Imatinib Therapy In Patients Research Articles

Is exon mutation analysis needed for adjuvant treatment of gastrointestinal stromal tumor?

Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting from an activating mutation of stem cell factor receptor (KIT), and an activating mutation of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. Most GISTs (90%-95%) are KIT-positive. About 5% of GISTs are truly negative for KIT expression. GISTs have been documented to resistant conventional chemotherapeutics. Due to the KIT activation that occurs in the majority of the cases, KIT inhibition is the primary treatment approach in the adjuvant treatment of metastatic GISTs. Imatinib mesylate is an oral agent that is a selective protein tyrosine kinase inhibitor of the KIT protein tyrosine kinase, and it has demonstrated clinical benefit and objective tumor responses in most GIST patients in phase II and III trials. The presence and the type of KIT or PDGFRA mutation are predictive of response to imatinib therapy in patients with advanced and metastatic disease. Molecular analysis in phase I-II trials revealed significant differences in objective response, progression-free survival, and overall survival between GISTs with different kinase mutations. The aim of this letter is to touch on the need for exon mutation analysis for adjuvant treatment with imatinib in GIST patients.

Evaluation of the Safety of Imatinib Mesylate in 200 Iraqi Patients with Chronic Myeloid Leukemia in the Chronic Phase: Single-Center Study

Objective: Imatinib mesylate, a tyrosine kinase inhibitor, is presently the drug of choice for chronic myeloid leukemia (CML). During therapy, a few patients may develop hematological and non-hematological adverse effects. Materials and Methods: The aim of this study was to evaluate the safety of imatinib therapy in patients with CML. Between December 2007 and October 2009 two hundred patients with CML in chronic phase were included in the study. Written informed consent was obtained from all patients prior to the start of the study. Imatinib was started at 400 mg orally daily. Patients were monitored carefully for any adverse effects. Complete blood count, liver, and renal function tests were done once in 2 weeks during the first month and on a monthly basis during follow-up. Toxicities that encountered were graded as per the National Cancer Institute common toxicity criteria version 2. Both hematologic and non-hematologic toxicities were managed with short interruptions of treatment and supportive measures, but the daily dose of imatinib was not reduced below 300 mg/day.Results: Two hundred CML patients in chronic phase were included in this study; the male:female ratio was 0.7:1 with mean age 39.06±13.21 years (ranged from 15-81 years). The study showed that the commonest hematological side effects were grade 2 anemia (12.5%) followed by leukopenia (8%) and thrombocytopenia (4%), while the most common non-hematological adverse effects were superficial edema and weight gain (51.5%), followed by musculoskeletal pain (35.5%), then gastro-intestinal symptoms (vomiting, diarrhea) (19%). Fluid retention was the commonest side effect, which responded to low-dose diuretics. The drug was safe and well tolerated. There were no deaths due to toxicity.Conclusion: Imatinib mesylate a well-tolerated drug, and all undesirable effects could be ameliorated easily. The most common hematological and non-hematological side effects were anemia and fluid retention, respectivelyConflict of interest:None declared.

Cost-effectiveness of 3-years of adjuvant imatinib in gastrointestinal stromal tumors (GIST) in the United States

