Low-dose Dasatinib Research Articles

Low-Dose Dasatinib As First-Line Treatment for Chronic Myeloid Leukemia: Preliminary Report

Low-Dose Dasatinib As First-Line Treatment for Chronic Myeloid Leukemia: Preliminary Report

The Efficacy of Reduced-dose Dasatinib as a Subsequent Therapy in Patients with Chronic Myeloid Leukemia in the Chronic Phase: The LD-CML Study of the Kanto CML Study Group.

Objective The aim of this study was to prospectively investigate the efficacy and safety profiles of low-dose dasatinib therapy (50 mg once daily). Methods Patients with chronic myeloid leukemia in the chronic phase (CML-CP) who were being treated with low-dose imatinib (≤200 mg/day), but were resistant to this agent were enrolled in the current study (referred to as the LD-CML study). Results There subjects included 9 patients (4 men and 5 women); all were treated with dasatinib at a dose of 50 mg once daily. Among 8 patients who had not experienced major molecular response (MMR; BCR-ABL1 transcript ≤0.1% according to International Scale [IS]) at study enrollment, 5 attained MMR by 12 months. In particular, 3 of 9 patients demonstrated a deep molecular response (DMR; IS ≤0.0069%) by 18 months. Five patients developed lymphocytosis accompanied by cytotoxic lymphocyte predominance. There was no mortality or disease progression, and all continue to receive dasatinib therapy at 18 months with only 2 patients requiring dose reduction. Toxicities were mild-to-moderate, and pleural effusion was observed in 1 patient (grade 1). Conclusion Low-dose dasatinib can attain MMR and DMR without severe toxicity in patients with CML-CP who are unable to achieve MMR with low-dose imatinib. Switching to low-dose dasatinib should therefore be considered for patients in this setting, especially if they are otherwise considering a cessation of treatment.

Therapy of Early Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Lower Dose Dasatinib

Therapy of Early Chronic Phase Chronic Myeloid Leukemia (CML-CP) with Lower Dose Dasatinib

Therapy with Lower Dose Dasatinib in Newly Diagnosed Early Chronic Phase-Chronic Myeloid Leukemia (CML-CP)

Therapy with Lower Dose Dasatinib in Newly Diagnosed Early Chronic Phase-Chronic Myeloid Leukemia (CML-CP)

Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) < 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) < 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]

Elderly Patients With Chronic Myeloid Leukemia Benefit From a Dasatinib Dose as Low as 20 mg.

The clinical outcomes of patients with chronic myeloid leukemia (CML) treated with BCR-ABL tyrosine kinase inhibitors has improved markedly; however, the occurrence of adverse events (AEs) means that elderly patients often cannot be administered the standard dose. Nevertheless, some patients treated with low doses of tyrosine kinase inhibitor have achieved good molecular responses. We retrospectively analyzed the efficacy and safety of low-dose dasatinib treatment of elderly CML patients. The study enrolled 21 patients with newly diagnosed, imatinib-resistant, or imatinib-intolerant chronic phase CML. All the patients were aged≥ 65 years and received dasatinib at a dose of< 100 mg/day. Of these 21 patients, 77% had newly diagnosed CML. Overall, 91% and 72% of patients received a mean dasatinib dose of≤ 50 mg and≤ 20 mg, respectively. A molecular response of MR3 (major molecular response, indicating > 3 log reduction in the number of leukemic cells), MR4, and MR4.5 were achieved in 96%, 77%, and 62% of the patients, respectively. Of the 15 patients who received a mean dose of≤ 20 mg, 94% achieved a major molecular response, and 74% achieved MR4. The most common nonhematologic AE was plural effusion (29%), which was controlled by diuretics and regulating the drug dose. Low-dose (eg,≤ 20 mg) dasatinib therapy generates an adequate molecular response in most elderly patients with chronic phase CML without causing severe AEs.

Low-dose dasatinib rescues cardiac function in Noonan syndrome.

