4453 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 3 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. Global survival (GS) was measured from the start of imatinib to the date of death from any cause. Results We analyzed data from 181 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 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 123 pts (68%) achieved CCyR, in this group the four year global survival was 97%. 58 (32%) were not in CCyR at 6 months of therapy, in this group the four year GS was 87%. This difference was significant (P=.024; Figure 1). The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and global survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.
4425 Adherence 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 Methods We 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). Results We 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). Conclusions In 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.
2296 Background: Comorbidity in cancer has been shown to be a major determinant in treatment selection and survival. The most used instrument for measuring comorbidity in Hematology is the Charlson comorbidities index (CCI). It is a list of 19 conditions with weight assigned from 1 to 6, derived from relative risk estimates of a proportional hazard regression model using clinical data. The ACE-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. Little is known about the impact of comorbidity in chronic myeloid leukemia (CML). Aims: Our objectives were to evaluate the impact of comorbidity in the outcomes of a cohort of chronic phase chronic myeloid leukemia (CP-CML) patients (pts) treated with imatinib and compare the results from the 2 indexes (CCI and ACE-27). 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 recommendations. Comorbidity conditions were registered at any point during evaluation and CCI and ACE-27 scores were applied to each patient. The outcomes were event-free survival rate (EFS) and imatinib temporary suspension rate. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Imatinib suspensions were considered if superior to 20 days. We conducted 3 types of analysis concerning treatment suspension: suspension for any reason (toxicity and nonadherence), suspension only due to toxicity and only due to nonadherence to treatment. Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (range 4 – 85). The median time from diagnosis to imatinib was 7 months (range 0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with interferon was used in 70% pts. CCI distribution among pts: score point 0 was assigned to 136 pts, score point 1 to 24 pts, score point 2 to 11 pts, score point 3 – 6 to 13 pts and 1 pt with missing information. ACE-27 distribution among pts: score point 0 was assigned to 92 pts, score point 1 to 51 pts, score point 2 to 21 pts, score point 3 to 19 pts and 2 pts with missing information. The indexes showed a strong correlation (Spearman's coefficient 0,7, P<0,0001). The projected EFS rate at 4 years was 68% after a median follow-up time of 4 years. We found a significant association between both indexes and EFS rate at 4 years. The EFS in each group of ICC was: 73% in score 0 group, 65% in score 1 group, 41% in score 2 group and 36% in score 3 to 6 group (P=0,04, Fig 1). The EFS in each group of ACE-27 was: 80% in score 0 group, 69% in score 1 group, 56% in score 2 group and 33% in score 3 group (P<0,001, Fig 2). A significant association between both indexes and drug temporary suspension rate was also found. For the CCI, 32% of score 0 pts had at least one suspension due to any reason, compared to 41% of pts with score 1, 46% of pts with score 2 and 73% of pts with score 3–6 (P=0,04). Subgroup analysis revealed a significant association between CCI and interruption due to toxicity (P=0,03) and due to nonadherence (P=0,03). For the ACE-27, 32% of score 0 pts had at least one suspension due to any reason, compared to 36% of pts with score 1, 27% of pts with score 2 and 69% of pts with score 3 (P=0,03). Subgroup analysis revealed a significant association between ACE-27 and interruption due to toxicity (P=0,02) but not due to nonadherence (P=0,69). Conclusions: In our population of pts with CP-CML, event-free survival, imatinib toxicity and nonadherence seem to be associated with the presence of comorbidities. Both CCI and ACE-27 can be used in the stratification of patients at risk to have major toxicities, lack of adherence or an event during treatment with imatinib. ACE-27 was a better tool in predicting EFS, in the other way, CCI was superior in predicting nonadherence. Disclosures: No relevant conflicts of interest to declare.
Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patients (pts), but in a subgroup of pts controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of imatinib therapy. The definitions of response, warning signs and failure to treatment, with the identification of pts at greater risk of progression or failure, were revised and published in 2013 by the European Leukemia Net group. Aims To apply the new recomendations of ELN2013 in order to verify the evolution of the patients according to the response criteria at 12 months (mo) of imatinib therapy. Methods Retrospective study in a cohort of patients with CP-CML from a southern Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN2013 criteria and were classified in 3 groups according to the cytogenetic and molecular responses at 12 mo: optimal, warning and failure. An event was defined as any of the following while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results Data from 98 pts with a median follow-up (FU) time of 40 mo was analysed. At 12 mo of imatinib therapy, 35 pts (36%) had optimal response according to the ELN2013 criteria. 26 (26,5%) were classified as warning and 37 (37,5%) as failure. Within the pts with optimal response, only 4 (11%) have had any event, with a median time-to-event (TTE) of 36 mo; in the warning group the event rate and TTE were 3 (12%) and 28 mo, respectively. There were no significant differences in the results between these two groups. On the other hand, within the pts with failure, 24 (65%) presented an event during FU with a TTE of 19 mo. This difference was significant compared to the two previous groups. Interestingly, within the warning group, 12 pts (46%) developed major molecular response (MMR) at any point during FU, while only 12 (32%) pts achieved RMM in the failure group. Conclusion In this cohort of CP-CML pts is established the diference in the event rate between the pts who achieve optimal or warning responses at 12 mo of imatinib treatment when compared with those with failure criteria, according to the new ELN2013 recomendations. Despite having some late responders, atention must be paid in pts in the failure group as they are in greater risk of progression or failure. As demonstrated in this analysis, the ELN2013 criteria can be applied in this population in the clinical practice. Disclosures: No relevant conflicts of interest to declare.
Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.
2300 Introduction: Imatinib mesylate (Gleevec) treatment for Chronic Myelogenous Leukemia (CML) was first introduced in Brazil in 2003, initially used as second line therapy for patients resistant or intolerant to interferon. In 2004 imatinib was adopted as front-line therapy for chronic phase (CP) and clinical experience improving since then. Close monitoring of responses achievement at scheduled time has proven to provide good predictive value for progression and event-free survival. Failure and sub-optimal responses correspond to indications for dose change or therapy switching and the identification of patients at greater risk for such events has a vital role. The aim of this study is to evaluate the impact of temporary imatinib therapy discontinuation on achievement of Major Cytogenetic Response (MCyR) and event-free survival (EFS). Materials and Methods: During the period of 1990 to 2010 a total of 185 patients from 7 CML treatment centers from Rio Grande do Sul, south Brazil, with a confirmed diagnosis of CML (Philadelphia chromosome positive [Ph+]) at CP under imatinib treatment were retrospectively analyzed. A major cytogenetic response was considered complete plus partial cytogenetic responses (Ph+ less than 35%). At least 20 metaphases were analyzed for a cytogenetic response to be evaluable. Temporary treatment discontinuation (TTD) corresponds to 20 days or more off-medication for any reason during the follow-up. Were included patients in imatinib second-line and first-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months from diagnosis and late-imatinib treatment when more then 12 months lapse. EFS was measured from the start of imatinib to the date of any the following events while on therapy: death of any cause, therapy failure, any response loss, disease progression, definitive treatment discontinuation or therapy change. Descriptive statistics and Kaplan-Meier analysis (to estimate event-free survival [EFS]) were performed using SPSS software. Results: The median age at diagnosis was 48 years (range, 4–85 years) median of follow-up was 47 months (range, 7–113 months) and 55% of male sex. Preferential previous treatment was interferon in 70% of the patients and 71% were early-imatinib treatment. TTD was observed in 63/185 patients (34%) and was related to toxicities in 35/63 patients (55%), including hematological and non-hematological. Nonadherence was attributed to the remaining TTD, 28/63 patients (44%). Late-imatinib patients had significant more TTD (62%) than early-imatinib patients (26,2% [p<0,001]). Subgroup analyzes showed that was a significant TTD rate due to toxicity in the late-imatinib patients (p=0,03), but not significant due to nonadherence (p=0,37). Patients who experienced TTD had lower proportion of MCyR at 12 months: only 43% compared to 70% of patients who did not had TTD (p<0,001 [Figure 1]). Finally the TTD had a relevant negative impact on EFS in 5 years. In the group who had TTD EFS was 47,5%, compared with 73% in the group without TTD (p=0,002 Figure 2). Conclusion: In our cohort, patients with TTD were associated with lower rate of MCyR and it may be a risk factor for failure or sub-optimal responses to imatinib therapy. TTD also has a negative effect in terms of EFS in patients under imatinib treatment, possibly related to worsen cytogenetic disease control. The late onset of imatinib therapy correlates with more toxicity leading to treatment interruptions and front-line imatinib therapy should be started as soon as possible. Special attention should be given to patients who presents with side effects of any nature that could preclude the correct use of the medication. Close monitoring and early management of such adverse reactions, frequent assessment of compliance should be warrant as effort to guarantee the best chance for therapy success. Disclosures: No relevant conflicts of interest to declare.
RESUMO O Brasil consolidou-se como um grande produtor e exportador de produtos agrícolas sendo destaque em diversas culturas de grãos. No entanto, o país ainda subutiliza os resíduos oriundos dessa atividade, que poderia ser eficientemente aproveitado no sistema energético no meio rural. O presente trabalho calcula o potencial de geração de energia elétrica utilizando biomassa oriunda dos resíduos agrícolas produzidos na região Centro-oeste do Brasil. Os resultados indicam que há o equivalente a três usinas de Itaipú ainda não aproveitadas na região. Contudo, apenas 9,1% do potencial pode ser aproveitada até 2024, face as limitações impostas pelo sistema de transmissão disponível. Assim, o reaproveitamento de resíduos agrícolas para produção de bioenergia é extremamente viável, gerando economia, diminuindo passivos ambientais e agregando valor à cadeia produtiva agrícola da região Centro-Oeste.
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