting effects of quercetin primarily in estrogen-dependent cancer revealed in animal studies, the supplementation of isolated quercetin at high doses were considered as critical for patients with a currently diagnosed estrogen-dependent cancer disease or a history for such a disease keeping also in mind that occasionally such disease has not yet been diagnosed.
• Individuals who take medications, especially regarding the drugs with known quercetin interaction or where no interaction data are available, are recommended to consult a physician prior to the use of isolated quercetin as a dietary supplement.

• Subjects received quercetin 500 mg three times daily and blood and urine samples were obtained.
• The oral clearance (CL/F) was high with an average terminal half-life of 3.5 h for quercetin. 

• In vitro, quercetin consistently tested positive for mutagenic activity in most standard strains of Salmonella typhimurium
• The mutagenicity observed in bacterial test systems was confirmed in eukaryotic cells, including yeast cells, at relatively high concentrations (up to 10 mg/incubation mixture).
• Additionally, in hamster and mouse cells and human lymphocytes, quercetin exposure induced chromosomal aberrations, DNA single-strand breaks, and micronucleus formation
• The results of quercetin-related mutagenicity/genotoxicity observed in vitro have not been confirmed by in vivo experiments. With oral administration to mice and rats, quercetin consistently did not induce any significant changes in several mutagenicity/genotoxicity endpoints (i.e., micronuclei, chromosomal aberrations, sister chromatid exchange, unscheduled DNA synthesis, and alkali-labile DNA damage) in somatic cells in comparison to untreated controls

• quercetin was safely tolerated up to 2000 mg.day in subjects with COPD 
• no serious adverse events 

• quercetin displayed safety in all trial participants with no adverse events or signs of toxicity
• Given quercetin’s affordability and tolerability, with doses up to 1 g/day demonstrating safety in numerous trials, we sought to determine its safety in patients with HCV at higher doses (up to 5 g daily) 

• The employ of dasatinib was associated with a 35% risk of cutaneous adverse reactions in one phase I trial and five phase II trials including a total of 911 patients.
• The patients with accelerated CML (22%) or chronic-phase CML (13–27%) showed a higher incidence of skin rashes compared with patients with myeloid blast crisis (11–14%) or lymphoid blast crisis (15– 17%).
• The most frequent cutaneous side-effects consisted of grade 1–2 (National Cancer Institute CTCAE version 3) localized and generalized erythema, maculopapular eruptions or exfoliative rashes with no more specific information. Moreover, mucositis and stomatitis were documented in 16% of the patients, while 11% had pruritus.
• In the CA 180-034 trial, a non-specific cutaneous rash was reported in 65 patients (10%) and peripheral edema in 36 patients (5%).
• In the phase II study (CA 180-013) of 186 patients with imatinib-resistant or -intolerant CML-CP designed to further establish the efficacy and safety of dasatinib, a skin rash was described in 41 patients (22%) and peripheral oedema in 33 patients (18%).
• Very few cases of other cutaneous adverse events of dasatinib are sparsely described in the literature, such as itch, skin exfoliation and irritation, pustular rashes and acne-like eruptions.
• To date, only a single case of skin and hair depigmentation in an adult CML patient has been described
• We reported a case of a 16-year-old-male patient affected by Philadelphia-positive ALL. Approximately 4 weeks after drug initiation, the patient presented achromic patches on his neck and the dorsal surfaces of his hands, and complete depigmentation of his hair, eyelashes and eyebrows. The patient, whose original phenotype was Fitzpatrick’s skin phototype III, had no history of vitiligo, thyroid disorders or autoimmune diseases. In light of these findings, a diagnosis of vitiligo-like lesions and hair depigmentation induced by dasatinib was rendered. The case described is the first report of dasatinib-induced hair and skin depigmentation in a paediatric patient, and emphasized the role of the c-Kit pathway in melanocyte biology.
• In another report, Assouline et al. reported two cases of painful panniculitis caused by the employ of dasatinib. During the fourth week of treatment, fever and painful subcutaneous nodules with overlying erythema on her thighs developed. Dasatinib was discontinued, and within a week the cutaneous reaction resolved. On rechallenge, the fever and rash recurred, this time on the arms, legs and genitalia. Biopsy of a skin lesion revealed lobular panniculitis with massive infiltration by polymorphonuclear leucocytes, without mention of vasculitic changes. Again, the drug was withheld and reintroduced after resolution of symptoms together with 50 mg of prednisone per day. No recurrence of panniculitis was noted even if the dose of dasatinib was increased, but the patient maintained a minimum of 5 mg daily prednisone to prevent recurrence.
• Three months later, she presented tender and painful skin nodules in a similar manner to the other patient. The histological examination proved the diagnosis of panniculitis. The discontinuation of the drug allowed a complete remission of the cutaneous reaction but differently from the first patient, the use of systemic steroids did not control the recurrence of panniculitis when dasatinib was restarted.
• Worthy of notice, other dermatological adverse events such as hyperhidrosis, alopecia, skin ulcers, xerosis, urticaria, photosensitivity reactions, non-specific nail disorders, bullous eruptions and palmoplantar erythrodysesthesia syndrome are reported in the package insert of the drug, even if more detailed and commented case reports or case series are not documented in the literature.

• With a minimum of 5 years of follow-up in DASISION, 28% of dasatinib-treated patients with CML-CP had drug-related pleural effusion of any grade (3% with grade 3/4; Table 1) compared with 1% of imatinib-treated patients.² In the study CA180-034, drug-related pleural effusion of any grade occurred in 33% of patients overall (Table 1) and in 28% of patients treated with the standard 100 mg q.d. dose, with a minimum of 7 years follow-up.³
• Pleural effusion can occur at any time during treatment with dasatinib (Table 1).^2, 3 In DASISION, the median time to first grade 1/2 pleural effusion was 114 weeks (range, 4-299 weeks).² New cases of pleural effusion occurred in 5% of patients at risk treated with dasatinib 100 mg q.d. compared with 8% in other treatment arms within year 7 of CA180-034.³ 
• pleural effusion can occur after only a few days of treatment

• However, the occurrence of PAH with late-onset in CML patients suggests a chronic pathological mechanism with an insidious onset rather than an acute inflammatory or cardiac etiology
• Dasatinib has a broader effect than other TKIs; the major known difference between dasatinib and other TKIs is the additional inhibition of Src family kinases.
• Therefore, Src inhibition was thought to play a role in the development of dasatinib induced PAH.
• However, recently, it was also speculated that chronic dasatinib therapy may cause pulmonary endothelial damage, attenuate hypoxic pulmonary vasoconstriction responses and increase susceptibility to PAH independently of the Src family kinase-induced mechanism.
• Dasatinib-induced PAH usually seems to be reversible with the cessation of the drug, and sometimes with PAH-specific treatment strategies.
• Transthoracic echocardiography can be recommended as a routine screening prior to dasatinib initiation, and this non-invasive procedure can be utilized in patients having signs and symptoms attributable to PAH during dasatinib treatment

• Soon after initiation of dasatinib treatment, the patient experienced severe diarrhea with abdominal pain, weight decrease, and anorexia that spontaneously resolved within 1 month despite dasatinib continuation. A transient cutaneous eruption was also noticed 4 months later.
• 5 months after starting dasatinib, the patient again complained of asthenia, anorexia and daily diarrhea
• Liver function tests were again within normal range in early July 2007 but revealed a moderate mixed acute hepatitis in early August with transaminase levels at 10 times the upper limit of the normal. 
• There were no clinical or biological signs indicative of hepatic failure.
• resolved 3 weeks after discontinuation of dasatinib 

• Preliminary data suggest that 100 mg once daily (od) may offer a more favorable benefit to harm balance in patients with chronic myeloid leukemia resistant to imatinib or in whom imatinib causes unacceptable adverse effects.
• Compared with conventional twice-daily dosing, intermittent tyrosine kinase inhibition produces clinical remissions with improved safety, with the lowest incidence of pleural effusion (all grades), neutropenia (grades 3–4), and thrombocytopenia (grades 3–4).
• The main adverse effects of dasatinib include grade 3/4 hematological toxicity (for example neutropenia and thrombocytopenia), liver abnormalities, diarrhea, headache, peripheral edema, and hypocalcemia. In addition, pleural effusion is of clinical concern and may need treatment with diuretics and thoracocentesis or pleurodesis
• Dasatinib is well absorbed from the gastrointestinal tract. However, its solubility is pH-dependent, and the AUC of dasatinib can be reduced significantly when antacids or famotidine are used concomitantly (by 55% and 61% respectively). Dasatinib undergoes extensive metabolism by CYP3A4 and has an active metabolite. Further enzymes involved in the metabolism of dasatinib include FMO-3 and UGT isozymes. Exposure to the active metabolite, which is equipotent with the parent compound, contributes to about 5% of the AUC of dasatinib. Dasatinib and its metabolites are primarily excreted via the feces. The half-life of the parent compound is 3–5 hours.
• Two female patients with chronic phase CML, who had failed to reach a cytogenetic response to imatinib developed severe panniculitis after exposure to dasatinib (70 mg bd) - one was mitigated with prednisone while the other was not steroid-sensitive
• Hemorrhage Dasatinib has been found to be associated with an increased risk of bleeding, especially from mucosal surfaces. Although major bleeding events were usually associated with high-grade thrombocytopenia, an aspirin-like effect on platelets may contribute to an increased risk of hemorrhage with dasatinib. Inhibition of secondary hemostasis could not be found.
• T-Cell Inhibition In vitro observations suggest that dasatinib haguet et al., 2016inhibits T-cell proliferation. Whether this effect translates into clinically significant problems such as an increased risk of infection or can be utilized for novel indications such as immunosuppression remains to be determined.

• Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib
• dasatinib (OR_PETO:3.32; 95%CI:1.37 to 8.01) 

• Dasatinib is associated with skin AEs in 35% of studied patients and causes rash (specified as macular, papular, or exfoliative) in 11-27% of patients.
• Rash occurs at a higher rate in patients with accelerated or chronic-phase CML than those with myeloid or lymphoid blast crisis, indicating rash may reflect modulation of certain underlying disease states.
• Dasatinib is associated with mucositis or stomatitis in 16%, pruritus in 11%, as well as rare panniculitis reported in two patients—steroid responsive upon rechallenge in one, and in patients who had prior tolerance of imatinib suggesting a dasatinib-specific effect or the result of its stronger abl inhibition

• The most common adverse event associated with dasatinib therapy is fluid retention, including pleural effusion. Dasatinib-related chylothorax has rarely been reported. The clinical manifestations, pathophysiology, management, and prognosis are not fully understood. Here we report a 40-year-old woman presenting with chylothorax following dasatinib use.

• Pleural effusion occurred in 35% (28/81) of the patients with dasatinib and led to dasatinib discontinuation in 14 patients (grade 2 of 79%). Pulmonary artery hypertension occurred in one patient with dasatinib

• Two weeks after the administration of dasatinib, he had severe lassitude and muscle weakness, and an elevated level of serum creatine kinase
• After the withdrawal of dasatinib, the myalgia reduced, and the CK returned to normal levels (156 U/L) within a week
• On follow-up, acute renal failure did resolve without requiring dialysis.
• Unfortunately, the patient died after clinical deterioration while receiving palliative therapy had progressive severe respiratory distress, with a rapid decline in performance status ultimately leading to cardiorespiratory arrest. The leading cause of death was thought to be severe pulmonary infection

• Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment.
• Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity.
• Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs.
• We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics.
• Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement.
• We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.

• Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Doseoptimization).
• In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034/Dose-optimization.
• With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively.
• A significant risk factor identified for developing pleural effusion by a multivariate analysis was age.
• We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not

• We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic-phase chronic myeloid leukemia patients at 17 Australian institutions.
• Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation.
• Age and dose were risk factors for pleural effusion
• Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced 
• however, recurrence still occurred at 50 mg.
• Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions
• Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients.
• Dose reductions and temporary cessations had minimal impact on MR rates.
• Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.

• Cardiovascular ischemic event incidence in clinical trials was evaluated in 2712 dasatinib-treated patients with Philadelphia chromosome-positive (Ph+) leukemias from 11 first- and second-line trials (pooled), newly diagnosed CML patients treated with dasatinib or imatinib (DASISION), and prostate cancer patients treated with dasatinib or placebo plus docetaxel/prednisone (READY).
• Overall, 2–4% of dasatinib-treated patients had cardiovascular ischemic events.
• Most dasatinib-treated patients with an event had a history of and/or risk factor for atherosclerosis (pooled 77 with history/ risk and event/96 with events; DASISION 8/10; READY 15/18).
• Most cardiovascular ischemic events occurred within 1 year of initiating dasatinib (pooled 69/96; DASISION 7/10; READY 16/18)

• Ten randomized clinical trials (3043 patients) were analyzed. The risk of vascular occlusive events was increased with dasatinib (OR, 3.86; 95% CI, 1.33-11.18), nilotinib (OR, 3.42; 95% CI, 2.07-5.63), and ponatinib (OR, 3.47; 95% CI, 1.23-9.78) compared with imatinib in patients with CML.

Lindauer & Hochhaus

• The drug is rapidly absorbed, and peak plasma concentrations occur 0.5–3 h after administration.
• The intake of food is not relevant to the pharmacokinetics of dasatinib.
• In a dose range of 25–120 mg twice daily, the area under the plasma concentration-time curve (AUC) increased proportionally.
• The drug is extensively metabolized in the liver, predominantly by cytochrome P450 (CYP) 3A4; only 30% remains unchanged.
• The metabolites of the compound are unlikely to play a pharmacologic role. There were linear elimination characteristics over the above-mentioned dose range with a terminal elimination half-life of 5–6 h.
• Elimination occurs mostly in the feces (85%) only little in urine (4%). Dasatinib is excreted as metabolites, and only 19% of a dose was recovered as unchanged drug in the feces 
• More than 300 clinical trials in almost all tumor entities have been performed so far with dasatinib, and about 60 are still ongoing
• The major AE associated with dasatinib was reversible myelosuppression.
• The most common nonhematologic AEs were pleural effusion (28%), myalgia (22%), diarrhea (19%)m, headache (13%), superficial edema (11%), rash (11%), nausea (10%) and pulmonary hypertension (5%) 

• most adverse events are manageable through dose interruption or dose reduction
• pleural effusions are largely manageable through dose reduction or interruption and/or corticosteroids and diuretics
• to minimize the risk of PAH patients should be evaluated for signs and symptoms of underlying cardiopulmonary disease before initiating dasatinib 
• bleeding events, dose interruption, and transfusion
• rashes can be managed with topical or systemic steroids 
• to avoid gastrointestinal upset, take with a meal and a large glass of water 
• supportive medications in case of headache and diarrhea didn't modify the response
• toxicity can be reduced by intermittent dosing (5 days per week 100 mg) 
• substrate and inhibitor of CYP3A4

78 women

+ 69 partners of dasatinib treated men

• Pregnancy-related outcomes in dasatinib-treated patients or their partners reported to Bristol–Myers Squibb from clinical trials or healthcare providers through December 2013 were reviewed.
• Outcomes were available in 46/78 dasatinib-treated women (59%) and 33/69 partners of dasatinib-treated men (48%). Fifteen women (33%) delivered a normal infant; 18 (39%) and 8 (17%) had an elective or spontaneous abortion, and 5 (11%) had an abnormal pregnancy.
• There were 7 reports of fetal/infant abnormalities (encephalocele, renal tract abnormalities, and hydrops fetalis).
• Thirty of 33 (91%) infants fathered by dasatinib-treated men were reported normal at birth. Also, animal studies evaluated the impact of dasatinib on fertility, embryo-fetal toxicity, and development, suggesting that dasatinib may be a selective developmental toxicant.
• The outcomes of most pregnancies conceived by men treated with dasatinib were normal, but due to the small number of cases, further monitoring is required.
• Significant effects on pregnancy outcomes in women treated with dasatinib were found, supporting current recommendations that women avoid becoming pregnant during dasatinib treatment and be informed of fetal risks

Outcomes of switching to dasatinib after imatinib-related low-grade adverse events in patients with chronic myeloid leukemia in chronic phase: the DASPERSE study.

• Dasatinib maintained a consistent safety profile; headache (33%), pleural effusion (26%), fatigue (23%), and rash (23%) were the most common treatment-related adverse events after the switch. 

• A 46-year-old Japanese woman was treated with dasatinib for 7 months after the diagnosis of CML and she achieved a major molecular response (MMR). However, dysphagia, hoarseness, and muscle weakness progressively developed over 2 weeks.
• Nerve conduction studies revealed extensive demyelinating changes. Dasatinib was discontinued and the patient received intravenous immunoglobulin (IVIg), resulting in the resolution of the symptoms.
• However, 1 month after the re-initiation of dasatinib therapy, muscle weakness developed again, indicating a possible involvement of dasatinib in the development of DPN. She was then treated with IVIg, followed by prednisolone and nilotinib instead of dasatinib.
• These treatments eventually led to improvements in the symptoms and helped her achieve an MMR. This case suggests that dasatinib may carry risks of DPN possibly through immune-mediated disorders.

• In this study, the most common nonhematologic adverse events in the Yinishu group were eyelid edema (35.1%, 20/57), followed by skeletal pain (15.8%, 9/57), pruritus (14.0%, 8/57), fatigue (14.0%, 8/57), palpitations (10.5%, 6/57), muscle cramps (8.8%, 5/57), rash (7.0%, 4/57), alopecia (7.0%, 4/57), diarrhea (3.5%, 2/57), pleural effusions (3.5%, 2/57), chest pain (1.8%, 1/57), nausea (1.8%, 1/57), abdominal pain (0%, 0/57), vomiting (0%, 0/57), elevated bilirubin level (0%, 0/57), and elevated levels of liver enzymes (0%, 0/57).
• In addition, for hematologic adverse events, the rates of leukopenia and thrombocytopenia were 21.1% (12/57) and 33.3% (19/57).
• In the SPRYCEL group, the rates of adverse events were as follows: eyelid edema (16.7%, 2/12), skeletal pain (8.3%, 1/12), diarrhea (25.0%, 3/12), pleural effusions (41.7%, 5/12), leukopenia (25%, 3/12) and thrombocytopenia (58.3%, 7/12).

• 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).
• 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.
• Screening for autoantibodies 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.

