scholarly journals BCR-ABL1 Transcript of 7.93% at 3 Months Is an Early Predictor for Long-Term Survival to Second-Line Therapy Using Next Generation Tyrosine Kinase Inhibitors in Imatinib-Resistant Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4564-4564
Author(s):  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Yun Jeong Oh ◽  
Soo-Hyun Kim ◽  
Hye-Young Song ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Third Generation ◽  
Second Line ◽  
Second Line Therapy ◽  
Term Survival ◽  
Long Term Survival ◽  
Line Therapy

Abstract Abstract Background: The first BCR-ABL1 tyrosine kinase inhibitor (TKI), imatinibmesylate (IM), has become a first-line therapy for chronic phase (CP) chronic myeloid leukemia (CML). However, approximately one third of IM-treated patients discontinue therapy due to an inadequate response or adverse event. More potent second or third generation TKIs such as nilotinib, dasatinib, radotinib, bosutinib and ponatinib have developed and these agents have shown high rates of hematologic and cytogenetic responses after failure of IM therapy. Although the new European Leukemia Net (ELN) recommendation serves provisionally the definitions of the response to second-line therapy, early molecular milestones which are associated with the best long-term are not confirmed. The aim of this study was to identify 3-month molecular milestone for predicting long-term survival to second-line therapy using second or third generation TKIs in CP CML patients who showed a failure or warning to IM. Methods: Between March 2005 and January 2014, 198 CP CML patients with failure or warning to IM (defined by 2013 ELN recommendation) had been treated with nilotinib, dasatinib, radotinib, bosutinib or ponatinib as a second-line therapy. Among them, 180 patients had available molecular data at 3 months from the initiation of second-line therapy. Based on receiver operating characteristic (ROC) curveanalysis, the predictive cutoffs of BCL-ABL1 transcripts at 3 months for progression-free survival (PFS), and overall survival (OS) were evaluated. OS included any death regardless of causes, and PFS included progression to AP or BP as well as death resulting from any reason. OS and PFS were also collected on patients who were treated with other TKIs after failure of second-line TKI therapy. Results: A total of 180 patients were treated with second-line TKI, dasatinib (n=66), nilotinib (n=61), radotinib (n=44), bosutinib (n=7), and ponatinib (n=2). 119 men and 61 women were included and their median age was 42 years (range, 15-75). Using a ROC curve analysis, BCR-ABL1 transcript level 7.93% on the international scale, at 3 months were predictive cutoffs for both PFS and OS. The median follow-up for survivors since the start of second-line TKI was 78.73 months (range, 6.3-114.0 months). 104 patients continue on therapy and 76 patients were permanently discontinued due to intolerance (n=38), failure (n=20), progression (n=14), and others (n=4). The7-year PFS and OS were 82.6% and 85.3%, respectively. The patients with transcript levels below 7.93% at 3 months had significantly better 7-year PFS (95.1% vs. 60.4%; P < 0.001) and OS (96.3% vs. 67.9%; P < 0.001). After adjusting for potential factors affecting PFS and OS in univariate analyses, multivariate analyses showed that BCR-ABL1 transcript of 7.93% at 3 months was the independent predictor for PFS (RR of 8.37, P < 0.001) and OS (RR of 13.53, P = 0.001). In addition, increasing age (RR of 1.05, P = 0.023) and presence of BCR-ABL1 kinase domain abnormalities (KDA) at baseline (RR of 5.83, P = 0.007) were associated with a lower OS. Conclusions: Our data showed BCR-ABL1 transcript of 7.93% at 3 months was an early independent predictor for long-term survival to second-line TKIs in IM-resistant CP CML. It implies that the patients who failed an achievement of reduction of BCR-ABL1transcripts to this level may require more precise monitoring on second-line therapy, allowing early clinical intervention using other third-line TKI therapy or allografting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-term survival estimates for imatinib versus interferon-? plus low-dose cytarabine for patients with newly diagnosed chronic-phase chronic myeloid leukemia