Background:Recent clinical trial data have demonstrated that 3 years vs 1 year of adjuvant imatinib therapy for patients with surgically resected Kit+ Gastrointestinal Stromal Tumors (GIST) leads to a significant improvement in recurrence-free survival and overall survival. This study assesses the cost-effectiveness of treating patients with 3 years vs 1 year of imatinib from a US payer’s perspective.Methods:A Markov model was developed to predict GIST recurrence and treatment costs. Patients enter the model after surgery and transition among three health states: free of recurrence, recurrence, and death. Recurrence, mortality, costs, and utilities were derived from clinical trial and published literature. Expected costs and quality-adjusted life years (QALYs) were estimated and discounted at 3%/year. Deterministic and probabilistic sensitivity analyses were conducted.Results:Patients receiving 3 years of imatinib had higher QALYs (8.53 vs 7.18) than those receiving 1 year of imatinib. Total lifetime per-patient cost was $302,100 for 3 years vs $217,800 for 1 year of imatinib. Incremental cost effectiveness ratio of 3 years vs 1 year of imatinib was $62,600/QALY. Model results were sensitive to long-term rate of GIST recurrence (beyond 5 years) and cost of imatinib. At a threshold of $100,000/QALY, 3 years vs 1 year of imatinib was cost-effective in 100% of simulations.Limitations:The model is a simplified representation of disease natural history and may not account for all possible health states and complications associated with disease. Resource utilization on treatment was estimated using the resource use data from previous trials, therefore calculated medical costs might be over-estimated compared to the real-world setting.Conclusions:Model results suggest that treatment with 3 years vs 1 year of imatinib is cost-effective at a $100,000/QALY threshold. Clinical and economic results suggest treating surgically resected Kit+ GIST patients with 3 years of imatinib would result in improved quality-adjusted survival.

Incidence and clinical characteristics of myeloproliferative neoplasms displaying a PDGFRB rearrangement

The myeloproliferative neoplasms displaying a PDGFRB rearrangement are rare diseases derived from a haematopoietic stem cell. The goals of the study were to assess the incidence of these disorders and to define the clinical and biological characteristics as well as the response to the imatinib therapy. A total of 556 patients with myeloproliferative neoplasms were studied by means of molecular cytogenetics. The incidence of myeloproliferative neoplasms (MPN) with PDGFRB rearrangement was low (10 cases, 1.8% of all MPN). Most of the patients showed moderate anaemia (median Hb was 10.0 gr/dL; range from 7.5 to 13 g/dL), leukocytosis (median white blood cells was 21.7 × 10(9) /L with a range from 4 to 43 × 10(9) /L) and eosinophilia (median circulating eosinophils was 2.4 × 10(9) /L with a range of 1.1-5.7 × 10(9) /L) with a median of bone marrow infiltration cells displaying PDGFRB rearrangement of 55% (range, 37-85%). In three cases, a t(5;12) was observed while two patients showed rearrangements of 17q21 region. In two cases, a del(5)(q31) was observed. Most of the patients responded to standard dosage of imatinib, and the response was maintained in the time in those patients with a follow-up higher than 9 years. The incidence of patients with PDGFRB rearrangement is low. These patients showed leukocytosis with eosinophilia and anaemia. The efficacy of imatinib therapy in patients showing PDGFRB rearrangement is high. For this reason, in all patients with MPN without any other molecular aberration, PDGFRB rearrangement should be ascertained.

The role of surgical cytoreduction before imatinib therapy in patients with advanced GIST.

10093 Background: Despite dramatic improvement of survival with introduction of imatinib mesylate, resistance to imatinib eventually develops in most of patients with advanced gastrointestinal stromal tumor (GIST). It is well known that baseline tumor size is an important factor related to imatinib resistance. We hypothesize that decreasing tumor size by surgery before starting imatinib may delay the emergence of resistance and improve prognosis in patients with advanced GIST. Methods: From 2001 to 2010, 102 patients with initially metastatic GIST and 147 patients with recurrent GIST were enrolled in this analysis. Patients with local relapse only were excluded because they were potentially curable by surgery alone. Patients were categorized into two groups according to the extent of cytoreduction; i.e., patients whose initial tumor bulk reduced >75% surgically before starting imatinib (group A) and the others (group B). Results: Among total 249 patients, 62 patients received initial surgery. 35 (14%) patients whose tumor bulk reduced > 75% were categorized into group A, and the remaining 214 (86%) were in group B. In group A, the median age was younger; more patients were initially metastatic; peritoneal metastases were more frequent; but liver metastases were less. The total tumor size was significantly reduced from median 122 mm before cytoreduction to 0 mm after on CT scans in group A. With a median follow-up of 42.7 months, progression-free survival (PFS) tended to be better in group A than in group B in univariate analysis (HR=0.60; 95% CI, 0.36-1.02; p=0.061), but PFS was not statistically different between the two groups in multivariate analysis (p=0.488). Meanwhile, absence of KIT exon 11 mutation (p=0.007), baseline total tumor size > 150mm (p=0.043), and granulocyte count > 5000/mm3 (p=0.009) remained independent poor prognostic factors. Conclusions: Despite marked decrease of total tumor size, the outcomes were not significantly improved in patients receiving initial cytoreduction more than 75% of baseline tumor bulk before starting imatinib. These results suggest that initial cytoreduction does not have beneficial role in advanced GIST, so imatinib should be still the first treatment of choice in this population.