Noonan syndrome (NS) is a common autosomal dominant disorder that presents with short stature, craniofacial dysmorphism, and cardiac abnormalities. Activating mutations in the PTPN11 gene encoding for the Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-2 (SHP2) causes approximately 50% of NS cases. In contrast, NS with multiple lentigines (NSML) is caused by mutations that inactivate SHP2, but it exhibits some overlapping abnormalities with NS. Protein zero-related (PZR) is a SHP2-binding protein that is hyper-tyrosyl phosphorylated in the hearts of mice from NS and NSML, suggesting that PZR and the tyrosine kinase that catalyzes its phosphorylation represent common targets for these diseases. We show that the tyrosine kinase inhibitor, dasatinib, at doses orders of magnitude lower than that used for its anticancer activities inhibited PZR tyrosyl phosphorylation in the hearts of NS mice. Low-dose dasatinib treatment of NS mice markedly improved cardiomyocyte contractility and functionality. Remarkably, a low dose of dasatinib reversed the expression levels of molecular markers of cardiomyopathy and reduced cardiac fibrosis in NS and NSML mice. These results suggest that PZR/SHP2 signaling is a common target of both NS and NSML and that low-dose dasatinib may represent a unifying therapy for the treatment of PTPN11-related cardiomyopathies.

A Network of Activated Cancer Signaling Pathways in a High Risk Subgroup of Acute Myeloid Leukemia Targetable By SRC-Kinase Inhibitors

Resistance to therapy including potent and selective targeted agents remains the major clinical challenge in AML. In fact, allogeneic stem cell transplantation remains the best curative treatment option for AML patients with high-risk features. This unmet clinical need may be addressed by novel approaches based on targeting networks of activated cancer signaling pathways (NACSPs) instead of only individual pathways. Signaling pathway activation in AML is not only related to class I mutations such as FLT3-ITD, but also to class II driver mutations. This is best exemplified by AML subtypes harboring non-random chromosomal aberrations, encoding driver mutations able to induce and maintain leukemia. Despite the contribution of class I mutations to a poor prognosis, targeting these lesions does not decisively contribute to the cure of AML in the great majority of the cases. AML with the translocation t(6;9)(p23;q34) encoding the related DEK/NUP214 fusion protein is a high risk group of AML patients characterized by young age and presence of FLT3-ITD in ~ 75% of the cases, which responds only transiently to FLT3-ITD inhibitors. Using this AML subtype as a model for high risk disease, we investigated the NACSPs activated by a class II driver mutation. In these patients FLT3-ITD represents the only established recurrent genetic aberration at diagnosis in addition to the t(6;9). We have shown that the driver mutation DEK/NUP214 transforms very immature hematopoietic stem cells with the contribution of activated STAT5, present also in FLT3-ITD-negative patients. Furthermore it has been reported that AKT/mTOR is activated in DEK/NUP214-positive cells.Here we investigated whether these signaling pathways are components of a leukemogenic NACSP and are therapeutically/clinically significant. We used different inhibitors to target either selectively or to determine a inhibition pattern of a.) PI3K/AKT/mTOR signaling (BKM120, BEZ2315, RAD001, Torin1 and AZD1208) at different levels; b.) receptor tyrosine kinases (RTK- ruxolitinib, sorafenib); and c.) members of the SRC kinase family (dasatinib, ponatinib, PF114, PP2). We employed four different models of t(6;9)-positive AML: U937 cells stably transfected with DEK/NUP214, t(6;9)-positive FKH1 cells, syngeneic DEK/NUP214-driven murine AML cells and primary t(6,9)-positive AML cells. Here we show that i.) STAT5 and AKT/mTOR activation was genetically determined by the t(6;9)-DEK/NUP214; ii.) STAT5 and AKT/mTOR activation were independent of JAK2 and PI3K activation, respectively; iii) selective inhibition of the AKT/mTOR cascades strongly increased STAT5 activation; iv.) both signaling pathways form a NACP, with activated members of the SRC kinase family (SKF - LYN and SRC) as a central node; v.) the NACSP was effectively targeted by inhibitors of the SRC-kinase activity (SKI) such as dasatinib, ponatinib, PF114 and the selective SKF inhibitor PP2, resulting in cell growth arrest and induction of apoptosis in t(6;9)-positive leukemic cells; vi.) SKI not only inhibited SKF/STAT5 but also the AKT/mTOR cascade; vii.) this NACP was independent of the activation of RTKs such as PDGFR, KDR, c-KIT, FLT3 a.o, as part of the target profile of many SKIs used above, as shown by the lack of activity of inhibitors such as ruxolitinib, sorafenib or ibrutinib; viii.) addition of AKT/mTOR inhibitors strongly increased effects of low dose dasatinib or ponatinib in primary t(6;9) leukaemic cells.Our findings implicate the t(6;9)-DEK/NUP214 oncogene as a central inductor of an NACSP including SFK, AKT/mTOR and STAT5 which is independent of the recurrent FLT3-ITD signaling in these patients. This NACSP is able to maintain the leukemia in the presence of effective inhibition of FLT3-ITD signaling by Sorafenib, AC220 and other inhibitors in clinical use. Furthermore, the increase of STAT5 activation upon AKT/mTOR inhibition, suggests that the use of such a treatment would not lead to the eradication of the disease, because of the role of activated STAT5 in the maintenance of leukemic stem cells. On the other hand, SKIs target the entire NACSP. In fact, hitting the central node of the NACSP abolished the activation of both STAT5 and AKT/mTOR.Taken together these data establish SKIs as a valid therapeutic concept not only in t(6;9)-positive AMLs but also in all other AML subtypes characterised by the same NACSP. DisclosuresOttmann:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Fusion Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Ariad: Consultancy, Honoraria.