Cancer ◽  
2004 ◽  
Vol 101 (11) ◽  
pp. 2584-2592 ◽  
Author(s):  
Kevin J. Anstrom ◽  
Shelby D. Reed ◽  
Andrew S. Allen ◽  
G. Alastair Glendenning ◽  
Kevin A. Schulman
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Term Survival ◽  
Long Term Survival ◽  
Low Dose Cytarabine

Allogeneic Myeloablative Hematopoietic Stem Cell Transplantation for Chronic Myelogenous Leukemia in the Imatinib Era.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 970-970
Author(s):  
Jiri Pavlu ◽  
Matthias Klammer ◽  
Ian Gabriel ◽  
Richard Szydlo ◽  
Eduardo Olavarria ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Scoring System ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Prognostic Scores ◽  
Second Line ◽  
Second Line Therapy ◽  
Hematopoietic Stem ◽  
Line Therapy

Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is no longer the first treatment option for patients with chronic myelogenous leukemia (CML) but there is a considerable debate about its use as a second line therapy. When used in this indication the second-generation tyrosine kinase inhibitors (2G-TKI) induce complete cytogenetic responses (CCyR) in 40–50% of patients in chronic phase but those without CCyR are unlikely to benefit in long term. It is therefore important to identify groups of patients with a good outcome after transplantation so that this may be offered as second line therapy where appropriate. The outcome of allo-SCT has improved over time so we restricted our analysis to the most recent 8 years to coincide with the introduction of imatinib into clinical practice. 131 patients received myeloablative transplants from January 2000 till December 2007. 67 patients were transplanted in chronic phase (14 in second and 2 in third chronic phase), 46 in accelerated phase and 2 in blastic phase. Forty-nine patients received imatinib at some point prior to transplantation and 30 of these experienced failure of imatinib therapy (as defined by European LeukemiaNet criteria). Conditioning consisted of cyclophosphamide and total body irradiation for 51 recipients of sibling stem cells. In addition in vivo T cell depletion with anti CD52 antibody (Campath 1H) was used for 80 unrelated donor transplants. The median age of the patients was 33.4 (15 to 56) years and the median disease duration at transplant was 13 (2 to 105) months. The probability of overall survival (OS) at 3 and 5 years was 64.8% and 62.6% respectively. We confirmed the prognostic value of the EBMT risk assessment score (Gratwohl) and pretransplant level of the C-reactive protein (CRP) and developed a combined additive pretransplant scoring system based on these predictive factors (EBMT risk assessment score plus 0 for CRP <2 mg/L, 1 for CRP from 2 to 10 mg/L, and 2 for CRP >10 mg/L). This identified 5 prognostic groups (Figure 1) with 3yr probabilities of survival of 92.6% (N= 27, score 0–1), 86.2% (N=29, score 2), 58.2% (N=29, score 3), 47.5% (N=20, score 4) and 30.8% (N=26, score 5 or more). The patients who failed imatinib (N=30) had significantly higher prognostic scores on the above described pre-transplant scoring system compared to the rest of patients transplanted (p=0.001). However, in a multivariate analysis adjusted for prognostic scores, their OS was significantly better (p=0.032). The OS in the best prognostic group is comparable with that of unselected patients treated with imatinib and it is possible that their long-term survival might be better. Allogeneic transplantation is unlikely to be preferred as the first line therapy even in selected patients due to its higher early mortality but our data support its use as second line therapy in patients in chronic phase who failed imatinib and have poor pre-2G-TKI predictive factors for CCyR as determined previously at our institution (namely Sokal risk score at diagnosis, the best cytogenetic response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib failure to onset of 2G-TKI therapy) but achieved good score on the pre-transplant scoring system. It should also be used for those whose disease is more advanced where the 2G-TKI do not offer durable remissions. Figure 1 Figure 1.

scholarly journals Imatinib in Children with Chronic Myeloid Leukemia in Chronic Phase: Long-Term Results of the French National Phase IV Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4147-4147
Author(s):  
Hélène Deutsch ◽  
Andre Baruchel ◽  
Joelle Guilhot ◽  
Arnaud Petit ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Median Time ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Second Line Therapy ◽  
Blastic Crisis ◽  
Line Therapy ◽  
Phase Iv