Prospective Observational Study of Imatinib Therapy in Japanese Patients with Advanced Gastrointestinal Stromal Tumors: Long-term Follow-up and Second Malignancy

ObjectiveLimited data are available concerning long-term results of imatinib therapy in patients with advanced gastrointestinal stromal tumors. We aimed to clarify the long-term outcomes of imatinib therapy in Japanese patients with advanced gastrointestinal stromal tumors.MethodsA prospective, observational study of imatinib therapy for unresectable and metastatic gastrointestinal stromal tumors was conducted in our institution. Imatinib was initiated at a dose of 400 mg daily and continued until disease progression. Safety, efficacy and long-term tolerability and survival were evaluated in an intent-to-treat population. The median follow-up period in this study was 68 months.ResultsSeventy patients were enrolled between December 2001 and December 2009. Treatment-related Grade 3/4 adverse events occurred in 49 patients (70.0%). Although 14 patients required adverse effect management with hospitalization, only 5 patients (7.1%) withdrew from the treatment owing to imatinib intolerance. The tumor response and clinical benefit rates were 61.4 and 85.7%, respectively. Thirty-seven patients (52.9%) maintained the treatment at 400 mg daily imatinib, whereas 33 patients (47.1%) had their dose reduced to 300 mg daily or less. The overall survival rate at 5 years was 60.9% and the median survival time was 70 months. The median progression-free survival time of all the 70 enrolled patients was 30 months. Seven patients (10.0%) suffered from second malignancies, including three patients with genitourinary carcinomas.ConclusionsDespite the need for dose reduction, the long-term results of imatinib therapy for advanced gastrointestinal stromal tumors were good in Japanese patients. Physicians should pay attention to the occurrence of second malignancies during imatinib therapy for gastrointestinal stromal tumor patients.

Complete response in a melanoma patient treated with imatinib

Imatinib therapy has been successful in gastrointestinal stromal tumours containing mutation of the KIT gene. However, there are few reported cases of successful imatinib therapy in patients with melanoma containing KIT gene mutation or c-kit protein expression. A 52-year-old man developed metastatic melanoma from a primary melanoma in the left side of the nasopharynx. The tumour was positive for c-kit protein, and there was a KIT mutation in exon 11. He was treated with imatinib. A follow-up scan one year later showed a complete response. Treatment targeting the biological characteristics of melanoma proved successful in this patient.

Cost-effectiveness of three years of adjuvant imatinib in gastrointestinal stromal tumors (GIST).

