Search

With high survival rates for chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKIs), emerging consequences, such as arterial ischemic events, require consideration when evaluating treatment options. 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). Comparison of observed and expected event rates through standardized incidence ratios indicates that dasatinib does not increase risk for cardiovascular ischemic events compared with external reference populations. [ABSTRACT FROM AUTHOR]

In patients with chronic myeloid leukemia (CML), use of the BCR-ABL1-specific tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib has greatly improved patient survival and prolonged disease remission. More than 10 years of data from imatinib clinical studies and many years of data for nilotinib and dasatinib have demonstrated that these TKIs are well tolerated in most patients with CML. However, these inhibitors are not entirely BCR-ABL1-specific, and this lack of specificity could account for the off-target effects of these drugs. Adverse events (AEs) are off-target effects that are detrimental to the patient. The underlying mechanisms that contribute to these effects are poorly understood and the long-term consequences of chronic TKI therapy remain largely unknown, particularly with the newer agents. Here, we review the preclinical and clinical data for several of the more frequent AEs associated with TKIs and discuss the therapeutic relevance of these AEs for patients with CML. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nilotinib is a selective, potent BCR-ABL inhibitor. Previous studies demonstrated the efficacy and safety of nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic phase (CML-CP) or accelerated phase who failed prior imatinib. METHODS: This expanded access trial further characterized the safety of nilotinib 400 mg twice daily in patients with CML-CP (N = 1422). RESULTS: In this large, heavily pretreated population, nilotinib demonstrated significant efficacy, with complete hematologic response and complete cytogenetic response achieved in 43% and 34% of patients, respectively. Responses were rapid, mostly occurring within 6 months, and were higher in patients with suboptimal response to imatinib, with 75% and 50% achieving major cytogenetic response and complete cytogenetic response, respectively. At 18 months, the progression-free survival rate was 80%. Most patients achieved planned dosing of 400 mg twice daily and maintained the dose >12 months. Nonhematologic adverse events (AEs) were mostly mild to moderate and included rash (28%), headache (25%), and nausea (17%). Grade 3 or 4 thrombocytopenia (22%), neutropenia (14%), and anemia (3%) were low and managed by dose reduction or brief interruption. Grade 3 or 4 elevations in serum bilirubin and lipase occurred in 4% and 7% of patients, respectively. The incidence of newly occurring AEs decreased over time. Of patients who experienced a dose reduction because of AEs and attempted a re-escalation, 87% successfully achieved re-escalation to the full dose. CONCLUSIONS: This large study confirms that nilotinib was well tolerated and that grade 3 or 4 AEs occurred infrequently and were manageable through transient dose interruptions. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Imatinib slows development of chronic myeloid leukemia (CML). However, available information on morbidity and mortality is largely based on sponsored trials, whereas independent long-term field studies are lacking. Patients and Methods Consecutive CML patients who started imatinib treatment before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (±3 months) were eligible for enrollment in the independent multicenter Imatinib Long-Term (Side) Effects (ILTE) study. Incidence of the first serious and nonserious adverse events and loss of CCyR were estimated according to the Kaplan–Meier method and compared with the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction. Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch–Prentice method. Standardized incidence ratios were calculated based on population rates specific for sex and age classes. Confidence intervals were calculated by the exact method based on the χ2 distribution. All statistical tests were two-sided. Results A total of 832 patients who were treated for a median of 5.8 years were enrolled. There were 139 recorded serious adverse events, of which 19.4% were imatinib-related. A total of 830 nonserious adverse events were observed in 53% of patients; 560 (68%) were imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (>1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = .08), with only six (30%) associated with CML progression. Conclusions In this study, CML-related deaths were uncommon in CML patients who were in CCyR 2 years after starting imatinib, and survival was not statistically significantly different from that of the general population. [ABSTRACT FROM PUBLISHER]

The article describes a study which examined the efficacy and safety of nilotinib in treating chronic myeloid leukemia patients who are immune to or intolerant of Imatinib. The study showed that the best responses to nilotinib were complete hematologic response (CHR) in 66% of 88 patients studied and major cytogenetic response in 43% of the study population. It concluded that patients who achieve CHR on imatinib therapy were more likely to respond positively to nilotinib and that nilotinib is safe for imatinib-resistant or intolerant patients.