Because of the rarity of Chronic Myeloid Leukemia (CML) in children and adolescents, only few studies reported on efficacity and tolerance of imatinib in the pediatric population and scant data are available regarding long-term follow-up. The aim of our analysis was to assess, the long-term efficacity and safety of imatinib in children with CML in early chronic phase included in the French multicentric prospective Glivec Phase IV trial (Millot et al, J Clin Oncol 2011). Methods: Children aged 0 to 18 years with newly diagnosis CML in chronic phase were eligible to received daily imatinib 260 mg/m² according the trial. Long-term analysis included overall survival (OS), progression-free survival (PFS), response to treatment and adverse events. Results: Between March 2004 and December 2008, 44 patients (median age 13.4 years; range 0.8 - 16.7 years) were included in the trial. As of April 2019, with a median follow-up of 10.6 years (range 1.8 - 13.4 years), 2 patients (pts) progressed to blastic crisis and only one death was recorded. The median age was 21.8 years (range 9.3 - 28.8 years) at the last follow-up. The median duration of imatinib therapy was 10.5 years (range 0.2 - 12.5 years) for the entire cohort. To date, 13 pts (29.5%) are still treated with imatinib. Thirty-one pts (70.5%) had discontinued first line treatment with imatinib after a median time of treatment of 2.4 years (range 0.2 - 10.6 years) for the following reasons: 10 pts did not achieve major molecular response (MMR), 1 pt developed blast crisis, 2 pts had unsatisfactory level of molecular response (MR) according to the clinician, 10 pts lost their response (loss of complete hematological response n=1, complete cytogenetic response [CCR] n=6 and MMR n=3), 4 pts attempted treatment free remission (TFR), 3 pts were intolerant to imatinib and 1 pt stopped because of pregnancy. Among these 31 pts who discontinued imatinib, 2 pts are still in TFR, and 29 pts switched to a second line therapy: second generation tyrosine kinase inhibitors (2TKI) (n=25), allogeneic hematopoietic stem cell transplantation (HSCT) (n=3), polychemotherapy (n=1). Sixteen of these 31 pts (51.6%) required subsequent lines of therapy including a second pt who transformed to blastic crisis under a second line therapy with dasatinib. Overall 11 pts (25%) underwent HSCT. Overall, regarding the best response, during the study follow-up 11 pts (25%) achieved MMR after a median time of 2.3 years (range 0.8-5.1), 7 pts (13.6%) achieved MR4 after a median time of 5.1 years (range 2.5-7.8), 25 pts (56.8%) achieved MR4.5 after a median time of 2.92 years (range 1.1-10.4) and 1 pt (2.3%) achieved CCR only. At last follow-up, 43 out the 44 pts were alive : 3 pts (7%) were in CCR, 12 pts (27.9%) in MMR, 6 pts (13.9%) in MR4 and 22 pts (51.2%) in MR4.5. Among the 13 pts still treated with imatinib, 1 pt (7.7%) was in CCR, 6 pts (14%) in MMR, 3 pts (23.1%) were in MR4 and 3 pts (23.1%) in MR4.5. Among the 11 transplanted patients, all pts except one are alive, in at least MR4.5. The death was related to post transplant infection. On an intention to treat basis, the 10-year OS of 44 patients treated was 97.7% (CI 95% 93.3-100). The 10-year PFS was 95.5% (CI 95% 89.3-100). We collected also the long-term safety of imatinib in the 25 pts who have received this therapy for more than 4 years. Newly occurring or worsening grade 3 or 4 hematologic or biochemical adverse events were infrequent after 4 years of imatinib. There is a decrease in the frequency of hematologic and extra hematologic sides effects reported during the first year and those reported after the fourth year of treatment with imatinib: musculoskeletal events 80 vs 24% (p<0,0001), abdominal pain 44% vs 16% (p=0,03), nausea 48% vs 16% (p=0,02), diarrhea 24% vs 0% (p=0,01) and neutropenia 84% vs 28% (p<0,0001), respectively. Conversely, the incidence of lymphopenia appeared with duration of imatinib treatment (p=0,04). Conclusion: With more than 10 years of follow-up, we showed that imatinib remains effective in one third of children included in the Glivec phase IV study with acceptable adverse effects and a low impact over time. Despite the notable proportion of switches, the OS and the PFS remain satisfactory in this pediatric cohort. Disclosures No relevant conflicts of interest to declare.