137 Background: Recent clinical trial data have demonstrated that 3 years (yr) of adjuvant imatinib therapy for patients with surgically resected GIST leads to a significant improvement in recurrence free survival and overall survival vs. 1 yr of therapy. The objective of this study is to assess cost-effectiveness of treating with 3 yrs vs. 1 yr of adjuvant imatinib in the US from a payer’s perspective. Methods: A Markov model was developed to predict GIST recurrence, treatment (txt) costs, and quality-adjusted survival over a lifetime horizon. Patients transitioned between 3 health states: recurrence free GIST, GIST recurrence, and death. Monthly recurrence and mortality rates for 3 yr and 1 yr imatinib were derived from SSGXVIII/AIO clinical trial. The 5-yr recurrence rate observed in the trial was extrapolated for the remaining duration of the model horizon. First recurrence after active txt was treated with imatinib 400mg daily (800mg daily if recurrence during active txt). For subsequent disease progression, patients were treated with imatinib 800mg, sunitinib or best supportive care. After 5 years, txt specific mortality rate was applied for patients with recurrence. Costs and utilities were derived from published literature. Expected costs and quality-adjusted life years (QALYs) were estimated for each txt strategy. Costs and QALYs were discounted at 3% per yr. Extensive sensitivity analyses were conducted. Results: Total lifetime cost per patient was $302,100 with 3 yrs vs. $217,800 for 1 yr of imatinib therapy. Patients on 3 yrs of imatinib had higher QALYs (8.53 vs 7.18) vs. 1yr of imatinib. Incremental cost effectiveness ratio of 3 yrs of imatinib vs 1 yr of imatinib was $62,600/QALY. Model results were sensitive to rate of GIST recurrence beyond 5 yrs and monthly cost of adjuvant imatinib. At a threshold of $100,000/QALY, 3 yr imatinib therapy was cost-effective in 100% of simulations vs. 1 yr of imatinib. Conclusions: Model results suggest that treating patients with 3 yrs of imatinib is cost-effective vs. 1 yr of imatinib below the widely used $100,000/QALY threshold. Both clinical and economic results suggest treating surgically resected GIST patients with 3 yrs of imatinib would result in improved quality-adjusted and overall survival.

Imatinib plasma trough levels in chronic myeloid leukaemia: results of a multicentre study CSTI571AIL11TGLIVEC

Imatinib has been accepted as frontline treatment for patients with chronic myeloid leukaemia (CML), and patients generally receive doses ranging from 400 to 800 mg/day. Previous studies have demonstrated that maintaining imatinib plasma levels (IMPLs) >1000 ng/mL leads to improved responses and long-term outcomes. However, IMPLs vary among patients because of factors such as drug-drug interactions, adherence, toxicity and differential levels of expression of cellular efflux/influx proteins. In this study, IMPLs were analysed in 191 patients with CML and were compared with achievement of molecular and cytogenetic responses (CyR). IMPLs were also correlated with renal and hepatic dysfunction. Additionally, self-reported adherence was monitored. The median and mean IMPLs were 994 ng/mL and 1070 ± 686 ng/mL, respectively, with 96 patients (50%) achieving plasma levels >1000 ng/mL. Self-reported patient compliance was 98%. Patients who achieved a complete CyR (CCyR) had significantly higher IMPLs (1078 ± 545 ng/mL) than those without CyR (827 ± 323 ng/mL, p = 0.045). When grouped together, patients who achieved a CCyR or partial CyR had significantly higher IMPLs than patients who achieved a minimal CyR or did not achieve a CyR (1066 ng/mL vs 814 ng/mL, p = 0.002). There was no significant difference observed in the IMPLs between patients who achieved molecular responses (n = 177) on treatment (major molecular response, 976 ± 385 ng/mL versus complete molecular response, 1138 ± 809 ng/mL, p = 0.387). Mean IMPLs were similar in patients with or without renal or hepatic impairment. Overall, this study confirmed previous reports that higher IMPLs correlate with clinical responses and demonstrated that imatinib exposure did not differ in patients with or without liver and/or renal dysfunction. The use of IMPL testing and patient diaries may be practical tools for the management of imatinib therapy in patients with CML.

Alternative splicing of apoptosis-related genes in imatinib-treated K562 cells identified by exon array analysis

Imatinib is the therapeutic standard for newly diagnosed patients with chronic myeloid leukemia (CML). In these patients, imatinib has been shown to induce an apoptotic response specifically in cells expressing the oncogenic fusion protein BCR-ABL. Previous studies in our lab revealed that imatinib-induced apoptosis in K562 cells involves a shift in production of Bcl-x splice isoforms towards the pro-apoptotic Bcl-xS splice variant. Here, we report the findings from our subsequent study to identify other apoptosis-related genes that are differentially spliced in response to imatinib treatment. Gene expression profiling of imatinib-treated K562 cells was performed by the Affymetrix GeneChip® Human Exon 1.0 ST array, and differences in exon-level expression and alternative splicing were analyzed using the easyExon software. Detailed analysis by reverse transcription-PCR (RT-PCR) and sequencing of key genes confirmed the experimental results of the exon array. Our results suggest that imatinib treatment of K562 cells causes a transcriptional shift towards alternative splicing in a large number of apoptotic genes. The present study provides insight into the molecular character of apoptotic leukemia cells and may help to improve the mechanism of imatinib therapy in patients with CML.