Subdural Hematoma Associated with Dasatinib and Intrathecal Methotrexate Treatment in Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

Dasatinib has been associated with an increased risk of bleeding, with the most prominent risk noted in patients with advanced-stage chronic myeloid leukemia and thrombocytopenia. We herein report two cases of Philadelphia chromosome-positive acute lymphoblastic leukemia in which a subdural hematoma developed in association with low-dose (40-50 mg/day) dasatinib treatment and lumbar puncture for intrathecal methotrexate injection. Both patients were in complete remission, with normal platelet counts and coagulation status. We suggest that dasatinib, even at a low dose, may impair platelet aggregation and that lumbar puncture may increase the risk of a subdural hematoma (occasionally bilateral) in patients receiving dasatinib.

Real-time analysis of imatinib- and dasatinib-induced effects on chronic myelogenous leukemia cell interaction with fibronectin.

Attachment of stem leukemic cells to the bone marrow extracellular matrix increases their resistance to chemotherapy and contributes to the disease persistence. In chronic myelogenous leukemia (CML), the activity of the fusion BCR-ABL kinase affects adhesion signaling. Using real-time monitoring of microimpedance, we studied in detail the kinetics of interaction of human CML cells (JURL-MK1, MOLM-7) and of control BCR-ABL-negative leukemia cells (HEL, JURKAT) with fibronectin-coated surface. The effect of two clinically used kinase inhibitors, imatinib (a relatively specific c-ABL inhibitor) and dasatinib (dual ABL/SRC family kinase inhibitor), on cell binding to fibronectin is described. Both imatinib and low-dose (several nM) dasatinib reinforced CML cell interaction with fibronectin while no significant change was induced in BCR-ABL-negative cells. On the other hand, clinically relevant doses of dasatinib (100 nM) had almost no effect in CML cells. The efficiency of the inhibitors in blocking the activity of BCR-ABL and SRC-family kinases was assessed from the extent of phosphorylation at autophosphorylation sites. In both CML cell lines, SRC kinases were found to be transactivated by BCR-ABL. In the intracellular context, EC50 for BCR-ABL inhibition was in subnanomolar range for dasatinib and in submicromolar one for imatinib. EC50 for direct inhibition of LYN kinase was found to be about 20 nM for dasatinib and more than 10 µM for imatinib. Cells pretreated with 100 nM dasatinib were still able to bind to fibronectin and SRC kinases are thus not necessary for the formation of cell-matrix contacts. However, a minimal activity of SRC kinases might be required to mediate the increase in cell adhesivity induced by BCR-ABL inhibition. Indeed, active (autophosphorylated) LYN was found to localize in cell adhesive structures which were visualized using interference reflection microscopy.

