Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION)

Key Points In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.

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Patient Outcomes with Proteosome Inhibitor Bortezomib in Multiple Myeloma at an English District General Hospital

Blood ◽

10.1182/blood.v124.21.5745.5745 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5745-5745

Author(s):

Anil Vaikunth Kamat ◽

Tariq Shafi ◽

Raphael A. Ezekwesili

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Progression Free Survival ◽

Second Primary ◽

Second Line ◽

First Line ◽

Free Survival ◽

Grade 3 ◽

Second Primary Malignancies

Abstract Bortezomib is a targeted proteosome inhibitor licensed & approved for in multiple myeloma both as first line and in relapsed setting. This is a retrospective non experimental cross sectional quantitative comparative group study using clinical case notes, laboratory & pharmacy records for patients treated with Bortezomib in 2011 & 2012. Outcomes studied included remission status, adverse events, progression free survival and overall survival at follow up. The study also looked at the comparative responses of cohort of patients administered Bortezomib through intravenous & subcutaneous route. The cohort consisted of 33 patients, 21 male, 11 female, median age 71 years, first line 10 patients, second line 23 , median number of cycles in 2011 & 2012 – first line 3 & 8 , second line 5 & 4, respectively. In 2011, 8 received intravenous treatment, 9 were switched from intravenous to subcutaneous route whilst all patients from 2012 received subcutaneous Bortezomib. The most frequently used regimen was Bortezomib Dexamethasone ( VD). The overall response rate ( ORR >/= Minor Response) was: First line 70% (7/10) ; Second line 47.8% ( 11/23); median PFS ( Figure 1) 6 months ( First line: 7 months ; Second line : 6 months) and median overall survival ( Figure 2) at follow up: 9 months ; 39.4 % ( 13/33) First line 8.5 months, Second line 11 months. Subcutaneous Bortezomib was equivalent to intravenous Bortezomib in terms of efficacy & tolerance. Of 33 patients, there were 12 dose reductions. Adverse events reported included: peripheral Neuropathy - grade 3 - 6% ( all grades 27.3%); Diarrhoea - grade 3 - 3% (all grades 6%); Nausea / Vomiting - grade 3 - 3% ( all grades 6%) and Second Primary Malignancies - 12% ( 4 of 33). Mortality at follow up was 20 patients from cohort of 33 ; causes included disease progression in 11, second primary malignancy with disease progression in 4, COPD 2, Systemic Amyloidosis 2, Tuberculosis 1 , Multiple co morbidities 1 and Asthma with mechanical failure in single patient. Second primary malignancies ( 4/33) included Prostate carcinoma ( 1), Renal Cell Carcinoma (1), Neuroendocrine tumour ( 1 ) and Unknown Primary in single patient. Beyond second line treatment, majority (14 of 23 patients; 60.9 %) did not have further active treatment. These data indicate that patient outcomes were modest compared to published data from VISTA and APEX trials. Majority of patients did not have further active treatment beyond second line which suggests the most effective treatment strategy should be used upfront as patients may not be fit to have further lines of therapy despite availability of recently introduced novel targeted agents. A higher percentage of second primary malignancies were noticed in this cohort which should be an area of further clinical research. Figure 1: Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 1:. Progression free survival with Bortezomib as first line & second line in multiple myeloma Figure 2: Overall survival with Bortezomib as first line & second line in multiple myeloma Figure 2:. Overall survival with Bortezomib as first line & second line in multiple myeloma Disclosures No relevant conflicts of interest to declare.

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Comparison of Phase 3 Ibrutinib Results Versus Standard of Care in Sweden in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v126.23.1751.1751 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1751-1751 ◽

Cited By ~ 1

Author(s):

Anders Österborg ◽

Anna Asklid ◽

Joris Diels ◽

Johanna Repits ◽

Frans Söltoft ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Proportional Hazards ◽