Increased NK Cells and Decreased CD3+CD8+CD62L+ T Cells in CML Patients Who Sustained Complete Molecular Remission After Discontinuation of Imatinib

Abstract 1697 Background and Aim:Recent study demonstrated that approximately 60% of chronic myeloid leukemia (CML) patients who stopped imatinib therapy (STOP-IM) after a period of stable complete molecular remission (CMR) relapsed molecularly within the next 6 months, whereas nearly all the remaining patients sustained a stable CMR beyond 18 months of follow-up. Study design:To elucidate the immunological diversity of CML patients, we assessed subsets of circulating lymphocytes obtained from 30 CML patients: 16 CML patients who had discontinued imatinib treatment for more than 6 months (STOP-IM), and 14 CML patients who were receiving imatinib with CMR for more than 2 consecutive years. Results:One-way analysis of variance revealed that certain cell fractions of lymphocyte subsets were significantly altered in STOP-IM patients compared with healthy volunteers and CML-CMR patients. We focused on the CD3+CD8+CD62L+ and CD3―CD56+ cell fractions, because other cell fractions, except CD19+CD20+, were not particularly different between STOP-IM and CML-CMR patients. The CD3+CD8+CD62L+ cell fractions in STOP-IM patients tended to down-regulate (P = 0.0658) and the CD3―CD56+ cell fraction increased significantly compared with that in CML-CMR (P = 0.0214). Our observations indicate that some lymphocyte subsets may be affected by imatinib therapy, even in CMR. The differences in subset cell fractions between CML-CMR and STOP-IM patients therefore may have some bearing on discontinuation of imatinib therapy. We were able to determine NK cell activity in 11 STOP-IM patients. This activity ranged from 24% to 69% (normal range, 18%–40%); 7 of the 11 patients had elevated NK cell activity, and a positive correlation was found between NK cell activity and NK cell percentages in the 11 STOP-IM patients. Discussion:We noticed deviation in some fractions of circulating lymphocytes in STOP-IM patients with CML, in comparison with CML patients who were CMR but were still taking imatinib. in STOP-IM patients in our study, an elevated cell fraction was detected only in CD3−CD56+ NK cells, and others were down-regulated. We were able to determine NK cell activity in 11 STOP-IM patients. This activity ranged from 24% to 69% (normal range, 18%–40%); 7 of the 11 patients had elevated NK cell activity, and a positive correlation was found between NK cell activity and NK cell percentages in the 11 STOP-IM patients. Two CMR patients satisfied criteria for both down-regulated CD3+CD8+CD62L+ cells and up-regulated CD3―CD56+ NK cells compared with those of healthy subjects. Conclusion:Our results therefore may aid in the selection of possible candidates for discontinuation of imatinib therapy in patients in CMR. The minimal requirements for discontinuation of imatinib treatment might be CMR duration of more than 2 years and low/intermediate Sokal scores at the time of CML diagnosis. In addition, increasing number of NK cells and decreased CD3+CD8+CD62L+ cell fractions may also be indications that imatinib therapy can be stopped. Disclosures:No relevant conflicts of interest to declare.