Analysis of Dasatinib-Induced Molecular Mechanisms of Apoptosis in Hypoxia-Adopted CML Cells Utilizing Quantitative Proteomics Technology.

AbstractAbstract 2773Development of the second-generation ABL tyrosine kinase inhibitor (TKI) dasatinib in CML aimed at overcoming resistance to imatinib, to eliminate persistent residual disease and thus prevent recurrence of active leukemia after TKI discontinuation in chronic myeloid leukemia (CML). Hypoxia has recently been reported as an essential component of the leukemia BM microenvironment that promotes leukemia cell homing, survival and chemoresistance (Benito et al, PlosOne 2011). In this study, we investigated the anti-CML efficacy and molecular mechanisms of action of dasatinib under hypoxic conditions.We developed a hypoxia-adopted subclone of the KBM5 CML cell line (KMB5-HA), which was selected under 1.0% oxygen conditions, and an imatinib-resistant KBM5 subline bearing the T315I mutation (KBM5-T315I). KBM5-HA cells cultured under hypoxia accumulated in G0/G1 and exhibited moderate spontaneous apoptosis compared to KBM5 parental cells in normoxia (sub G1 %: KBM5 3.8±0.8, KBM5-HA 8.7±0.9; p=0.01; proportion of cells in G0/G1: KBM5 36.5±1.1%, KBM5-HA 52.4±6.6%; p=0.02, PI analysis). These cells displayed higher sensitivity to dasatinib than parental KBM cells (IC50; 1.3 nM for KBM5, 0.3 nM for KBM5-HA, at 48hrs by MTT). Low-dose dasatinib (0.5nM) which failed to cause inhibition of proliferation in parental KBM5 cells, caused significant apoptosis induction with cell cycle arrest in KBM-HA cells (sub G1 %: control 8.7±0.9, datatinib 49.1±16.9; p=0.02, G0/G1 %: control 52.4±6.4%, dasatinib 74.1±3.5%; p=0.01). In KBM5-T315I cells, dasatinib induced more prominent cell growth inhibition under hypoxia compared to normoxia (IC50 at 48hrs: normoxia 16.2 nM, hypoxia 3.7 nM). Treatment with 5nM dasatinib, which did not affect KBM5-T315I cell growth under normoxia, induced significant apoptotic effects under hypoxia (sub G1 %: control 6.9±0.9, dasatinib 20.3±3.3; p=0.05, G0/G1 %: control 57.3±5.8, dasatinib 67.4±8.9; p=0.41).We next investigated dasatinib-induced changes of Stat-5 and ERK activation in CML cells by immunoblotting Treatment with 0.5 nM dasatinib resulted in marked down-regulation of phosphorylated (p-) Stat-5 and p-ERK in both, KBM5 and KBM5-T315I cells. In KBM5-HA cells, however, no baseline expression of p-Stat-5 or p-ERK was detected. These results suggest that in KBM5-HA cells dasatinib induces apoptosis and cell cycle arrest via Stat-5 or ERK-independent pathways. To investigate the candidate signaling factors responsible for dasatinib effects on KBM-HA, we performed the proteomic analysis utilizing proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ, Applied Biosystems) coupled with two-dimensional-liquid chromatography-tandem mass spectrometry. A total of 1,234 proteins were detected, and 296 proteins were found to be significantly up-regulated in response to dasatinib treatment in KBM5-HA cells. Among the up-regulated proteins, we found 39 proteins involved in apoptosis induction including Cytochrome C and Cytochrome C oxydase subunits (p<0.001). Mass spectrometry further revealed the up-regulation of apoptosis related mitochondrial chaperones HSP10 and HSP60 (p<0.001), suggesting a role of HSP60/HSP10 in mitochondrial membrane permeabilization.In summary, these findings unravel novel mechanisms of action of dasatinib under conditions mimicking the hypoxic BM microenvironment via induction of Cytochrome C oxydase and mitochondrial chaperones HSP10 and HSP60, which lead to loss of mitochondrial transmembrane potential and release of apoptogenic Cytochrome C in CML cells. Disclosures:Tabe:Bristol-Myers Squibb: Research Funding.