In chronic myeloid leukaemia (CML), dendritic cells (DC) and leukaemic cells share a common progeny, leading to constitutive expression of putative tumour antigens, such as bcr/abl, in DC. In this phase-I/II study, autologous DC were used as a vaccine in patients with chronic phase bcr/abl+ CML, who had not achieved an adequate cytogenetic response after treatment with α-interferon or imatinib. Ten patients were enrolled, DC were generated from peripheral blood monocytes and vaccination consisted of four subcutaneous injections of increasing numbers of DC (1–50 × 106 cells per injection) on days 1, 2, 8 and 21. Vaccination was feasible and safe. Improvement of the cytogenetic/molecular response, as detected by fluorescence in situ hybridization of peripheral blood mononuclear cells (PBMC), was possibly related to vaccination in four of 10 patients. In three of these patients, T cells recognizing leukaemia-associated antigens became detectable. The proliferative capacity of PBMC in response to autologous DC increased after vaccination in all evaluable patients. We conclude that vaccination with autologous, non-irradiated ‘leukaemic’ DC is feasible, safe and induces anti-leukaemic T-cell responses in some CML patients. DC vaccination might be useful in CML as postremission therapy, i.e. after treatment with tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

Therapy with imatinib mesylate is limited by cellular resistance in chronic myeloid leukaemia (CML). Further, the limited availability of matching stem cell donors or an unfavourable risk profile for allogeneic stem cell transplantation (SCT) reduces the number of therapeutic options in a number of patients. To assess the possibility of stem cell mobilization (SCM) during imatinib therapy we performed granulocyte colony-stimulating factor (filgrastim)-induced SCM and subsequent aphaeresis in 15 chronic phase and three accelerated phase CML patients. Aphaeresis was successful in 13 patients (72%) (≥2·0 × 106 CD34+ cells/kg body weight) and five (28%) harvests could be obtained, which were negative for BCR/ABL mRNA as assessed by nested-reverse transcription polymerase chain reaction (RT-PCR). All harvests, except one, were negative after first round RT-PCR, implicating a low level of CML cell contamination. There was no significant change in peripheral BCR/ABL transcript load after SCM as assessed by quantitative real-time RT-PCR. Fifteen patients remained stable in complete cytogenetic remission (CCR) during a median observation period of 9·3 months. One patient achieved a molecular remission shortly after SCM. Another patient who exhibited rising BCR/ABL mRNA levels before SCM achieved CCR after autologous SCT with the generated harvest. One patient with a Philadelphia chromosome-negative, BCR/ABL-positive CML showed a cytogenetic relapse 6 months after SCM. We conclude that filgrastim-induced CD34+ cell aphaeresis under simultaneous imatinib medication is safe and feasible in CML patients. Additionally, we found evidence that this procedure could generate stem cell harvests that exhibit non-detectable levels of BCR/ABL mRNA. [ABSTRACT FROM AUTHOR]

Abstract. Imatinib (glivec®, formerly known as STI571) effectively blocks the ATP-binding site of the bcr/abl fusion protein thereby inactivating selectively the tyrosine kinase activity of bcr/abl. Therefore, it is a promising drug in Philadelphia chromosome positive chronic myeloid leukemia showing high hematologic and cytogenetic response rates combined with a mild toxicity profile. Here we report two cases of squamous cell carcinoma of the skin, which appeared in the photoexposed areas in two elderly patients treated for advanced chronic myeloid leukemia with imatinib. The role of chemotherapy, chronic sun exposure and of possible additional risk factors such as human papillomavirus infection is discussed. [ABSTRACT FROM AUTHOR]

The article focuses on the role of imatinib for the treatment of chronic myeloid leukaemia (CML) and its limitations as well as the development of nilotinib in response for patients with advanced CML. Imatinib, however in the advanced stage of CML, it is ineffective as BCR-ABL, mutant gene that is formed when a piece of chromosome 9 attaches to the end of chromosome 22, reactivates through phosphorylation that leads to leaukaemic phenotype. Nilotinib inactivates the BCR-ABL kinase and has minor effects on proto-oncogene protein c-KIT and platelet-derived growth factor receptor (PDGF-R) kinases.