Long-Term Continuing Second Complete Remission (CCR2) despite Allogeneic Stem Cell Transplantation in CR1: Results from the International Randomised Phase III Study Pediatric Relapsed AML 2001/01

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2977-2977
Author(s):  
G.J.L. Kaspers ◽  
M. Zimmermann ◽  
D. Reinhardt ◽  
B. Gibson ◽  
R. Tamminga ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Late Relapse ◽  
Second Line ◽  
Second Line Therapy ◽  
Term Survival ◽  
Probability Of Survival ◽  
Line Therapy

Abstract Relapse remains the commonest adverse event in newly diagnosed AML patients, and the reported long-term survival after relapse in pediatric AML is 20–30%. Allogeneic stem cell transplantation (allo-SCT) in CR1 is employed by several groups with the aim of reducing the relapse rate. There is a widely held view that patients with AML who relapse after an allo-SCT in CR1 have no or minimal chances of long-term survival. However, such a cohort has never been described in the literature. Therefore, the outcome of children with AML who received an allo-SCT in CR1 and who subsequently relapsed and were enrolled in study Relapsed AML 2001/01 is described. This is a prospective, randomised study for relapsed AML, excluding AML M3 and those &gt;18 years of age at initial diagnosis comparing FLAG with Daunoxome-FLAG. FLAG is given for 2 consecutive courses: fludarabine 30 mg/m2/day × 5 days, cytarabine 2 g/m2/day × 5 days, G-CSF 200 μg/m2/dose × 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX; a new anthracycline with potentially less cardiotoxicity) at 60 mg/m2/day on days 1, 3 and 5 is added or not in a 1:1 randomised fashion to the first course of FLAG. After two courses, patients are eligible for allo-SCT, sometimes bridged by high-or low-intensity consolidation chemotherapy. Efficacy data for both arms are still blinded as the study remains open until the end of 2008. Thirteen groups worldwide are enrolling patients. More than 500 patients were registered by April 2008, but this analysis relates to 329 fully evaluable patients diagnosed before July 2007, who are known to have or have not received an allo-SCT in CR1. Reasons for allo-SCT in CR1 differ between groups, but in general it is reserved for higher-risk patients and predominantly those with a matched-sibling donor. As part of relapsed treatment, 214 patients underwent allo-SCT to consolidate second line therapy, and for 11 patients this was their second allo-transplant. Twenty-two (7%) of these 329 patients had undergone allo-SCT in CR1, 12 boys and 10 girls, the majority being between 1 and 10 years of age. Three out of these 22 patients had a favorable karyotype, i.e. inv(16) or t(8;21). The majority of these patients (17/22, 77%) had a late relapse (occurring at least one year from initial diagnosis) compared to 47% of relapsed AML patients who had not received an allo-SCT in CR1 (p=0.01). There was no significant difference in chemotherapy related morbidity or mortality between those children who had received an allo-SCT in CR1 and those who had not, including cardiotoxicity. The percentage of so-called poor early responders (more than 20% bone marrow blasts on day “28” sampled shortly before the 2nd reinduction course) was 24% versus 23% (n.s.) and the CR2 rate 45% versus 65% (p=0.09) in the yes and no allo-SCT in CR1 patients, respectively. Within late relapsed AML only, the rate of poor early responders was 23% versus 15% (n.s.) and the CR2 rate 50% versus 77% (p=0.03) in the yes and no allo-SCT in CR1 patients, respectively. Finally, 4-year probability of survival from relapsed AML was 27% (95%-C.I. 8–47%) in the “yes allo-SCT in CR1” subgroup compared to 33% (27–39%) in the remaining patients (n.s.). Limiting this analysis to late relapsed AML patients, it was 29% (6–53%) versus 45% (36–54), respectively (n.s.). Five of the 6 patients who survived after allo-SCT in CR1 (median follow up 2 years) received a second allo-SCT. In conclusion, the small number of trial patients who relapsed early and who had received an allo-SCT in CR1 suggests that clinicians may have been reluctant to enter these patients into trial. In general, patients with an early relapse of AML treated in this study have a reasonable chance of cure (Kaspers et al., ASH 2007 and 2008), but the very small number of such patients who had an allo-SCT in CR1 preclude any firm conclusions for that subgroup. Patients with a late relapse who have received an allo-SCT in CR1 appear to have a somewhat (but statistically not significant) inferior outcome compared to patients who were not transplanted in CR1. The probability of survival at 4 years from relapse of nearly 30% warrants the use of second line therapy in patients with a late relapse despite allo-SCT in CR1.