Determinants and Impact of Treatment Interruptions and Nonadherence to Imatinib Therapy in Patients with Chronic Myeloid Leukemia in a South Brazilian Cohort

Abstract 4425Adherence to imatinib therapy has proven to be a major determinant of treatment results, but the degree of impact and the determinants of nonadherence are still contradictory. There is no information regarding adherence to imatinib therapy in the Brazilian public health system. The aims of this study were to identify the characteristics related to treatment interruptions and nonadherence and to examine how these interruptions affect treatment responses and survival. Materials and MethodsWe conducted a retrospective study in a cohort of patients (pts) with CP-CML enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. Two levels of analysis were performed: all kinds of interruptions (nonadherence and toxicity) and only nonadherence ones. Information for nonadherence was taken from medical and pharmacy registers (pt self-report, missing scheduled appointments and pill counts). ResultsWe analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 70% pts. The median of follow-up was 47 mo. Treatment interruption was observed in 63/185 patients (34%) and was related to toxicities in 35/63 pts (55%) and to nonadherence in 28/63 pts (45%). The adherence rate was 85%. In a multivariate analysis, only late-onset imatinib treatment (Odds Ratio [OR]=36,05; p<0,001) and severe comorbidity (OR=27,05; p=0,03) were associated with higher risk of interrupting imatinib for any reason. The only variable associated with nonadherence was late-onset imatinib treatment (OR=14,76; p<0,001). Although not statistical significant, male and comorbidity showed a tendency to be linked with nonadherence (Table 1). Nonadherent pts, compared with adherent ones, had lower complete cytogenetic response (CCyR) rates at 12 mo (39% and 65%; p=0,004, respectively; Figure 1) and lower major molecular response (MMR) rates at 18 mo (9,5% and 35%; p=0,002, respectively; Figure 2). Finally, treatment interruption had a relevant negative impact on EFS in 4 yr. In the group that had treatment interruption, EFS was 52%, compared with 78,5% in the group without interruptions (p=0,002; Figure 3). Analysis performed only on nonadherence treatment interruption groups showed no significant difference (53% and 71%; p=0,15, respectively). [Display omitted] ConclusionsIn this cohort, a substantial proportion of pts failed to take imatinib properly, decreasing the chances of disease control. The late onset of imatinib therapy correlates with lower adherence, so front-line imatinib therapy should be started as soon as possible. Special attention should be given to pts with severe comorbidities, as they are more prone to suffer side effects or to lack adherence. Finally, pts who interrupted treatment had lower CCyR, MMR and EFS.Clinical and patient characteristics related to nonadherence Disclosures:No relevant conflicts of interest to declare. [Display omitted] [Display omitted]

Increased natural killer cells and decreased CD3+CD8+CD62L+ T cells in CML patients who sustained complete molecular remission after discontinuation of imatinib

Increased natural killer cells and decreased CD3⁺CD8⁺CD62L⁺ T cells in CML patients who sustained complete molecular remission after discontinuation of imatinib

Early cytogenetic and molecular response during first-line treatment of chronic myeloid leukemia in chronic phase

Chronic myeloid leukemia (CML) depends on the kinase activity of the BCR-ABL1 fusion protein. This dependency has led to the development of BCR-ABL1 inhibitors, such as imatinib, dasatinib, and nilotinib, which have proved to be highly efficacious treatments for CML. The European LeukemiaNet guidelines have established the importance of achieving a certain depth of response at different time points during imatinib therapy for patients with newly diagnosed CML in chronic phase. Patients who achieve a complete cytogenetic response by 12 months or a major molecular response by 18 months are classified as optimal responders and deemed to have excellent long-term outcomes. Conversely, failing to achieve such milestones is associated with an increased risk of worse long-term outcomes, such as loss of response, disease progression, or death. With ongoing treatment, patients not in complete cytogenetic response face a decreasing probability of ever achieving a complete cytogenetic response or major molecular response and increasing risk of disease progression. Available data therefore support treatment recommendations based on achieving defined levels of response within a specified duration of treatment. Recent data have shown that dasatinib and nilotinib used as frontline CML therapy result in higher response rates that are achieved at earlier time points compared with standard-dose imatinib therapy. Future analyses will need to determine whether these higher rates of deep and fast responses translate into improved long-term survival.

Sustained Superior Long-Term Outcomes of Imatinib Therapy In Japanese Patients with Newly Diagnosed Chronic Myelogenous Leukemia In Chronic Phase: Sub-Analysis According to the Mean Daily Dose of Imatinib and the Plasma Trough Levels In JALSG CML202 Study After 66 Months Follow-up.