Glucocorticosteroids Rescue Basophils from Dasatinib-Augmented Immunoglobulin E-Mediated Histamine Release

Background: Dasatinib is a multikinase inhibitor active against several tyrosine kinases including ABL, KIT, Lyn and Btk. Apart from its known antileukemic activity, the drug produces several side effects including edemas and pleural effusions, which are supposedly triggered by activated immune cells. Effusion formation can be treated effectively by glucocorticosteroids. We have recently shown that low concentrations of dasatinib (<0.1 µM) promote IgE-dependent secretion of histamine in basophils, especially in allergic individuals. In the current study, we asked whether glucocorticosteroids inhibit dasatinib-induced activation of basophils. Methods: Basophils were preincubated with dexamethasone, prednisolone and hydrocortisone for 24 h, and were then exposed to an anti-IgE antibody (normal basophils) or the allergens Bet v 1 and Phl p 5 (allergic patients) with or without low concentrations of dasatinib (0.025 µM). After incubation, basophils were examined for histamine release and expression of CD63 and CD203c. Results: All three glucocorticosteroids were found to counteract IgE-dependent and dasatinib-enhanced histamine release in basophils in nonallergic and allergic individuals. In addition, glucocorticosteroids were found to inhibit anti-IgE-induced upregulation of CD63 and CD203c in the presence or absence of dasatinib. The inhibitory effects of glucocorticosteroids were dose-dependent (effective range: 1–10 µM) and seen in all donors examined. Conclusions: Glucocorticosteroids rescue IgE receptor cross-linked basophils from additional costimulatory effects of low-dose dasatinib which may have clinical implications in dasatinib-treated patients.

Dasatinib as Salvage Therapy for Steroid Refractory and Imatinib Resistant or Intolerant Sclerotic Chronic Graft-versus-Host Disease

Sclerotic chronic graft-versus-host disease (scGVHD) is a severe form of this disease that resembles systemic sclerosis and has limited and disappointing treatment options. Tyrosine kinase inhibitors (TKI) targeting up-regulated profibrotic pathways, such as imatinib mesylate, have been proposed as a potential therapeutic approach for patients with scGVHD. Dasatinib, a second-generation TKI with a well-established safety and efficacy profile in chronic myeloid leukemia patients, who are refractory or intolerant to imatinib, has also shown potent antifibrotic effects. We present here the first direct clinical evidence, from 3 patients treated in a small single-center series, suggesting that dasatinib can be a therapeutic option for patients with severe scGVHD resistant or intolerant to imatinib. All patients achieved partial response, with improvement in scGHVD target organs severity, joint mobility, lung impairment, and deep fibrotic lesions. This clinical response has remained stable or continued to improve after a median of 22 months (20-25) on dasatinib treatment, with very good tolerance. In addition, corticosteroids could be discontinued or significantly reduced in all patients. This clinical evidence suggests that dasatinib could be a safe and effective alternative for scGVHD patients refractory to corticosteroids and resistant or intolerant to imatinib. Based on these preliminary findings, and in order to address appropriate patient selection, time of intervention, and choice of drug, future larger studies should more formally establish the efficacy and safety of second-generation TKI for the treatment of scGVHD.