Drug Toxicities in Second-Line Treatment of Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5173-5173
Author(s):  
Tarcila S Datoguia ◽  
Hugo R C Silva ◽  
Amauri M C R Junior ◽  
José Salvador Oliveira ◽  
Monika Conchon
Keyword(s):  
Side Effects ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Cutaneous Rash

Abstract Introduction Chronic myeloid leukemia (CML) is known to be a myeloproliferative neoplasm that involves a genetic abnormality defined as Philadelphia chromosome. Part of chromosome 9 becomes attached to chromosome 22, forming the BCR-ABL fusion gene, which is an oncogenic tyrosine kinase. The rise of the tyrosine kinase inhibitors (TKIs) has transformed the outcome of CML. Imatinib was the first TKI approved for treating patients diagnosed with CML in 2001. Dasatinib and Nilotinib were accredited as second-line therapy in 2006 and 2007, respectively, for patients who had failed previous therapy. Although these new drugs improved response compared with imatinib, they also have important side effects that can lead to non-adherence to treatment. Given the importance to maintain regular treatment to avoid disease progression, this paper aims to discuss the drug toxicities in patients undergoing second-line therapy. Patients and methods This study was an observational analysis using medical records in Santa Marcelina Hospital, a public service located in São Paulo, Brazil. Results A total of 58 CML patients taking second-line therapy were included, 28 with dasatinib and 30 with nilotinib. In dasatinib group, only 3 patients were diagnosed accelerated phase and each one had different side effects, as hematological toxicity, pleural effusion and ulcerative colitis. Of 25 chronic phase patients taking dasatinib, 12 (48%) presented with clinical and laboratorial abnormalities: 3.5% had hematological toxicity (2% with severe bleeding), 4% had cutaneous rash, 10.7% with ulcerative colitis (confirmed in bowel biopsy) and 18% developed pleural effusion. 25% of all dasatinib patient with side effects lost molecular response and started a third TKI. In nilotinib cohort, 7 patients were diagnosed with CML accelerated phase and only two developed liver toxicity. 23 patients were chronic phase and 60% presented with several side effects: 3% hypertriglyceridemia, 6% had hematological toxicity, 6% with dyspepsia, 10% had cutaneous rash and 27% presented with higher liver transaminase. 7% of all nilotinib patients who developed side effects lost molecular response and had to discontinue therapy. Discussion Several examples of side effects can be described with all TKI including cytopenias, fatigue, pain, fluid retention, GI disorders, skin complains, cardiac and liver toxicities but grade 3-4 occurs in less than 2-3% of patients as Jabour et al reported. Despite of important adverse effects, dasatinib and nilotinib induce rapid and durable hematologic and cytogenetic response. In general, the most related toxicities are self-limited and manageable as Kantarjian related. Comparisons between these two second-line therapy using intolerance criteria can be difficult to represent because studies published until now have two different types of population in terms of cytogenetic response achieved previously with imatinib, for example. So, to have a successful treatment, it is important to consider other variables as comorbidities and mutational status as referred Mathisen et al. Individualized risk assessment, between CML and patients characteristics, should influence treatment choices and clinical management. In conclusion, the efficacy and safety of dasatinib and nilotinib have been confirmed by long-term outcome. Clearly these drugs have unique pharmacologic profiles and response patterns in every single patient, but the goal of treating these patients is the correct management of adverse events without losing molecular response. Disclosures No relevant conflicts of interest to declare.

scholarly journals Is the Sokal or EUTOS long-term survival (ELTS) score a better predictor of responses and outcomes in persons with chronic myeloid leukemia receiving tyrosine-kinase inhibitors?