AbstractAbstract 3417 Background:Now, imatinib has been established as a first line therapy for the patients with chronic myelogenous leukemia (CML) in chronic phase (CP), and a standard initial dose is 400 mg daily. Although less than 300 mg showed unsatisfactory results, 300 mg or more appears effective in some patients intolerant to standard dose. However, large studies have not yet explored the response to lower dose of imatinib. In this CML202 study, although initial dose of imatinib was scheduled to be 400 mg, many patients actually received reduced dose mainly due to adverse events. However, overall efficacy and outcomes had been comparable to other studies. We performed subgroup analysis regarding long-term survivals according to the mean daily dose during the first 6 months, 12 months, and 24 months, respectively. We also measured imatinib plasma trough concentration (Cmin) in patients receiving imatinib at a dose of 300 mg or 400 mg, and compared efficacy and survivals between them. Methods:The prospective multicenter study of imatinib therapy in Japanese patients with newly diagnosed CML-CP was conducted in Japan Adult Leukemia Study Group (JALSG CML202 study). The objectives of this study were to determine the efficacy, safety and long-term outcomes of imatinib therapy in patients with newly diagnosed CML-CP. Primary end point of imatinib therapy was overall survival (OS). Initial daily dose of imatinib was 400 mg. The plasma concentration of imatinib was measured using liquid chromatography-tandem mass spectrometry. Results:488 patients were enrolled between 2002 and 2006, and data at a median follow-up of 66 months were analyzed. The cumulative best response rates of major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) were 99%, 98% and 81%, respectively. At 66 months, the estimated rate of overall survival (OS) was 93% (95% CI, 90 to 96), and that of survival without progression to accelerated phase (AP) or blast crisis (BC) was 97% (95% CI, 96 to 99). In the landmark analysis at 12 months or 18 months according to the cytogenetic response or the molecular response, patients who had CCyR or MMR showed significantly better event free survival (EFS) rates than those who had not, respectively. Mean daily doses of imatinib administered during the first 24 months were 400 mg or more (400 mg group) in 294 patients, less than 400mg and 300mg or more (300 mg group) in 108 patients, and less than 300 mg (200 mg group) in 86 patients. The efficacy and outcomes at 66 months were evaluated according to the mean daily dose (400, 300, 200 mg group). The estimated rates of OS were 98%, 92% (P=0.09), and 74% (P<0.0001), and those of EFS were 91%, 79% (P=0.003), and 56% (P=0.0004), respectively. The estimated rates of survival without AP/BC were 99%, 97% (P=0.20), and 90% (P=0.03), respectively. OS, EFS and survival without AP/BC in 200 mg group were significantly inferior to those in 300 mg or more groups. OS and survival without AP/BC were not significantly different between 300 mg group and 400 mg group. However, EFS was significantly different between 300 mg group and 400 mg group. The cumulative CCyR and MMR rates in 200 mg group were inferior to those in 300 mg or more groups, however, they were not significantly different between 300 mg group and 400 mg group. OS and survivals without AP/BC in both 400 mg and 300 mg groups seem better as compared with the results of the IRIS study. However, EFS in 300 mg group was inferior to that of the IRIS study. The median (range) Cmin of imatinib in patients receiving 300 mg (n=24) and 400 mg (n=26) were 1,130 ng/mL (439-2,140) and 1,035 ng/mL (710-2,420), respectively. Cmin in patients receiving 300 mg distributed toward lower concentration as compared to those with 400 mg, even though they were not significantly different. Conclusion:The long-term results of the JALSG CML202 study revealed almost similar to those of the European countries in spite of the relatively lower mean daily dose. Imatinib at 400 mg or more induced excellent long-term outcomes in Japanese patients, however, EFS in 300 mg group was inferior to that in 400 mg group. These results suggest that higher daily dose is associated with better outcomes, however, imatinib at least 300 mg might be acceptable for patients intolerant to dose at 400 mg. Monitoring Cmin might be useful to find the optimal dose. Disclosures:Ohnishi:Novartis: Research Funding. Miyazaki:Novartis: Research Funding. Kiyoi:Novartis: Research Funding. Naoe:Novartis: Research Funding.

Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.

AbstractAbstract 4487 Background:Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims:To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods:We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results:We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions:In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures:No relevant conflicts of interest to declare.

Current treatment of gastrointestinal stromal tumours

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Imatinib dose escalation in two patients with chronic myeloid leukemia, with low trough imatinib plasma levels measured at various intervals from the beginning of therapy and with suboptimal treatment response, leads to the achievement of higher plasma levels and major molecular response

Despite the prognostic value of trough imatinib plasma levels (IPL) identified in some studies, no recommendations for the use of IPL results in routine management of CML patients have been issued. We report two patients in whom daily imatinib dose was increased from 400 to 600 or 800 mg because of low IPL found at various intervals from the beginning of treatment (7 measurements; mean IPL values = 616.33 and 764.5 ng/mL, respectively). Both patients achieved suboptimal response according to the European LeukemiaNet criteria (complete cytogenetic response was not achieved after 1 year of treatment in patient 1 and major molecular response after 47 months of standard-dose imatinib therapy in patient 2). In addition, we have demonstrated low hOCT-1 expression at diagnosis in both patients, retrospectively. Escalation of imatinib daily dose resulted in a significant increase of IPL (6 measurements; mean = 1790 and 1416.66 ng/mL, respectively) and in the achievement of complete cytogenetic response in patient 1 after 3 months and major molecular response within 15 and 6 months in both patients. Our cases demonstrate that low IPL identified at various non-predefined intervals from the beginning of therapy may be used for deciding on dose escalation in selected CML patients in the routine clinical setting, especially in cases with suboptimal treatment response.

Adherence Is the Critical Factor for Achieving Molecular Responses in Patients With Chronic Myeloid Leukemia Who Achieve Complete Cytogenetic Responses on Imatinib

There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence. Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed. Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence <or= 90%; in 12 of these patients (14%), adherence was <or= 80%. There was a strong correlation between adherence rate (<or= 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was <or= 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006). In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.

Early intervention during imatinib therapy in patients with newly diagnosed chronic-phase chronic myeloid leukemia: a study of the Spanish PETHEMA group

Despite the favorable results of imatinib front line in chronic-phase chronic myeloid leukemia there is room for improvement. Early intervention during imatinib therapy was undertaken in 210 adults with chronic-phase chronic myeloid leukemia less than three months from diagnosis (Sokal high risk: 16%). Patients received imatinib 400 mg/day. At three months, dose was increased if complete hematologic response was not achieved. At six months, patients in complete cytogenetic response were kept on 400 mg and the remainder randomized to higher imatinib dose or 400 mg plus interferon-alfa. At 18 months, randomized patients were switched to a 2(nd) generation tyrosine kinase inhibitor if not in complete cytogenetic response and imatinib dose increased in non-randomized patients not in major molecular response. Seventy-two percent of patients started imatinib within one month from diagnosis. Median follow-up is 50.5 (range: 1.2-78) months. At three months 4 patients did not have complete hematologic response; at six months 73.8% were in complete cytogenetic response; among the remainder, 9 could not be randomized (toxicity or consent withdrawal), 17 were assigned to high imatinib dose, and 15 to 400 mg + interferon-alpha. The low number of randomized patients precluded comparison between the two arms. Cumulative response at three years was: complete hematologic response 98.6%, complete cytogenetic response 90% and major molecular response 82%. On an intention-to-treat basis, complete cytogenetic response was 78.8% at 18 months. At five years, survival was 97.5%, survival free from accelerated/blastic phase 94.3%, failure free survival 82.5%, and event free survival (including permanent imatinib discontinuation) 71.5%. These results indicate the benefit of early intervention during imatinib therapy (ClinicalTrials.gov Identifier: NCT00390897).