On the safety of low-dose dasatinib in comorbid and non-comorbid patients: what is real-life? (Reply)

We are writing in response to the Letter of Dr. Guiseppe Visani and colleagues, ‘The incidence of pleural and pericardial effusion is not higher in patients receiving dasatinib at low doses’.1 We agree that in our study, noncomorbid and comorbid patients and those with accelerated phase disease were included.2 We also agree that in patients with Ph+ chronic myeloid leukemia (CML) treated with low-dose dasatinib (50–100 mg/day), the incidence of pleural and pericardial effusions is lower (definitively not higher) compared to high-dose dasatinib (140 mg/day).3 This was also found in our patients.2,4 In addition, we agree that in ‘chronic phase-patients’ without comorbidity the frequency of effusion formation may be lower.5 Finally, first-line dasatinib at low dose6 may even be less toxic compared to second-line dasatinib used in pre-treated patients.3,5 However, unfortunately, the ‘real-life’ to which the authors refer in their letter usually includes both patients without and patients with comorbidities, and in the second-line setting, to which most published data and our data refer, many patients have suboptimal response or even show signs of disease-acceleration2–5 (then 140 mg dasatinib/day is often recommended). In addition, such patients tend to develop comorbidities such as infections and weight-loss during dasatinib.4 Therefore, we do not agree with the authors’ conclusion that our information is misleading, but would rather argue that their statement1 is questionable, as it would suggest that real life exists without comorbidities, drug resistance, or disease-acceleration. Where we agree is the fact that the frequency of pleural effusions in second-line patients treated with low-dose dasatinib is lower compared to second-line patients treated with high-dose dasatinib (140 mg/day). Notably, in our (small) patients’ cohorts, including both comorbid and non-comorbid patients, the difference in the frequency of pleural effusions is clearly visible:2,4 in fact, whereas 75% of patients at 140 mg daily developed pleural effusions (grade II or higher) over time,4 only 56% of those who started at 50 or 100 mg/day developed pleural effusions.2 Why these frequencies are still higher when compared to the available literature may have several explanations. One may be the fact that this side effect is accumulating over time. Another explanation may be under-reporting in clinical trials.7 Notably, in most studies, chest X-rays were only performed routinely until ‘month 6’, and later only if symptoms were noted,3,6 whereas in our center, all dasatinib-treated patients had repeated chest X-rays over the entire time period (at least once a year). In other words, most other published data refer only to the frequency of symptomatic pleural effusions. There may also be other reasons for under-reporting which we have discussed recently.7 Finally, we would like to state that we believe that a repeated chest X-ray should indeed be considered in both younger (non-comorbid) and older (often comorbid) patients: in older patients because of the comorbidity-associated risk, and in younger patients because they are potential candidates for stem cell transplantation. For such patients it may be a less favorable scenario if effusion-formation or viral infection/reactivation is overlooked before they are referred.

Is there something wrong in paradise? Christian beliefs and the safety of novel BCR/ABL1 inhibitors

We take the liberty and opportunity to discuss adverse events and event reporting in patients with chronic myeloid leukemia (CML) treated with second generation BCR/ABL1-targeting drugs. The study of Ahmet Emre Eskazan[1][1] suggests that CML patients treated with low-dose dasatinib (100 mg daily)

Pleural and pericardial effusions in chronic myeloid leukemia patients receiving low-dose dasatinib therapy