Leukemia ◽  
2021 ◽  
Author(s):  
Xiao-Shuai Zhang ◽  
Robert Peter Gale ◽  
Xiao-Jun Huang ◽  
Qian Jiang
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Intermediate Risk ◽  
Term Survival ◽  
Long Term Survival ◽  
Sokal Score

AbstractData from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2nd-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR4, MR4.5, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR4, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p < 0.001~0.061), FFS (p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.

Similar Efficacy of Dasatinib and Nilotinib As Second-Line Therapy in Patients with Chronic Phase Chronic Myeloid Leukemia Failing Imatinib: A Retrospective, Real-Life Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5434-5434
Author(s):  
Mario Tiribelli ◽  
Massimiliano Bonifacio ◽  
Gianni Binotto ◽  
Alessandra Iurlo ◽  
Francesca Cibien ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Similar Efficacy ◽  
Molecular Response ◽  
Second Line ◽  
Second Line Therapy ◽  
Secondary Resistance ◽  
Line Therapy ◽  
Mean Time

Abstract Background. Use of 2nd generation tyrosine kinase inhibitors (2G-TKIs) dasatinib (DAS) and nilotinib (NIL) in chronic phase (CP) chronic myeloid leukemia (CML) patients failing imatinib (IM) results in around 50% of sustained cytogenetic response, and around 40% major molecular response (MMR). However, these are historical data and it's unclear if there's a significant difference in efficacy of the two 2G-TKIs, especially in the long-term. Aims and methods. We retrospectively analysed 163 CP-CML patients resistant or intolerant to IM that received either DAS (n=95) or NIL (n=68) as second-line therapy. We compared the characteristics of the two groups at the time of CML diagnosis and at the time of IM failure, including the cause of switch to 2G-TKI, duration of IM therapy, IM dose escalation and Hammersmith score to predict the probability of response to 2G-TKIs. Cytogenetic and molecular responses were evaluated according to the ELN recommendations. Sustained deep molecular response (DMR) was defined as MR4 or better lasting ≥ 2 years, ongoing at the last contact, and with at least a Q-PCR test every 6 months. Time to treatment failure (TTF) was calculated from the start of 2G-TKI to any of the followings: progression to accelerated or blast phase (ABP), death for any cause at any time, treatment discontinuation for primary or secondary resistance or intolerance. Progression free survival (PFS) was calculated from the start of 2G-TKI to ABP or death. Overall survival (OS) was calculated from the start of 2G-TKI to death. Results. DAS and NIL cohorts were comparable for age, sex and risk score (Sokal and EUTOS) at diagnosis. Median duration of IM therapy was similar (DAS 19 months, NIL 14 months), but 27/95 patients (28%) had IM dose escalation before DAS compared to only 9/68 (13%) before NIL (p=0.03). There was a higher rate of switch to DAS than to NIL for secondary resistance (26/95, 27% vs 7/68, 10%; p=0.01) while more patients changed from IM to NIL due to intolerance (31/68, 46%, vs 21/95, 22% for DAS; p=0.002). Rates of primary resistance did not differ (47/95, 49% for DAS vs 28/68, 41% for NIL; p=0.37), as well as other causes of switch (1/95, 1% for DAS vs 2/68, 3% for NIL; p=0.77). Hammersmith score was almost identical in the two groups. Complete cytogenetic response (CCyR) was attained in 53/73 (73%) patients not in CCyR at the time of DAS start, and in 31/48 (65%) patients not in CCyR at the time of NIL start (p=0.46). Mean time to CCyR was similar (7.1 months for DAS and 5.3 months for NIL; p=0.30). MMR was achieved in 55/89 (65%) patients not in MMR at the time of DAS start and in 39/61 (65%) patients not in MMR at the time of NIL start (p=0.82). Again, mean time to MMR was not different in the DAS e NIL cohorts (12.4 vs. 8.5 months; p=0.14). DMR was obtained in 39/88 (44%) patients not in DMR at the time of DAS start and in 30/65 (46%) patients not in DMR at the time of NIL start (p=0.95). Sustained DMR was evaluable in 127 patients: 37 patients (29%) achieved sustained DMR, without difference between DAS (24/82, 29%) and NIL (13/45, 29%; p=1.00). With a median follow-up of 44 months (range 1-124), 5-year TTF was similar for DAS (65%, 95%CI 52-75%) and NIL (61%, 95%CI 43-74%; p=0.40) [Figure 1a]. Thirty-two of 95 patients (34%) stopped DAS due to toxicity (19/32, 59%), resistance (11/32, 31%) or other causes (3/32, 10%); 22/68 patients (32%) interrupted NIL for toxicity (11/22, 50%), resistance (8/22, 36%) or other causes (3/22, 14%). Probability of survival and progression were almost identical, with a 5-year PFS of 84% (95%CI 68-89%) for DAS and 92% (95%CI 79-97%) for NIL (p=0.27) [Figure 1b] and a 5-year OS of 89% (95%CI 78-95%) and 96% (95%CI 85-99%) (p=0.31), respectively. Conclusions. With the limits of a retrospective analysis, our data suggest similar efficacy of DAS and NIL after IM failure in CP-CML, with rates of cytogenetic and molecular responses higher than those previously reported and excellent long-term survival. Around 30% achieved sustained DMR with second-line therapy, thus being potentially candidate for TKI discontinuation. Disclosures Tiribelli: Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Amgen: Consultancy. Fanin:Novartis: Speakers Bureau.