• 10 patients treated with dasatinib 
• 50% developed hypothyroidism (40% subclinical and 10% clinical)
• hypothyroidism occurred after a median of 22 weeks (range 1–135) 

• Fluid retention (34%)
• Pleural effusion (20%)
• Superficial edema (14%)
• Diarrhea (20%)
• Headache (18%)
• Bleeding (20%)
• CNS bleeding (3%)
• Nausea (20%)
• Fatigue (20%)
• Rash (15%)
• Febrile neutropenia (12%)
• Neutropenia (90%)
• Thrombocytopenia (93%)
• Anemia (97%)
• Leukocytopenia (83%)

• A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib.
• Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib, and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively.

Hepatic adverse events associated with tyrosine kinase inhibitors in patients with chronic myeloid leukemia

paper unavailable online 

• Liver biochemistry parameters [including ALT (alanine aminotransferase), AST (aspartate aminotransferase), ALP (alkaline phosphatase), and TBil (total bilirubin)] during the first 6 months on imatinib (Gleevec(®)), dasatinib (Sprycel(®)) or nilotinib (Tasigna(®)) in CML-CP patients were collected and analyzed retrospectively.
•  A total of 436 patients were enrolled in this study, including 271 with imatinib, 58 with dasatinib, and 107 with nilotinib. The incidences of any abnormality of liver injury were 21.8%(59/271), 15.5%(9/58), and 32.7%(35/107) in the imatinib, dasatinib and nilotinib groups, respectively.
• Most of the hepatic AEs were CTCAE grade 1 or 2 and mild or moderate liver injury except 1.9% of TBil CTCAE grade 3 in the nilotinib group.
• Multivariate analyses showed nilotinib [OR=2.9(1.3-6.6), P=0.012; OR=4.4(1.2-15.6), P=0.023] and male gender [OR=2.3(1.4-3.9), P=0.002; OR=3.0(1.2-7.6), P=0.018] were significantly associated with moderate liver impairment. 
• TKIs including imatinib, dasatinib, and nilotinib were well tolerated with mild to moderate hepatic AEs in CML-CP patients. Nilotinib and male sex were associated with the occurrence of liver biochemistry abnormalities and moderate hepatic injury.

• The dose was very variable (from 50 to 140 mg) and always administered in a single daily dose.
• The PE appeared within 2–60 months after starting the treatment, after having ruled out other causes of PE.
• The PE grades (according to the National Cancer Institute Common Terminology Criteria for adverse events, version 3.0) were from 1 to 3, with no accompanying pulmonary lesions or mediastinal masses in the chest computed tomography.
• The treatment ranged from the administration of diuretics (two patients) and oral corticosteroids (one case) to therapeutic thoracentesis (two patients), a decrease in the dose of the drug (in all of them) and finally stopping it in two cases.
• The response was a decrease in the PE in two patients and resolving it in the other two.

• Interestingly, dasatinib-associated hemorrhages occurred both in patients with and without thrombocytopenia
• In vitro and in vivo investigations demonstrated that dasatinib affects both platelet functions (i.e., platelet aggregation, secretion, and activation) and platelet formation by impairment of megakaryocyte migration.
• Furthermore, dasatinib decreases thrombus formation in vitro, in vivo, and ex vivo and decreases the number of procoagulant platelets (i.e., phosphatidylserine exposing platelets)
• Several dasatinib off-targets are implicated in platelet signaling and functions including members of the SFKs (e.g., Src, Lyn, Fyn, Lck, and Yes)
• dasatinib and mostly nilotinib are associated with an increase of cholesterol level
• Dasatinib and nilotinib might also decrease blood lipid clearance (e.g., disturbance of LDLR and LPL synthesis). The development of dyslipidemia might contribute to the occurrence of arterial occlusive events that occurred with nilotinib and dasatinib
• Therefore, in vivo and in vitro studies investigated the effect of imatinib and dasatinib on pulmonary ECs and demonstrate that dasatinib induces apoptosis on pulmonary ECs mediated by increased mitochondrial ROS production.
• Finally, dasatinib is associated with decreased T-cell functions and particularly it decreases the production of proinflammatory cytokines (e.g., TNF-α, IFN-γ) and chemotactic mediators.

• 370 chronic myeloid leukemia patients receiving dasatinib, nilotinib, or imatinib therapy ≥3 months were retrospectively reviewed.
• During TKI-therapy, the mean fasting glucose, triglyceride, cholesterol, and LDL-cholesterol levels increased significantly in both dasatinib and nilotinib cohorts compared with the imatinib cohort.
• In multivariate analyses, dasatinib was the factor significantly associated with both poor hyperglycemia- and hypertriglyceridemia-free survival.
• In addition, nilotinib was significantly associated with more occurrences of hyperglycemia and hypercholesterolemia; increasing age was significantly associated with more occurrences of hyperglycemia and hypertriglyceridemia.
• We concluded that dasatinib, similar to nilotinib, has an adverse impact on glucose-lipid metabolism compared with imatinib.

• The patient noted swelling of her face and erythema of the cheeks, forehead, and chin 1 to 2 days after initiation of the drug. She reported that the areas did not itch and were not painful.
• Cutaneous examination demonstrated erythema with slight scaling on the forehead, malar cheeks, upper lip, and chin area of the face. The facial erythema and scaling favored the diagnosis of a seborrheic dermatitis-like eruption.
• The sequence of events and time course suggested that this facial eruption occurred secondary to dasatinib. Topical desonide 0.05% ointment was initiated twice daily. Within a few weeks, the patient developed dehydration and failure to thrive requiring hospitalization for rehydration and correction of her electrolyte imbalance. Dasatinib was discontinued and her facial rash resolved.

• Patient 1: Therapy with dasatinib (100 mg daily) was initiated in January 2008. One week later, the patient developed grade I pulmonary edema. Dose-reduction to 50 mg dasatinib daily was followed by regression of symptoms. In February 2009, the patient developed symptomatic pleural effusions and received diuretics and glucocorticosteroids. In March 2009, the patient presented with grade III pleural effusion and pneumonia requiring hospitalization. In May 2009, the patient also relapsed with herpes zoster. Dasatinib was discontinued
• Patient 2: Dasatinib (100 mg/day) was started in March 2009. A few days later, pneumonia and massive pleural effusions with consecutive right heart failure developed. The patient was hospitalized and received antibiotics and diuretics. Dasatinib was discontinued for two weeks
• Patient 3: In August 2009 dasatinib (100 mg/daily) was started. However, after four months dasatinib had to be discontinued because of grade IV cytopenia and pericardial effusion. Dasatinib was again started in January 2010 at 50 mg daily. However, after one month the patient developed a gastrointestinal infection as well as pericardial and pleural effusions
• Patient 4: In April 2008, dasatinib at 100 mg was started. No relevant side-effects were recorded until May 2010 when the patient developed bronchitis followed by severe dyspnea. A chest X-ray revealed marked pleural effusion without pneumonia. The patient received diuretics and prednisolone (25 mg/day) which resulted in a rapid improvement in clinical condition

• Grade 2‐5 non‐hematological AEs were observed in 22 (40%) patients treated with nilotinib and in 21 (42%) treated with dasatinib arm (p=0.83).
• The median time to AE onset was 29 months for dasatinib
• 96% of AEs were Grade 2 or 3
• 4% of patients suffered a vascular event
• 26% pleural effusion
• 4% metabolic/biochemistry ALT, AST, bilirubin, glucose, lipids
• 6% skin rash
• 2% pericardial effusion
• 4% pulmonary hypertension
• 6% musculoskeletal pain 
• 2% diarrhea

• After treatment with dasatinib, he had multiple pleural effusions that were suspected to be caused by congestive heart failure.
• Later a transthoracic Doppler echocardiography and right-sided heart catheterization revealed severe pulmonary hypertension with pulmonary vascular resistance of 12 Wood units and mean pulmonary artery pressure of 53 mmHg.
• Computed tomography ruled out a possible pulmonary embolism; laboratory-specific tests for human immunodeficiency virus, rheumatoid factor, and anti-nuclear antibodies were negative, and dasatinib-induced pulmonary arterial hypertension was diagnosed.
• A follow-up right-sided heart catheterization and 6-minute walk test done a month after the discontinuation of dasatinib showed significant improvement: mean pulmonary artery pressure of 34 mmHg and pulmonary vascular resistance of 4 Wood units.

• Six patients (29%) developed PE within 6 months of treatment; all were ≤ grade 2. PE resolved after treatment with diuretics and reduction/interruption of the dasatinib dose. Twenty patients (96%) received diuretic drugs, irrespective of PE.
• All patients with PE had LGL lymphocytosis. No patient suffered pulmonary arterial hypertension (PAH).

• A rare side effect of dasatinib treatment is the reactivation of latent cytomegalovirus (CMV) infection. Never before has dasatinib therapy shown to be the cause of CMV hepatitis in an immunocompetent patient.
• We present a case of an immunocompetent patient who was treated with the standard dose of dasatinib therapy and subsequently developed CMV hepatitis. Well-known side effects of dasatinib therapy are understood and documented; unknown adverse drug reactions can occur and should be monitored for.
• This is a significant finding given the high rate of CMV seropositivity in the general population

• She was started on dasatinib therapy, titrated to a dosage of 100 mg/d, and had complete hematologic remission within 3 months of initiation. At her 3-month follow-up visit, she had protein (3) on urine dipstick, quantitated as 3,853 mg of protein per 24 hours.
• The morphologic features were consistent with low-grade endothelial injury and chronic thrombotic microangiopathy.
• Dasatinib treatment was discontinued and replaced with imatinib, 400 mg daily. Two weeks later, the spot urine protein creatinine ratio had decreased from 2.8 to 0.13 g/g. Serum creatinine level remained normal. At the patient’s 4-month follow-up visit, CML remained in remission and 24-hour urine protein excretion was 176 mg/24 h. With the patient’s rapid response to changing medications, this likely was dasatinib induced.