They reported 4 patients who developed effusions with 50 or 100 mg daily dasatinib out of a total number of 13 patients. Pleural and pericardial effusions were grade III/IV in 2 of the patients. There were no reports of pre-existing cardiac or pul monary diseases for any of the 4 patients. In 3 cases, dasa tinib had to be discontinued because of the persistence of the pleural fluids despite treatment with diuretics and glu cocorticosteroids. In conclusion, Krauth et al. suggest that all patients should be examined for pre-existing comorbidities and risk factors before the initiation of dasatinib, and they should have repeated chest X-rays during the followup period because of the possibility of pleural or pericardial effusions even under low doses of dasatinib treatment. We report our experience of chronic myeloid leukemia patients receiving low-dose dasatinib who had developed pleural and pericardial effusion. In our institute, a total number of 23 chronic phase chronic myeloid leukemia patients receive dasatinib (50-100 mg daily) due to resist ance or intolerance to imatinib. Among these 23 patients, 10 of them (43%) had pleural and pericardial effusions (9 with pleural effusion and one with pericardial effusion). Eight patients were males and 2 were females. Median age was 61.5 (range 44-69). Nine patients out of 10 were in late chronic phase who were switched to dasatinib because of imatinib resistance. Only one patient was in early chronic phase since she started receiving dasatinib due to intolerance of imatinib. The median duration of dasatinib use was 26 months (range 13-33). All of the patients had grade I/II effusions. In 7 patients dasatinib therapy was interrupted and furosemide plus glucocorti costeroids were initiated; effusions were totally resolved in 4 of the 7. Dasatinib was restarted in those 4 patients and effusions did not reoccur. The remaining 3 patients had just started receiving furosemide and glucocorticosteroids and are under follow up so we were unable to make a comment on the success of the treatment. Dasatinib treatment was not stopped in one patient when he developed pleural effusion; we only added gluco corticosteroids and the effusion improved. No other inter vention was made in the other 2 patients other than inter rupting dasatinib treatment and the pleural effusions improved. After restarting dasatinib in those 2 patients, one of them developed pleural effusion which was then managed with furosemide and glucocorticosteroids, dasa tinib was discontinued and he then fully recovered. Pleural effusion is the most frequent non-hematologic adverse event in dasatinib-treated patients. 2 Although effu sion formation may require some time and the risk of effu sion formation is lower in patients treated with 100 mg dasatinib than patients receiving 140 mg dasatinib daily, patients treated with dasatinib at 100 mg daily dose may also develop pleural effusions.

Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib

Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib

Low-Dose Dasatinib as Front-Line Therapy for Elderly (> 60 Years) Patients with CML

AbstractAbstract 2293 Background.Dasatinib is a tyrosine kinase inhibitor that has 325-fold greater in vitro activity against native BCR-ABL (breakpoint cluster region-Abelson leukemia virus) compared with imatinib and can overcome primary (intrinsic) and secondary (acquired) imatinib resistance. A phase III dose optimization study showed that in patients with chronic phase (CP) chronic myeloid leukaemia (CML), dasatinib at 100 mg once daily improved the safety profile while maintaining efficacy compared with the previously recommended dose of 70 mg twice-daily. Few data exist on the efficacy and safety of dasatinib in elderly CML patients. Aims.The aim of the study was to evaluate the impact of dose reduction on dasatinib efficacy. Methods.We revised 129 unselected pts with CP CML aged >60 yrs treated in 21 Italian haematological Institution, who received dasatinib after being resistant/intolerant to imatinib. Among this group 70 pts were given dasatinib at adjusted-dosage below the standard recommended dose of 100 mg daily for > 6 months. In relation to the dose modulation, patients were divide in 2 groups: group-a (21/70, 30%) received a starting dose of 20 mg daily dose excalated to the maximum tolerated dose of 70 mg daily; group-b (49/70=70%) received a starting dose of 100 mg daily, successively adhusted according to tolerance. Sokal score was evaluable for 59/70 patients (low for 16, intermediate for 28, high for 15). All patients were analyzed for haematological, cytogenetic and molecular response. Results.All patients were fully evaluable for response at a median FU time of 25 mos (range 0,7- 56,3 mos). Eight pts (11.4%) discontinued treatment due to intolerance. Response rates were 25,7% (18pts), 24.3% (17 pts), 15.7% (11 pts), 10% (7 pts), 12.8% (9 pts) for complete haematologic response (RHC), complete cytogenetic response (RCyC), major molecular response (RMolM), complete molecular response (RMolC), partial cytogenetic response (RCyP), respectively. Median Cumulative event free survival (EFS) and overall survival (OS) were 21.3 and 27.3 mos respectively. We did not observe any significative difference in term of response between group A and B receiving different doses. Interestingly, 3/9 patients in group A who had a transient loss of molecular response achieved major molecular response after dose escalation to 50 mg. Conclusions:Dasatinib given at a lower dose than currently recommended is still effective in elderly CML patients. However, more close molecular monitoring is advised when lower doses are prescribed. Studies in larger series are warranted to better define optimal dose and schedule of dasatinib in this frail patient population. Disclosures:Rosti: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau.