Dasatinib As a Late Second Line Therapy in Chronic Myeloid Leukemia Patients: A Retrospective Study From a Tertiary Care Centre in India

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4438-4438
Author(s):  
Tulika Seth ◽  
Vandana Sharma ◽  
Sanjeev Sharma ◽  
Manoranjan Mahapatra ◽  
Pravas Mishra ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Tertiary Care ◽  
Chronic Phase ◽  
Hematologic Toxicity ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Late Failure

Abstract Abstract 4438 Introduction- Chronic myeloid leukemia in Indian patients manifests a decade earlier than reported in the West. However, patients present later to the hospital, with advanced disease as evinced by large spleen size, fever and other symptoms and a high Sokal score. The cost of medicines and lack of health insurance means that most will receive Imatinib mesylate (Glivec) from the GIPAP program only, or locally produced Imatinib. The usual option for imatinib failure is to increase the dose to 600 or 800mg. Switching patients to second line therapy is difficult due to financial constraints; patients who fail Imatinib are offered allogeneic stem cell transplantation. Methods- We present a single-institution retrospective data of Dasatinib as second line therapy in CML patients resistant to imatinib. In a total of 1200 CML patients followed in our clinic, 24 patients were treated with dasatinib over a period of 4 years. 17 of whom were in chronic phase (switched after failure of Interferon and Imatinib -2, not in CHR at time of switch- 4), accelerated phase-5 and blast crisis-2 patients, at the time of starting dasatinib. They either refused transplant, did not have donor or had co-morbid factors (3-diabetes mellitus and CVD, 1- chronic renal disease along with diabetes) which made transplant difficult. Results- The median age of patients was 45 years (26–65 years) with 12 males and 12 females. They had received imatinib for a median of 50 months (20–98 months) before starting dasatinib. After a median follow up of 12 months (6.6 – 39.6 months), there was 2 deaths (CML-BC-1, CML-AP-1). Non-hematologic toxicity was generally mild to moderate (grades 1 or 2); dyspnea, gastrointestinal disorders (diarrhea, nausea) and fluid retention were seen. Pleural effusion occurred in two patients. Conclusions- Toxicities with Dasatinib were generally reversible and could be managed effectively with dose adjustments. Our limited experience showed this to be effective and well tolerated even in late failure patients with high disease burden. Disclosures: No relevant conflicts of interest to declare.

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