• Seventeen studies were included in the network meta‐analysis.
• Our data show that dasatinib was generally considered worse than the other TKIs, with SUCRA values for 140 mg dasatinib of 90.3% for anaemia, 87.4% for leucopenia, 90.6% for neutropenia and 97.2% for thrombocytopenia.
• Dasatinib appeared as the least safe drug for chronic myeloid leukaemia, probably because it binds to multiple key kinase targets, being more prone to cause serious haematological adverse events. Nilotinib demonstrated a safer profile, mostly due to its selective binding capacity.

Study on efficiency and safety of dasatinib in Chinese patients with chronic myelogenous leukemia who are resistant or intolerant to imatinib

paper unavailable online

• Grade 3-4 of hematologic AEs related to dasatinib were frequent but manageable by dose interruption/reduction or supportive care.
• 52.5% and 61.0% of pts in CP experienced grade 3-4 of neutropenia and thrombocytopenia.
• More than 80% of pts in AP/BP had grade 3-4 cytopenia.
• The common non-hematologic AEs related to dasatinib were including grade 1-2 pleural effusion, headache, pneumonia, and diarrhea.
• The frequency of non-hematologic AE was higher in pts with AP/BP than in pts with CP.

• We report a 58-year-old female dasatinib-treated patient with Ph+ chronic phase CML who was admitted to our hospital due to persisted dyspnoea and fever.
• After reviewing the laboratory and clinical findings, we determined our patient as having simultaneously ARF and PE related to dasatinib therapy.
• Dasatinib was discontinued, and after 10 days of treatment with ampicillin-sulbactam, allopurinol, amlodipine, furosemide, and methylprednisolone, she was discharged home effusion free and with ameliorated renal function

• We report a case of hemorrhagic colitis associated with dasatinib use in a patient with chronic myelogenous leukemia.
• The process rapidly resolved following drug discontinuation but relapsed when rechallenged with a reduced dose of dasatinib.
• Colitis did not recur when the patient was treated with an alternative agent.
• A literature review of prior cases involving dasatinib-induced T-cell mediated colitis provides insight into commonalities that may facilitate the recognition and management of this entity.
• Most incidences occurred after 3-month drug exposure and may be accompanied by large granular lymphocytes

• acute myocardial infarction (1061 days of treatment)
• arrhythmia (22 days of treatment)
• stroke (2909 days of treatment) 

• The most common drug-related toxicities were gastrointestinal complaints, headache, asthenia, and pleural effusion.
• Grade 3-4 toxicity occurred in 37% of patients and was comparable between doses; drug-related serious adverse events were less frequent with 70 mg twice daily than 100 mg twice daily.

• Grade 3-4 toxicities were gastrointestinal (mostly nausea and emesis; n=4), pulmonary (dyspnea and/or pleural effusion; n=4) and pain (n=5), and infrequent instances of anemia, malaise, insomnia, rash, and central nervous system hemorrhage. 

• Rates of grade 3 or 4 hematologic AEs were higher for dasatinib versus imatinib (neutropenia, 29% v 24%; anemia, 13% v 9%; and thrombocytopenia, 22% v 14%, respectively). Except for pleural effusion, drug-related, nonhematologic AEs were reported less frequently with dasatinib than imatinib or were comparable
• Drug-related pleural effusion was more common with dasatinib (28%) than with imatinib (0.8%). Sixty-six patients (26%) experienced grade 1 or 2, seven patients (3%) experienced grade 3 or 4, and no patients experienced grade 5 pleural effusion on dasatinib. Pleural effusion developed in approximately 8% of at-risk dasatinib-treated patients in year 1 of therapy and was comparable each subsequent year (Appendix Table A3, online only). The percentage of patients who developed pleural effusions was higher in patients age 65 years (15 of 25 patients; 60%) compared with patients younger than age 65 years (58 of 233 patients; 25%). Drug-related pleural effusion was managed with dose interruption (62%) and/or dose reduction (41%), diuretics (47%), corticosteroids (32%), or therapeutic thoracocentesis (12%
• Pulmonary hypertension (PH), which was diagnosed with two-dimensional echocardiography, was reported in 14 dasatinib treated patients (5%)
• Arterial ischemic events were uncommon in both the dasatinib (5%) and imatinib (2%) treatment arms. Seven of 10 cardiovascular ischemic events occurred within year 1 of dasatinib therapy.

• As to hematologic toxicity, 24 patients (22%) experienced thrombocytopenia, with an incidence of grade 3/4 events of 45.8% (10% of overall cohort).
• Eleven patients experienced neutropenia, with an incidence of grade 3/4 events of 64% (6% of the overall cohort).
• Anemia of grade 3 was observed in 7 patients (6%) requiring in most of them the use of erythropoietic stimulating agents during treatment.
• One patient developed lymphocytosis that persisted during the whole follow-up.
• Twenty-eight patients (25.6%) experienced non-hematologic toxicity with the major side effects reported being headache, skin rash and diarrhea (grade 1–2 events), with only a few grade 3 events.
• Nine patients (8%) experienced a pleural effusion, which was recurrent in 3 patients for whom was the final reason for permanent therapy discontinuation. Pleural effusion occurred after a median time of 6 months (range 2–10 months): all patients were treated with temporary discontinuation and low doses of steroids plus diuretic treatment.
• Other recorded particular side effects reported were papilledema in 1 patient, bone pain in 1 patient, vomiting and nausea in 1 patient, increased pancreatic enzymes in 1 patient, and lymphadenopathy in 1 patient. In this latter patient, a biopsy was performed with a final diagnosis of follicular hyperplasia

• Of the 65 patients with score 0, 29% had at least one suspension (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)
• During dasatinib treatment, 41/125 patients (32.8%) presented with a pleural effusion, which was of grade 2 in 31 patients and of grade 3 or 4 in ten patients (24.4%
• the 41 patients with pleural effusion and 8% of the entire cohort of patients), according to the WHO scale; in 11/41 patients (26.8%), there was a concomitant pericardial effusion. In addition, pleural effusion was recurrent in 19/41 patients (46.4%).
• The median time from starting dasatinib treatment to the occurrence of the first pleural effusion was 10.4 months (interquartile range, 2.2 – 18.1).

• Bleeding in patients with chronic myeloid leukemia (CML) receiving the second-line tyrosine kinase inhibitor (TKI) dasatinib is a well-documented side effect, occurring in up to 24% of patients.
• In most cases, it is attributed directly to a secondary grade 3 or 4 thrombocytopenia. Platelet dysfunction precipitated by dasatinib has been demonstrated in multiple in vitro and in vivo studies; however, there is currently no correlative data that definitively associate this with clinically significant bleeding.
• In this case, we report a patient with chronic-phase CML receiving dasatinib who developed significant gastrointestinal bleeding secondary to angiodysplasia in the absence of severe thrombocytopenia or coagulopathy.
• Platelet function testing on the PFA-100 assay and formal platelet aggregometry demonstrated impaired platelet aggregation, however, upon cessation of dasatinib, platelet function normalized and the bleeding resolved without further intervention. This case demonstrates that dasatinib-induced platelet dysfunction can cause clinically significant bleeding and highlights the need for physicians to be aware of this adverse effect.

• Recently, lymphadenopathy with morphologic features of reactive follicular hyperplasia was described in a cohort of patients with CML on long-term dasatinib therapy.
• Herein, we report 3 cases of unexplained lymphadenopathy resulting in multiple diagnostic procedures in patients with CML and a history of long-term dasatinib therapy.
• Morphologic examination demonstrated preserved nodal architecture showing hybrid features of progressive transformation of germinal centers and Castleman-type changes in a background of florid follicular hyperplasia.
• Large germinal centers were disrupted by complex infolding of IgD+ mantle zones arranged as cuffs surrounding perforating capillaries. Other abnormalities variably present included decreased CD20 expression among polytypic B cells and increased Epstein-Barr virus reactivity in scattered paracortical cells and/or individual germinal centers.
• B-cell clonality studies showed no predominant clonal rearrangements. Consideration of dasatinib-related lymphadenopathy may pre-empt unnecessary repeat diagnostic procedures in patients with CML or other dasatinib-susceptible malignancies and persistent lymphadenopathy

• Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia.