Non-Standard Doses of Dasatinib Sustain Cytogenetic Response In Chronic Myeloid Leukemia (CML) Patients

AbstractAbstract 2285Non-standard doses of dasatinib sustain cytogenetic response in chronic myeloid leukemia (CML) patients Introduction:Dasatinib (Sprycel; Bristol Myers Squibb, New York, NY, USA), a second-generation tyrosine kinase inhibitor (TKI), is effective for treating patients with chronic myeloid leukemia (CML) as a first or second line drug. The standard doses are 100mg per day for chronic phase (CP), 140mg per day for accelerate phase (AP) or blast phase (BP). Up to 73% patients require dose reductions and 25% have to suspend therapy permanently due to intolerance. We analysed factors that may influence the outcomes of patients who received low-doses of dasatinib after failure or intolerance to other TKIs. Since most of our patients were not eligible for allogeneic SCT and other second-generation TKI was not available in our hospital, off-label doses of dasatinib were occasionally used. Methods:We reviewed the records of 74 patients treated with dasatinib in our hospital from November 2005 until July 2010 with CML all phases, 27 patients required dose reductions for intolerance. All patients had previously received imatinib (Gleevec; Novartis, Basel, Switzerland) and four patients had also been treated with nilotinib (Tasigna; Novartis). In general, dose interruptions were done in patients with grade 3 or 4 hematological or non-hematological toxicity. The severity and the duration of the adverse events were considered for dose reduction. Criteria for CML phases and response were previously reported by Baccarani et al1. Results:Five patients already had complete cytogenetic response (CCyR) before starting dasatinib and sustained it with non-standard doses with median daily dose of 63mg (50-71mg); four of them also maintained (n=3) or achieved (n=1) major molecular response (MMR). The remaining 22 patients, who had no cytogenetic response with a prior TKI, were analysed (Table 1). With low-dose dasatinib, 4 patients (18%) achieved CCyR and MMR, one (5%) had a major cytogenetic response; 17 patients (77%) had no cytogenetic response to dasatinib. Discussion:Dose reductions are frequent among patients on dasatinib therapy, but dose intensity is not associated with failure-free survival and does not impact response2. Our analysis also showed that dose intensity as well as disease phase was not significant to achieve response. Patients resistant to first-line TKI had a higher chance to not achieve CCyR submitted to a lower dose regimen, but in those with CCyR when low-dose regimen was initiated, response was maintained. In conclusion, non-standard doses of dasatinib may be effective to sustain CCyR in patients intolerant to this TKI, and at the same time is ineffective for patients who developed resistance to first-line TKI.

Development of resistance to dasatinib in Bcr/Abl-positive acute lymphoblastic leukemia

Dasatinib is a potent dual Abl/Src inhibitor approved for treatment of Ph-positive leukemias. At a once-daily dose and a relatively short half-life of 3-5 hours, tyrosine kinase inhibition is not sustained. However, transient inhibition of K562 leukemia cells with a high-dose pulse of dasatinib or long-term treatment with a lower dose was reported to irreversibly induce apoptosis. Here, the effect of dasatinib on treatment of Bcr/Abl-positive acute lymphoblastic leukemia (ALL) cells was evaluated in the presence of stromal support. Dasatinib eradicated Bcr/Abl ALL cells, caused significant apoptosis and eliminated tyrosine phosphorylation on Bcr/Abl, Src, Crkl and Stat-5. However, treatment of mouse ALL cells with lower doses of dasatinib over an extended period of time allowed the emergence of viable drug-resistant cells. Interestingly, dasatinib treatment increased cell surface expression of CXCR4, which is important for survival of B-lineage cells, but this did not promote survival. Combined treatment of cells with dasatinib and a CXCR4 inhibitor resulted in enhanced cell death. These results do not support the concept that long-term treatment with low dose dasatinib monotherapy will be effective in causing irreversible apoptosis in Ph-positive ALL, but suggest that combined treatment with dasatinib and drugs such as AMD3100 may be effective.