Progression Free Survival ◽

Standard Of Care ◽

Cox Proportional Hazards ◽

Phase 3 ◽

Free Survival ◽

Line Of Therapy

Abstract Background Ibrutinib (Ibr), an oral, first-in-class covalent Bruton's tyrosine kinase inhibitor, showed in the Phase 3 RESONATE trial significantly improved progression-free survival (PFS, hazard ratio [HR] =0.22, p<0.001) and overall survival (OS, HR=0.39,p=0.001) compared with ofatumumab (ofa) in patients with previously treated CLL who were not eligible for chemoimmunotherapy (Byrd et al, NEJM 2013). Long-term follow-up data from a single arm Phase 2 study have also demonstrated that patients treated with ibrutinib have long durable responses with a PFS at 2.5 years of 69% (Byrd et al, Blood 2015). While ofatumumab is a licensed comparator and included in treatment guidelines, some Health Technology Assessment (HTA) bodies require comparisons with a wider range of treatments. In the absence of direct head-to-head comparison of single-agent ibrutinib with other frequently used treatments in this patient population, additional comparative evidence against standard of care as observed in clinical practice can provide useful insights on the relative efficacy of ibrutinib. Naïve (unadjusted) comparisons of outcomes from different sources are prone to bias due to confounding, as treatment assignments were not randomly assigned, and populations can vary in important prognostic factors. The objective of this analysis was to compare the relative efficacy of Ibr versus physician's choice in R/R CLL-patients based on patient-level data from RESONATE pooled with an observational cohort, adjusting for confounders using multivariate statistical modelling. Methods Patient-level data from the Phase 3 RESONATE trial (Ibr: n=195; ofa: n=196) were pooled with data from a retrospective observational study conducted in the Stockholm area in Sweden. This retrospective study collected efficacy and safety data from a detailed, in-depth retrospective review of individual patient files from 148 consecutively identified patients with R/R CLL initiated on second or later line treatment between 2002 and 2013 at the four CLL-treating centers in Stockholm, Sweden, with complete follow-up. Longitudinal follow-up in subsequent treatment lines was available for patients in 3rd (n=91), 4th (n=51), 5th (n=29), and 6+ (n=15) line, and as such individual patients could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. A multivariate cox proportional hazards model was developed to compare PFS and OS between treatments, including line of therapy, age, gender, Binet stage, ECOG, and refractory disease as covariates. Adjusted HRs and 95% CIs are presented vs. Ibr. Results Across all treatment lines, fludarabine-cyclophosphamide (FC) (n=64), chlorambucil (n=59), alemtuzumab (n=33), FC+rituximab (FCR) (n=30), bendamustine+rituximab (BR) (n=28), and other rituximab-based combination chemotherapy (n=28) were the most frequently used treatments. Line of therapy, age and gender, Binet stage, ECOG performance status, and refractory disease were all independent risk factors for worse outcome on both PFS and OS. The adjusted HR for PFS and OS pooled observational data versus Ibr were 6.80 [4.72;9.80] (p<0.0001) and 2.90 [1.80;4.69] (p<0.0001). HR's for PFS/OS versus most frequent treatment regimens ranged between 2.50/1.82 (FCR) and 14.00/5.34 (anti-CD20 Mab). Baseline adjusted results for the Ofa-arm in RESONATE were comparable for both PFS and OS to outcome data from the consecutive historical cohort, however OS outcomes for Ofa were partly confounded by cross-over to Ibr. Conclusions Comparison of results from the Phase 3 RESONATE study with treatments used as part of previous standard of care in a well-defined cohort of consecutive Swedish patients shows that ibrutinib is superior to physician's choice in patients with relapsed/refractory CLL, suggesting a more than 6 fold improvement in PFS and almost 3 fold improvement in OS. Results were consistent across all different physician chosen treatments and provides further evidence that ibrutinib improves both PFS and OS vs current and prior standard of care regimens. Figure 1. Adjusted Hazard ratio's for PFS and OS of physician's choice versus Ibrutinib (RESONATE) (Multivariate Cox proportional hazards regression) a. Progression-free survival b. Overall survival Figure 1. Adjusted Hazard ratio's for PFS and OS of physician's choice versus Ibrutinib (RESONATE) (Multivariate Cox proportional hazards regression). / a. Progression-free survival b. Overall survival Disclosures Österborg: Janssen Cilag: Research Funding. Asklid:Janssen Cilag: Research Funding. Diels:Janssen: Employment. Repits:Janssen Cilag: Employment. Söltoft:Janssen Cilag: Employment. Hansson:Jansse Cilag: Research Funding. Jäger:Janssen Cilag: Research Funding.

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First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.7500 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 7500-7500 ◽

Cited By ~ 14

Author(s):

Ian Flinn ◽

Richard van der Jagt ◽

Julie E. Chang ◽

Peter Wood ◽

Tim E. Hawkins ◽

...

Keyword(s):

Progression Free Survival ◽

Complete Response ◽

Rank Test ◽

First Line ◽

Open Label ◽

Free Survival ◽

Non Hodgkin Lymphoma ◽

Duration Of Response ◽

Treatment Naïve

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.

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Management of Grade 3B Follicular Lymphoma (FL) Outside Clinical Trials: A Multicentric Retrospective Analysis on Behalf of Fondazione Italiana Linfomi (FIL)

Blood ◽

10.1182/blood.v126.23.2716.2716 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2716-2716

Author(s):

Barbara Botto ◽

Federica Cavallo ◽

Manuela Zanni ◽

Antonella Anastasia ◽

Chiara Rusconi ◽

...