• While the most commonly reported cutaneous side effects with this therapy include a morbilliform eruption, skin exfoliation, and skin irritation, pigmentary abnormalities have also been observed, albeit much more rarely.
• We present the case of a 72-year-old South Asian male with CML who presented with new-onset hypopigmentation of his face and scalp three years after a dose increase of dasatinib therapy, in the setting of newly discovered borderline hypovitaminosis D.
• Dasatinib and the other TKIs are believed to induce dyschromia via modulation of the c-kit receptor and its associated signaling pathway, which is involved in melanocyte survival, proliferation, and migration.
• 5 other cases have reported dasatinib-related hypopigmentation that ranged from 4-24 weeks time to onset

• Dasatinib produced substantial and sometimes severe or even life-threatening side effects with ‡ 10% body weight loss (6 ⁄ 16 patients), pleural effusions grade II or higher (12 ⁄ 16), and infectious complications (12 ⁄ 16), including atypical infections not seen in imatinib-treated patients.
• One patient developed Epstein–BarrVirus-positive mucosal leucoplakia, one died from pneumonia caused by pneumocystis carinii and three patients developed skin cancer.
• Most events were recorded within the first 2 years of therapy, only skin tumors developed after the second year.
• In ex vivo experiments performed in dasatinib-treated patients, transient suppression of IgE-dependent activation of blood basophils and TcR-dependent activation of T-lymphocytes was found.
• Moreover, in drug-binding studies, dasatinib was found to bind to several key kinase-targets of the immune system including Lyn and Btk, in mast cell, basophil, B-cell, and T-cell lines.

in vivo

in vitro

• Dasatinib at 0.03 and 0.3 mg/kg was intravenously administered to the halothane-anesthetized dogs for 10 min with an interval of 20 min between the dosing (n=4).
• Meanwhile, 0.1, 0.3, and 1 μM were cumulatively applied to the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (n=7).
• In the dogs, the low and high doses provided peak plasma concentrations of 40±5 (0.08) and 615±38 ng/mL (1.26 μM), respectively.
• The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period.
• The high dose prolonged the repolarization period, induced hemorrhagic tendency, and increased plasma cardiac troponin I level in addition to enhancement of the changes observed after the low dose, whereas it neither affected the cardiac conduction nor induced ventricular arrhythmias.
• In the hiPSC-CMs, dasatinib prolonged the repolarization and refractory periods like in dogs, while it did not induce apoptotic or necrotic process, but that it increased the conduction speed. 

• Pulmonary adverse events are common abnormalities associated with the use of dasatinib in chronic myeloid leukemia. We present a case of a 69-year-old man who suddenly developed a rare chylothorax pulmonary adverse event following 10 months of dasatinib treatment.

• This report describes a case of osteonecrosis of the jaw that developed following a routine dental extraction in a patient being treated with dasatinib, a tyrosine kinase inhibitor, for chronic myelogenous leukemia. As the role of tyrosine kinase inhibitors in cancer treatment expands, patterns of debilitating complications involving the osseous structures of the oral cavity have begun to emerge, and many long-term side effects of this promising therapy remain unknown. To limit the occurrence of known complications, health care providers and patients must be aware of the potential for serious complications of dasatinib and have appropriate protocols developed prior to their administration.

• Although pneumonia is not uncommon among dasatinib-treated patients, dasatinib-associated PJP has been reported only once in the literature, without a description of the clinical details. We report herein two cases of PJP in patients receiving treatment containing dasatinib.
• One patient developed PJP at 7 months following dasatinib in combination with chemotherapy for the treatment of acute lymphoblastic leukemia.
• The other patient developed pleural effusion and PJP at 2 years following dasatinib treatment for chronic myeloid leukemia.
• Both patients recovered well after management with sulfamethoxazole/trimethoprim.

• A 51-year-old man with chronic myeloid leukemia undergoing treatment with dasatinib received colonoscopy for a positive fecal occult blood test.
• Colonoscopy revealed more than 100 erythematous, multilobulated polyps with mucoid discharge.
• Endoscopic mucosal resection was performed for diagnosis, and the histological analysis of polyps showed hyperplastic glands and proliferative smooth muscle cells.
• Our findings suggested that the polyposis was caused by inflammation triggered due to the adverse effects associated with dasatinib.
• The patient discontinued dasatinib; the follow-up colonoscopy performed four months later revealed significantly improved polypoid lesions in the colon. The erythematous heads of the polyps and mucoid discharge disappeared.
• The cessation of dasatinib seemed to contribute to the improvement of inflammatory reactive polyposis; therefore, we inferred that the polyposis was caused by dasatinib in the present case.

• A 63-year-old man with multiple vascular risk factors and chronic myelogenous leukemia (in molecular remission) on dasatinib presented with signs and symptoms of right hemispheric stroke owing to acute intracranial internal carotid artery occlusion that was treated with intravenous thrombolysis and mechanical thrombectomy resulting in near-complete resolution of stroke symptoms.
• The patient developed clinical worsening (>24 hours of thrombolytic therapy) after receiving a second dose of dasatinib that was due to symptomatic intracerebral hemorrhage and necessitated decompressive hemicraniectomy. Routine coagulation profile was normal.
• The etiology of this hemorrhagic complication was likely secondary to primary platelet dysfunction due to dasatinib as reported in some recent in vitro and ex vivo studies.

• Grade 2 to 4 neutropenia and/or thrombocytopenia occurred in 94 (72%) patients during dasatinib therapy and grade 3 to 4 occurred in 67 (52%) patients.
• Of the 94 patients who developed grade 2 to 4 neutropenia and/or thrombocytopenia, 64 (68%) also developed at least grade 2 anemia, and 16 (17%) developed grade 3 to 4 anemia.
• Management of cytopenias included transient dasatinib interruption in 35 (37%) patients, filgrastim in 12 (14%) patients, recombinant erythropoietin in 29 (45%) patients, and interleukin-11 in 3 (5%) patients.
• Factors associated with an increased risk for developing grade 2 to 4 cytopenias were longer time from diagnosis to treatment, prior interferon or imatinib therapy, and a lower white blood cell count at the initiation of dasatinib therapy. 

• This study reports a very rare case of a 60-year-old male who suffered from severe thrombocytopenia after dasatinib administration. Time to onset was less than one month and an aggravation occurred at 5 months
• The platelet count did not increase even after dasatinib had been discontinued for more than 6 months.
• Various means had been tried, but the count of platelet did not increase, and the result was not optimistic. This is the first report of so severe thrombocytopenia after dasatinib treatment, and the pathophysiology underlying this reaction remains unknown.

• Eleven of 15 patients (73%) who initiated treatment with dasatinib at a dose of 100 mg twice daily required protocol-specified dose reduction for toxicity compared with 53 of 174 patients (31%) who initiated treatment at a dose of 70 mg twice daily. 
• the treatment schedule was changed from 50 mg twice daily (dosing level 1) to 100 mg once daily (dosing level 2) in 15 patients (9%).
• A total of 86 patients experienced a total of 127 serious AEs, 50 of which were attributed to dasatinib. One event of sudden death was possibly related to dasatinib, but the other deaths that occurred on treatment were attributed to sarcoma progression.
• Electrocardiograms were available for 198 patients and 143 patients, respectively, before and after 4 weeks of treatment.
• The mean and median corrected QT intervals before and after 4 weeks of treatment were 424 milliseconds and 427 milliseconds and 432 milliseconds and 436 milliseconds, respectively, and lengthened to >500 milliseconds in only 2 patients.
• Other cardiovascular events included 1 episode each of atrial and ventricular tachyarrhythmia; 2 episodes each of hypotension, palpitation, and pericardial effusion; and 1 episode of syncope.
• Hematologic toxicity was infrequent with grade 1 neutropenia, lymphopenia, and thrombocytopenia occurring in 4.1%, 3.6%, and 6.7% of patients, respectively; however, anemia was reported in 24% of patients

• Overall, significantly fewer patients treated with 100 mg once daily experienced grade 3 to 4 AEs than patients receiving the currently approved 70-mg twice-daily dose (30% v 48%), particularly grade 3 to 4 thrombocytopenia (22% v 37%).
• In general, cytopenia was reversible and could be managed effectively through dose interruption or reduction and/or with the addition of growth factors or transfusions.
• Significantly fewer patients experienced pleural effusions (of any grade) with dasatinib 100 mg once daily than with 70 mg twice daily (7% v 16%). In general, pleural effusions resolved with temporary dose interruption, diuretics, and/or pulse corticosteroids. Grade 3 to 4 pleural effusions were reported in 1% to 2% of patients in each treatment group. Grade 2 pleural effusions (also symptomatic) were reported in 4% (100 mg once daily), 7% (50 mg twice daily), 10% (140 mg once daily), and 11% (70 mg twice daily) of patients. Grade 1 pleural effusions (asymptomatic and detected by routine chest x-rays) were reported in 2% (100 mg once daily, 50 mg twice daily, 140 mg once daily) or 4% (70 mg twice daily) of patients.
• Drug-related nausea (15% v 25%) and vomiting (5% v 10%) of any grade occurred in fewer patients receiving 100 mg once daily than 70 mg twice daily. Rates of other treatment-related nonhematologic AEs were similar between treatment groups. The most commonly reported grade 3 to 4 nonhematologic AEs among all four treatment groups were diarrhea (2% to 5%), dyspnea (1% to 5%), fatigue (0% to 3%), and headache (0% to 3%).

• We describe a case of a man with chronic myeloid leukemia who achieved remission through dasatinib therapy after being unable to tolerate several tyrosine kinase inhibitor (TKI) regimens due to severe physical side effects.
• However, this coincided with the onset of distressing agitation, insomnia, and motor restlessness leading him to take a large zopiclone overdose.
• The start of appropriate therapy with clonazepam, venlafaxine, and mirtazapine in combination led to a rapid improvement in symptomatology.

• 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.

• Most commonly seen side effects with Tyrosine kinase inhibitors (TKI’s) are hematologic toxicities.
• Besides, with dasatinib autoimmune side effects can be seen.
• Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that can be related to various causes mainly autoimmune disorders or antineoplastic drugs.
• Few cases of TKI associated secondary thrombotic microangiopathies (TMA) have been reported in the literature.
• Most of the cases were diagnosed as a hemolytic uremic syndrome (HUS) rather than TTP.
• Herein, we describe a 37-year-old CML patient who was diagnosed as immune-mediated TTP related to dasatinib.