Background: Data about haematologic malignancies from Tanzania are sparse. African studies show that chronic myeloid leukaemia (CML) is the most common leukaemia, and registry data display a lower mean age at diagnosis. Prognosis is generally good with tyrosine kinase inhibitors, but the molecular response of Imatinib treatment has never been studied in East Africa, and the outcome remains unknown. This study assessed the early molecular response (MR) as a predictor for long-term outcome and barriers to access treatment. Methods: A case series of patients with CML from Northern Tanzania documented demographics and laboratory and clinical findings at diagnosis and after 3 months. The regression analysis has been performed on early MR and clinical and demographic variables using the χ ²-test. The barriers of potential treatments have been assessed. Results: A total of 30 patients have been analysed. The mean age was 41 years. All patients had splenomegaly, whereas 16 had hepatomegaly. Complete haematologic response was achieved in 16 and early MR in 9 patients. Hepatomegaly was positively correlated with unfavourable early MR. The average kilometre from home to hospital was 282 km (5-1,158 km). Travel expenses and time investments pose an impediment to treatment. Conclusion: Patients are younger, and early MR rates are lower compared to other studies. The finding of hepatomegaly as a risk factor for unfavourable early MR was described previously in West Africa. Adherence to therapy is high in the first months of treatment. Furthermore, research is needed to understand the poor MR and the common presentation of hepatomegaly. Outreach clinics might be a solution to reduce impediments to treatment. [ABSTRACT FROM AUTHOR]

Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Vascular safety is an emerging issue in patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Whereas imatinib exhibits a well-documented and favorable long-term safety profile without obvious accumulation of vascular events, several types of vascular adverse events (VAEs) have been described in patients receiving secondor third-generation BCR/ABL1 TKIs. Such VAEs include pulmonary hypertension in patients treated with dasatinib, peripheral arterial occlusive disease and other arterial disorders in patients receiving nilo-tinib, and venous and arterial vascular occlusive events during ponatinib. Although each TKI interacts with a unique profile of molecular targets and has been associated with a unique pattern of adverse events, the mechanisms of drug- induced vasculopathy are not well understood. Here, recent data and concepts around VAEs in TKI-treated patients with CML are discussed, with special reference to potential mechanisms, event management, and strategies aimed at avoiding occurrence of such events in long-term treated patients. [ABSTRACT FROM AUTHOR]

We present long-term follow-up of a dasatinib phase 3 study of patients with imatinibresistanf- intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on S1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. lmatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCRABL <10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474. [ABSTRACT FROM AUTHOR]

Background: Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase. Methods: In this phase 3, randomized, open-label, multicenter study, we assigned 846 patients with chronic-phase Philadelphia chromosome–positive CML in a 1:1:1 ratio to receive nilotinib (at a dose of either 300 mg or 400 mg twice daily) or imatinib (at a dose of 400 mg once daily). The primary end point was the rate of major molecular response at 12 months. Results: At 12 months, the rates of major molecular response for nilotinib (44% for the 300-mg dose and 43% for the 400-mg dose) were nearly twice that for imatinib (22%) (P<0.001 for both comparisons). The rates of complete cytogenetic response by 12 months were significantly higher for nilotinib (80% for the 300-mg dose and 78% for the 400-mg dose) than for imatinib (65%) (P<0.001 for both comparisons). Patients receiving either the 300-mg dose or the 400-mg dose of nilotinib twice daily had a significant improvement in the time to progression to the accelerated phase or blast crisis, as compared with those receiving imatinib (P=0.01 and P=0.004, respectively). No patient with progression to the accelerated phase or blast crisis had a major molecular response. Gastrointestinal and fluid-retention events were more frequent among patients receiving imatinib, whereas dermatologic events and headache were more frequent in those receiving nilotinib. Discontinuations due to aminotransferase and bilirubin elevations were low in all three study groups. Conclusions: Nilotinib at a dose of either 300 mg or 400 mg twice daily was superior to imatinib in patients with newly diagnosed chronic-phase Philadelphia chromosome–positive CML. (ClinicalTrials.gov number, NCT00471497.) N Engl J Med 2010;362:2251-9. [ABSTRACT FROM AUTHOR]

Abstract: Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-β protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-β, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop. [Copyright &y& Elsevier]