• The patient received intensive chemotherapy and dasatinib 100 mg/day. After achieving complete cytogenetic and major molecular response after 9 months of therapy, she developed bloody diarrhoea and pancytopenia.
• Colonoscopy showed inflammation of the descending colon and histopathology revealed patchy increase in intraepithelial lymphocytes. Dasatinib was stopped with prompt resolution of diarrhoea.
• The current literature suggests that there is an association in a subset of patients on dasatinib between clonal T-cell lymphocytosis in the peripheral blood and developing colitis and pleural effusions

• 140 mg of dasatinib was administered once daily instead of imatinib, which had been administered to him until then. After dasatinib treatment, his peripheral white blood cell and myeloblast counts were shown to have decreased.
• 2 months after dasatinib administration, watery diarrhea occurred four to six times a day. Although he did not take any drug except those prescribed by the authors and had already stopped taking deferasirox, which might cause diarrhea, his diarrhea persisted.
• 3 months after using dasatinib, he came to the emergency department with hematochezia and fever. The abdominal computed tomography (CT) scan showed only generalized bowel wall edema. In a colonoscopy, several mucosal hyperemia and edema with spontaneous bleeding were observed without definite ulceration or mass
• Colonoscopic biopsy specimen stained with hematoxylin and eosin stain was consistent with active colitis
• Microbial and parasite examination using the stool specimen isolated no organism. He was diagnosed with acute colitis and recovered via conservative management and intravenous hydration. In a follow-up 1 month later, dasatinib was re-administered, and then bloody diarrhea occurred again.

• The patient opted for dasatinib as upfront therapy, which was started as 100 mg orally once daily and the patient was followed up as per European leukemia net (ELN) guidelines.
• She achieved CHR, CCyR, and MMR after receiving dasatinib for 30 months. However, during her last clinic visit, she complained of diarrhea, which she described as having been watery for the past 2 months.
• During the last week, she described bloody diarrhea. The patient was admitted to the hospital for further evaluation and management. Her workup showed normal hemogram and normal serum concentrations of creatinine, urea, hepatic enzymes, and electrolytes on admission.
• Colonoscopy showed multiple, linear, polypoidal-like lesions all over the colon up to the hepatic flexure. Endoscopic diagnosis revealed a picture of infectious colitis suggestive of CMV

• Bleeding occurred in 32 (23%) patients (grade ≥3 in 9 [7%] patients [according to National Cancer Institute Common Toxicity Criteria]), including in 12% of patients treated in chronic phase, 31% of patients treated in accelerated phase (AP), and 35% of patients treated in blast phase (BP)
• The majority of episodes (81%) affected the gastrointestinal tract.
• Basic coagulation studies were normal in 97% of patients who developed bleeding complications. Although 37% of episodes occurred with platelet counts >100 × 109 /L, multivariate analysis identified thrombocytopenia and advanced phase CML as risk factors for bleeding. A trend toward an increased risk with a twice-daily schedule was observed (P = .17). Management included dasatinib interruption for a median of 17 days (range, 3–51 days) in 47%, of patients and transfusions in 72% of patients.
• The median time to the development of bleeding was 6 weeks (range, 0.5–38 weeks), and this occurred within the first 3 months of therapy in 22 (69%) patients.

• We report the case of a 12-year-old male known case of CML, who presented to the dermatology clinic approximately 2 years after initiating dasatinib treatment, with new-onset hypopigmentation of his upper limb, upper chest, and both knees of six months’ duration.
• #1 12 yr old male with chronic myeloid leukemia treated with D 70 mg once daily -onset of hypopigmentation after 18 months
• #2 72 yr old male with chronic myeloid leukemia, 100 mg once daily, onset of hypopigmentation at  37 
• #3 52 yr old female with hemangiopericytoma, 70 mg twice daily, onset of hypopigmentation at 2 months 
• #4 27 yr old female with chronic myeloid leukemia, 100 mg once daily, onset of hypopigmentation after 6 months 
• #5 16 yr old male with acute lymphoblastic leukemia, 100 mg twice daily, onset of hypopigmentation after 1 month
• #6 56 yr old female with chronic myeloid leukemia,70 mg once daily, onset of hypopigmentation after 2 months
• #7 29 yr old female with chronic myeloid leukemia 70 mg once daily, onset of hypopigmentation after 2 months

• We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers.
• We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR).
• DAS was temporarily interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases.
• Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent the recurrence of this AE.
• Therefore, once an MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.

• A 67-year-old female patient who was taking 50 mg/day dasatinib for one month because of imatinib-resistant Ph (+) CML admitted to hospital because of diarrhea, nausea, and vomiting
• Renal biopsy was performed, and microscopic findings were compatible with acute tubular necrosis
• After reviewing the laboratory and clinical findings, we determined our patient as having acute renal failure related to dasatinib therapy and we discontinued the drug. After 10 days, with conservative treatment, laboratory data were as follows: BUN 26 mg/ dL, serum creatinine 1.6 mg/dL, blood pH 7.49, and blood HCO3 26.1 mmol/L. We began nilotinib 400 mg twice a day. On her follow-up, there were no pathological clinical findings.

• In this case, we report a patient affected by precursor B-cell acute lymphoblastic leukemia (ALL) positive for the Ph chromosome translocation treated with the tyrosine kinase inhibitor (TKI) dasatinib. During treatment with dasatinib, the patient developed a subdural hematoma (SDH). She did not have any head trauma, thrombocytopenia, coagulopathy, or meningeal involvement, making dasatinib-induced platelet dysfunction the most likely cause of SDH.
• intermittent use of dasatinib over two years

• Dasatinib was generally well tolerated. The majority of nonhematologic adverse events occurring during the course of the study were grade 1 to 2.
• The most common adverse event was diarrhea, which occurred in 52% of patients, and was grade 3 or 4 in 8%. Grade 3 to 4 gastrointestinal bleeding was reported by 6% of patients (all grades, 9.5%)
• Cytopenia was common, including grade 3 to 4 neutropenia (76%) or thrombocytopenia (82%). These were usually reversible and manageable through transient dose interruption or dose reduction. Similarly, infections that occurred in patients with or without neutropenia were manageable in the majority of all patients, although some developed severe life-threatening infections during dasatinib (at least nine deaths were attributable to infections).
• Grade 3 to 4 pleural effusions occurred in eight patients (5%; all grades, n 47, 27%; grade 1, n 5, 3%; grade 2, n 34, 20%). The median time to appearance of grade 2 to 4 pleural effusions was 124 days (range, 15 to 500 days).
• Few patients experienced cardiac events. One patient (1%) had a grade 1 ECG change, and another patient ( 1%) had a grade 2 arrhythmia. 

• growing evidence suggests that dasatinib can cause drug-induced pulmonary arterial hypertension (PAH), with more than 100 cases of dasatinib-induced PAH (DASA-PAH) having been reported
• dasatinib (100 mg daily), was chosen as his second-line therapy 5 years before presentation. Concomitant pleural effusion and anemia was thought to have caused the dyspnoea 2 years prior to presentation; subsequently, an additional dose of diuretics and a reduced dose of dasatinib (50 mg daily) resulted in a transient improvement of dyspnoea following a decrease in the amount of pleural effusion and a slight increase in hemoglobin without further evaluation

• Dasatinib is associated with an increased risk of bleeding among patients with chronic myeloid leukemia, even in the absence of thrombocytopenia, suggesting the presence of a hemostatic defect.
• We tested platelet aggregation in 91 patients with chronic myeloid leukemia in the chronic phase either off-therapy (n 4) or receiving dasatinib (n 27), bosutinib (n 32), imatinib (n 19), or nilotinib (n 9).
• All but 3 patients simultaneously receiving imatinib and warfarin had normal coagulation studies.
• All 4 patients off therapy had normal platelet aggregation.
• Impaired platelet aggregation on stimulation with arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively.
• Dasatinib 400 nM induced rapid and marked prolongation of closure time to collagen/epinephrine in normal whole blood on the PFA-100 system. 

• An amendment in dasatinib dosing from 100 to 70 mg twice daily was made in an attempt to decrease the incidence of pleural effusions. However, on analysis, there was no significant difference between the two cohorts, and pleural effusions (any grade) were reported in 51% of the overall population. Pericardial effusions were also similar between dosing cohorts, occurring in 23% of all patients (grade 1 only).
• Aside from pleural effusion, the most common adverse events were diarrhea (62%), nausea (47%), and fatigue (45%).
• Most adverse events experienced were grade 1/2 in severity. This included 15 of 47 (32%) patients who developed grade 1/2 hypocalcemia, none of which worsened with ongoing dasatinib treatment.
• Adverse events were generally reversible and manageable with dose interruptions or reductions. 
• The median duration of therapy was 2.8 months (range 0.03–13.8 months). 

• Sixteen patients were treated with dasatinib in the following doses: 100 mg (nine patients), 150 mg (three patients), and 200 mg (four patients).
• The most frequent adverse events (AE; ‡50%) were anorexia, fatigue, pleural effusion, anemia, constipation, diarrhea, vomiting, and increased aspartate aminotransferase (AST).
• The most frequent AE of grade ‡3 (‡10%) were anemia, decreased lymphocyte count, fatigue, and increased blood magnesium.
• Dose-limiting toxicities were observed in two patients: grade 2 pleural effusion and bronchial wall thickening at the 100-mg level and grade 3 dyspnea at the 200-mg level.
• In addition, grade 2 pleural effusion was observed in all four patients treated with 200 mg. Therefore, 150 mg was determined to be the MTD.

• A 52-year-old African American female with a history of metastatic hemangiopericytoma was initiated on dasatinib as part of a clinical trial.
• After 2 months of treatment, she developed generalized skin hypopigmentation.
• Within 1 month of discontinuing the drug, the patient’s skin pigmentation returned to normal.
• However, she then developed diffuse skin hyperpigmentation over the next couple of months.
• The hyperpigmentation was self-limited, and eventually resolved after several months

• The patient had complained of a mild headache shortly after initiation of dasatinib therapy, which gradually aggravated over the next 4 weeks. She had no prior history of head trauma. No abnormal findings were observed upon examination of cranial nerve function. Platelet count was 42,000/mm3, and the coagulation profiles were within normal ranges
• A computed tomography (CT) scan of the head revealed bilateral SDH
• The patient’s headache improved after surgical intervention, and she was rechallenged with dasatinib 100 mg once-daily 22 days after dasatinib discontinuation. The patient complained of a headache again 1 month after dasatinib re-administration 

Hair depigmentation during chemotherapy with dasatinib, a dual Bcr-Abl/Src family tyrosine kinase inhibitor.

paper unavailable online

• This article reports the case of a patient who experienced depigmentation of her eyelashes, eyebrows, and temporal scalp hair six-to-eight weeks after initiating treatment with dasatinib (BMS-354825 or Sprycel), a novel dual Bcr-Abl/Src family tyrosine kinase inhibitor for chronic myeloid leukemia (CML).
• This case illustrates a previously unreported side-effect of dasatinib that is most likely due to the drug's inhibition of the c-kit, Src family, and platelet-derived growth factor receptor beta (PDGFRbeta) tyrosine kinases.

• Three years after initiation of treatment with dasatinib the patient was admitted to hospital with a two-month history of diarrhea (bowel frequency 8 times/24 hours), rectal bleeding, and weight loss
• Seven days after withdrawal of dasatinib he was asymptomatic—opening his bowels once per day with no further rectal bleeding.

• Dasatinib was generally well-tolerated. Treatment discontinuation due to AEs occurred in 11.9% of patients with CML-CP and 8.0% of patients with CML-AP. Overall, drug-related AEs of any grade were experienced by 69.5% of patients with CML-CP and 84.0% of patients with CML-AP. A total of 18.6% and 64% of patients with CML-CP and CML-AP, respectively, experienced grade 3–4 AEs.
• The most frequently reported AEs (any grade) were pleural effusion, headache, thrombocytopenia, and neutropenia, and most common grade 3–4 AEs were thrombocytopenia and neutropenia
• Pleural effusion was reported in 23.7% (14/59) and in 40% (10/ 25) of patients with CML-CP and CML-AP, respectively. Two of the CML-CP patients and none of the CML-AP patients developed grade 3–4 pleural effusion. Cumulative rates of pleural effusion increased gradually over time
• The median time to onset of pleural effusion was 14.7 months (range, 0.7–27.2 months) in CML-CP patients and 21.2 months (0.3–50.1 months) in CML-AP patients. In one CML-CP patient, pleural effusion led to study discontinuation.
• Pulmonary hypertension was reported in 6.8% (4/59) and 8.0% (2/25) of patients with CML-CP and CML-AP, respectively. For one patient, pulmonary hypertension was resolved once but recurred and led to the patient’s disqualification from the study.
• For the other five patients, pulmonary hypertension was resolved in three patients with symptomatic treatment (one patient experienced dasatinib interruption and symptomatic treatment), but the other two patients discontinued participation in the study. 
• The most common cardiovascular AE reported in all patients was pericardial effusion, which occurred in 3.4% and 12.0% of the patients with CML-CP and CML-AP, respectively. No ischemic cardiovascular events were reported for the CML-CP patients after a median of 50.1 months of follow-up

• The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%).
• No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). 

• diarrhea 38.7%/ 12.9%
• fatigue 38.7%/3.2%
• constipation 25.8%/3.2%
• nausea 25.8%/12.9%
• vomiting 25.8%/12.9%
• cough 25.8%/3.2%
• headache 25.8%/16.1%
• peripheral edema 19.4%/19.4%
• rash 19.4%/6.5%
• anemia 19.4%/ 3.2%
• dyspnea 16.1%/ 6.5%
• arthralgia 16.1%/ 3.2%
• insomnia 16.1%/0%
• pleural effusion 12.9%/9.7%
• skin ulcer 12.9%/0%
• sinusitis 12.9%/0%
• upper respiratory tract infection 12.9%/ 0
• urinary tract infection 12.9%/ 3.2%
• dizziness 12.9%/3.2%
• depression 12.9%/0%

• 21 incident, right heart catheterization-confirmed cases of dasatinib-induced PAH were identified from the French Pulmonary Hypertension Registry.
• Clinical and hemodynamic variables were compared from baseline to last follow-up (median (range) 24 (1–81) months).
• The median age was 52 years and 15 patients were female (71%).
• 19 patients received dasatinib for chronic myelogenous leukemia for a median (range) duration of 42 (8–74) months before PAH diagnosis.
• No bone morphogenic protein receptor-2 (BMPR2) mutations were found in the 10 patients tested.
• Dasatinib was uniformly discontinued and 11 patients received PAH medications.
• Four patients died during follow-up. New York Heart Association functional class improved from 76% in class III/IV to 90% in class I/II ( p<0.01).
• Median (range) 6-min walk distance improved from 306 (0–660) to 430 (165–635) m ( p<0.01). Median (range) mean pulmonary arterial pressure improved from 45 (30–70) to 26 (17–50) mmHg ( p<0.01) and pulmonary vascular resistance from 6.1 (3.2–27.3) to 2.6 (1.2–5.9) Wood units ( p<0.01).
• Patients treated with PAH medications had worse baseline hemodynamics but similar long-term outcomes to untreated patients.
• PAH persisted in 37% of patients. Dasatinib-induced PAH frequently improves after discontinuation but persisted in over one-third of patients, therefore systematic follow-up is essential

• Pericardiocentesis was done and 600 ml of pericardial fluid was removed
• Patient symptoms were relieved following pericardiocentesis. However, repeat pericardial collection was seen on repeat echocardiogram the next day. Repeat pericardiocentesis of 600 ml was done

Cardiac Tamponade Associated with Dasatinib Use for Chronic Myeloid Leukaemia

• the patient presented 3 weeks after initiating dasatinib therapy increasing dyspnea, pleuritic chest pain
• echo confirmed a large effusion with tamponade physiology, early diastolic right ventricular collapse, inferior vena cava dilation and loss of respiratory variation
• dasatinib was temporarily ceased and prednisolone was commenced
• repeat echo showed complete resolution with an improvement in symptoms and dasatinib was recommenced at a reduced dose

• A 7-day interruption of dasatinib showed a return to the baseline of the ventricular arrhythmia on a 24 h electrocardiogram (ECG), which is consistent with an adverse drug reaction
• dasatinib presented with an aggravation of previously known ventricular arrhythmias on an anatomically healthy heart. 

• The most common TEAEs were fatigue (76%), skeletal pain (69%), and ocular symptoms (68%).
• Skeletal pain included joint pain, back pain, bone pain, limb pain, and chest wall pain.
• Ocular symptoms included blurry vision, dry eyes, watery eyes, eye redness, cataract, photophobia, and eye pain.
• Pleural effusions (PEs) occurred in 26% of patients, with grade 3 and 4 PEs occurring in 3%. The first occurrence of PE arose in 15% of patients during the first year of treatment, in 2% to 5% per year over the next 3 years, and then in approximately 1% or 2% per year subsequently.
• Four patients developed grade ≤2 pulmonary hypertension (detected in patients 2 by echocardiogram and in 2 by right-heart catheterization). Two patients were successfully treated with sildenafil, 1 patient continues on sildenafil, and the other stopped sildenafil after 1 year. All 4 patients with pulmonary hypertension were changed to another TKI.
• The most frequent grade 3 and 4 AEs were fatigue (13%), thrombocytopenia (11%), and infections (11%).
• There have been 119 serious adverse events (SAEs). The most common SAEs were infections (n = 18) and pregnancy (n = 18). Arteriothrombotic events occurred in 13 patients (9%). These included cardiovascular events in 9 patients (3 with 6 myocardial infarctions, 4 with coronary artery disease, and 2 with chest pain), cerebrovascular events in 3 patients (stroke or transient ischemic attacks), and peripheral arterial disease in 2 patients (1 with carotid artery stenosis and 1 with peripheral arterial disease who also had coronary artery disease)

• at 9 months it was noted that the patient had iron deficiency and subclinical colitis was then discovered by colonoscopy
• multiple nodules found throughout the colon
• given that there were no symptoms, D was continued

• the patient presented with blood diarrhea 2.5 years after initiation of D
• features were consistent with D-induced colitis
• the patient was maintained on D and did not develop a relapse 

• case series of 5 patients with dasatinib induced CMV colitis
• the earliest onset was 2 months
• others after  3,5,14,14,30 months

• Neutropenia 65%, severe 21%
• Thrombocytopenia 70%, severe 19%
• Anemia 90%, severe 10%
• Fluid retention 19%, severe 1%
• Superficial edema 9%
• Pleural effusion 10%
• Other 5%
• Diarrhea 17%, severe <1% 
• Nausea 8%
• Vomiting 5%
• Myalgia 6%
• Muscle inflammation 4%
• Musculoskeletal pain 11%
• Rash 11%
• Headache 12%
• Fatigue 8%, severe <1%

• A 63-year-old man presented to our tertiary care hospital with acute onset left-sided weakness and admission National Institutes of Health Stroke Scale score of 15. The patient’s history included type 2 diabetes mellitus (glycated hemoglobin 8.2%, on metformin), hyperlipidemia (low-density lipoprotein cholesterol 82 mg/dL, on atorvastatin), cigarette smoking, and chronic myelogenous leukemia (on dasatinib 20 mg daily) in molecular remission.
• The half-life of tPA is 45 minutes, although its effect on the fibrinolytic pathway may last longer. Hence, sICH in our case was unlikely to be due to tPA, as clinical deterioration occurred >24 hours after tPA administration.
• Although dasatinib has poor blood-brain barrier penetration, it can penetrate the barrier when it is disrupted, as in acute ischemic stroke, and participate in multikinase inhibition.
• Vascular endothelial growth factor is essential in the reformation of the blood-brain barrier after any brain injury, through tyrosine-kinase related adhesion molecule.

• fluid retention: 25% (superficial edema 11%, pleural effusion 14%)
• myalgia 22%
• nausea 10%
• diarrhea 19%
• vomiting 5%
• rash 11%
• headache 13%
• fatigue 9% 

• a case of a 34-year-old Sudanese female with CML who developed AVNFH after receiving dasatinib as second-line therapy
• though the mechanism by which dasatinib can cause avascular necrosis (AVN) is not clear, it can be postulated because of microcirculatory obstruction of the femoral head
• to the best of our knowledge and after extensive literature search, this is the first reported case of AVNFH induced by dasatinib in a patient with CML
• onset after 18 months

Phase I Dose-Escalation and Pharmacokinetic Study of Dasatinib in Patients with Advanced Solid Tumors

• Sixty-seven patients were treated.
• The maximum tolerated doses were 120 mg twice daily
• DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia
• The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities.
• DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria.
• Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. 

• A serum HVA concentration of 387 ng/ml was measured by high-pressure liquid chromatography (HPLC); normal concentration is less than 40 ng/ml
• Analysis of a second blood sample 10 days later yielded a normal HVA level (38 ng/ml), but urine obtained 16 days after the initial blood sample contained 270 g HVA/mg creatinine (normal range 8.5–23.5).
• VMA levels were normal in all samples, a finding inconsistent with the usual combined elevation of HVA and VMA that result from catecholamine production by a pheochromocytoma or neuroblastoma.
• Review of his history indicated that the patient suffered from food allergies and periodically received quercetin (1000 mg/day, 82.6 mg/kg)
• elevated HVA levels in our patient might be secondary to quercetin administration because quercetin, like dopamine, is a substrate for catechol-O-methyl transferase (COMT), and reportedly can be metabolized by intestinal flora to yield HVA and other metabolites that are absorbed and excreted 
• In a subsequent study approved by our institutional review board, four healthy adults consented to ingest a daily dose of 1200 mg of quercetin (Nature’s Life, Garden Grove, CA) delivered in three 400 mg doses.
• In each volunteer, serum HVA increased 5–20-fold during the first 24 h after administration and returned to normal or nearly normal by 50 h, with no significant change in serum concentrations of VMA, norepinephrine, epinephrine, dopamine, or the VMA precursor, 3-methoxy-4-hydroxyphenylglycol
• The serum concentration of the intermediate dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), also increased and continued to be abnormally high at 50 h

• After 9 months of dasatinib treatment, she developed exertional dyspnea.
• A chest x-ray demonstrated small bilateral effusions.
• Transthoracic echocardiography demonstrated a right ventricular (RV) systolic pressure of 74 mm Hg, a mildly dilated RV with mild-to-moderately reduced systolic function.
• The left ventricle and valves appeared normal with an ejection fraction of >55%
• Dasatinib was discontinued, imatinib was resumed, and she improved significantly over the following 4 months.
• There are currently no known biomarkers or methods to identify patients predisposed to PAH or pleural effusions after dasatinib initiation
• Baseline pretreatment chest x-ray and echocardiography could help rule out pre-existing pleural effusions, pulmonary hypertension, and intracardiac shunts

• A 24-year-old male patient consulted the cardiovascular department because of shortness of breath
• Ten days after starting dasatinib, the patient complained of dyspnea [World Health Organization (WHO) functional class IV dyspnea
• After dasatinib was stopped, the patient’s symptoms improved to WHO functional class I. Follow-up transthoracic echocardiography 1 week after the cessation of dasatinib showed decreased RV size and improved RV systolic function

• congestive heart failure or cardiac dysfunction was reported in 2% (of 258 patients) at the one year follow up
• cardiac monitoring is recommended 
• therapy for heart failure is standard

• 2.5 months after initiating treatment, the patient began to notice a loss in his visual field, which was subjectively perceived by the patient as a scotoma located in the superior region of both eyes
• After conducting all complimentary evaluations, it was suspected that dasatinib could be the cause of the optical neuropathy, and treatment with this drug was suspended. Treatment with oral prednisone, at 100 mg daily, was initiated for 3 weeks, followed by a progressive decrease in the dose until its suspension 1 month after initiation

• Headache 63 (34) 2 (1)
• Diarrhea 56 (30) 4 (2)
• Fatigue 52 (28) 2 (1)
• Dyspnea 51 (27) 6 (3)
• Rash 41 (22) 1 (0.5)
• Asthenia 37 (20) 3 (2)
• Nausea 36 (19) 2 (1)
• Pleural effusion 35 (19) 6 (3)
• Peripheral edema 33 (18) 0 (0)

Serum chemistry

• Elevated bilirubin 26 (14) 0 (0)
• Elevated activity of ALAT 96 (52) 3 (2)
• Elevated activity of ASAT 111 (60) 4 (2)

Cytopenias grade 3 to 4

• Leukocytopenia NA 46 (25)
• Neutropenia NA 92 (49)
• Thrombocytopenia NA 88 (47)
• Anemia NA 40 (22) 

• 16 yr old with Ph+ ALL 
• approximately 4 weeks after the start of therapy, the patient was first seen for the appearance of achromic patches on his neck and the dorsal surfaces of his hands, and complete depigmentation of his hair, eyelashes, and eyebrows. 
• although further investigation is required fully to understand the exact mechanism of hair depigmentation, the appearance of this cutaneous side-effect after chemotherapy with dasatinib is highly indicative of c-Kit modulation and blockade of SCF/c-Kit signal transduction

• after a total of 6 months of dasatinib therapy, she noted subsequent diffuse thinning and whitening of her scalp, eyebrow, and eyelash hair 
• She had no personal or family history of alopecia areata.
• Scalp biopsy revealed normal numbers of hair follicles with a lack of melanocytes within hair bulbs without significant peribulbar inflammation
• The c-Kit, PDGFR, and Src family kinases are implicated in hair pigmentation and growth. In combination with stem cell factor, c-Kit activates the tyrosine gene promoter leading to pigment production.
• The downstream effects regulate the development, migration, and survival of melanocytes. Mutations in c-Kit are associated with skin and hair hypopigmentation

• Approximately 2 months after initiating dasatinib treatment, she noticed diffuse cutaneous depigmentation of her face, trunk and extremities, and subsequently eyebrows, eyelashes, and scalp hair.
• She could not discontinue dasatinib because her CML was in the accelerated phase.
• Twelve months after initiating dasatinib therapy, depigmentation of her face continued, and her eyebrows, eyelashes and scalp hair turned white

• In spite of this wide spectrum of pharmacological properties, the use of QC in the pharmaceutical field is limited due to its poor aqueous solubility and instability in physiological medium. These properties of QC result in poor bioavailability, poor permeability, instability, and extensive first-pass metabolism before reaching the systemic circulation 
• QC is a poorly water-soluble drug (about 1g/mL in water, 5.5g/mL in simulated gastric fluid, and 28.9 g/mL in simulated intestinal fluid).
• Following the administration of an oral dose of radiolabeled QC to male rats, only 20% of the radiolabel was estimated to be absorbed 
• Evaluated in ileostomy patients, 24% of total QC was absorbed following ingestion of 100 mg of the QC aglycone, while in healthy subjects provided 100 mg of radiolabeled QC, up to 53% of the total administered radioactivity was absorbed.
• Following single intragastric treatment of male Sprague-Dawley rats with 50 mg QC/kg body weight, free QC was found in the plasma only at a concentration of 0.27 μg/mL, and 93% of QC was metabolized after one hour.
• In another study, plasma samples did not contain any detectable levels of the aglycone in weanling rats administered QC in the diet at 0.45% for a period of 6 weeks.
• While low concentrations of free QC were identified in liver and kidney tissues (i.e., less than 8% of total QC) following intragastric treatment of rats, the authors suggested that this might have occurred as a result of ex vivo hydrolysis of the QC metabolites