Keyword(s):

Overall Survival ◽

Follicular Lymphoma ◽

Retrospective Analysis ◽

Progression Free Survival ◽

Line Treatment ◽

First Line ◽

Free Survival ◽

Rituximab Maintenance ◽

First Line Treatment

Abstract Introduction: Follicular lymphoma grade 3 is recognized as a distinct entity in the World Health Organization classification of lymphoma. It is further classified into grade 3a and 3b depending on percentage of centroblasts. There is no consensus about its clinical course because some studies indicate an indolent behavior but others describe a more aggressive. Large systematic studies are missing in particular for 3b follicular lymphoma which is often considered as a separate entity. Methods: We performed a retrospective multicentric study on a group of 3b FL patients diagnosed in nine Italian FIL centers between November 2002 and January 2015. Planned inclusion criteria at enrollment were first line Rituximab containing regimen treatment and diagnostic samples availability for central pathologic review. Aim of the study was to determine clinical response, OS and PFS. Tumor response was based on the International Working Group response criteria. Survival analysis was performed with Kaplan-Meier method. Results: We enrolled a total of 51 patients, 50 evaluable for response at the time of analysis; median age was 62 yrs (range 48-71), 29 (56%) in stage III-IV, 10 (20%) with B symptoms. First line treatment was R-CHOP in the majority of patients 47 (92%), R-Bendamustine and R-CVP in 2 (4%) respectively. Seven patients (14%) received Rituximab maintenance after first line, six (12%) underwent high dose chemotherapy and autologous stem cell transplant (ASCT) as consolidation therapy and 5 (10%) were treated with local radiotherapy on residual disease. We observed CR in 48 patients (96%), PR in 1 (2%), PD in 1(2%). Ten patients relapsed or progressed after first line treatment and four of them died, three for progressive disease and one due to senile dementia while in CR. No relapses were recorded in pts receiving Rituximab maintenance but the advantage was not statistically significant and the number of patients receiving maintenance was low. With a median follow up of 63 months from diagnosis (IQR 33-82), 3-yrs PFS and OS rates were 82% and 93% (fig 1 and 2) with the evidence of a plateau in both survival curves after 5 years observation. Central pathologic review is ongoing. Conclusion: With the limit of a retrospective analysis our study confirms the clinical benefit of a combined modality treatment with Rituximab plus antracycline-containing chemotherapy in patients with 3b FL. Our results compare favorably with those previously reported in studies without Rituximab, that failed to show a plateau with 3-yrs PFS ranging between 22% and 52%. This results need to be confirmed with a longer follow up and after the planned pathologic review. Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 1. Progression-Free Survival. Median Follow-up 62 months (IQR 33-82). Figure 2. Overall Survival. Median Follow-up 63 months. Figure 2. Overall Survival. Median Follow-up 63 months. Disclosures No relevant conflicts of interest to declare.

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Evaluation of the Imatinib Treatment of Patients with Chronic Myeloid Leukemia (CML). a Retrospective Study from Algerian Working Group on CML (GAT-LMC)

Blood ◽

10.1182/blood.v128.22.5454.5454 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5454-5454

Author(s):

K Djouadi ◽

A Bouchakour ◽

S Taoussi ◽

MT Abad ◽

Z Ouchenane ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Molecular Response ◽

Imatinib Treatment ◽

Free Survival ◽

Sokal Score ◽

Eutos Score

Abstract Introduction: The advent of anti-tyrosine kinase has revolutionized the treatment of chronic myeloid leukemia. Indeed, from 2000, the IMATINIB has become internationally the gold standard of treatment for CML chronic phase, while the allogeneic bone marrow transplant was previously, the 1st intention choice, when an HLA-matched donor is available. The aim of this study is to evaluate the efficiency and the toxicity of a treatment with Imatinib(copy), drug used in Algeria to treat patients with a CML chronic phase. The main objective is to evaluate the overall survival and the progression-free survival to these patients. Materials and methods: This is a longitudinal study, National, multicenter, retrospective, which included Algerian patients with chronic phase CML and treated with Imatinib between January 2007 and December 2013. A technical form was established and distributed to different hematology services nationwide, to collect and analysis the following data: Patient's general characteristics, disease circumstances of discovery, clinical and para-clinical examinations at diagnosis (blood count, blood smear, bone marrow aspiration, karyotype, molecular biology, Sokal prognostic classification score and Eutos score). The treatment: Imatinib 400 mg / d, a therapeutic assessment is made according to the ELN recommendations adapted to our conditions and capabilities in Algeria: The complete hematologic response (CHR) at 03 months and molecular response and / or cytogenetic and / or Fish at 03, 06.12, 18.24 months and more according to capabilities. At 03mois and / or 6 months we search a bcr / abl rate <10%. At 12 months we research a major molecular response (MMR), defined by a bcr / abl ratio lower than 0, 1% according to the ELN. A ratio between 0.1 to 1% is considered a good response according to GAT-LMC (the CML study Algerian group) so the Imatinib treatment is continued. The median follow-up of patients in December 2014 is 48 months (12-84 months). Overall survival and progression-free survival are determined by using the Kaplan-Meier method. The descriptive analysis of the quantitative variables by calculating averages, medians and the qualitative variables, by using percentages and 95% confidence interval. The Chi2 test is used to compare between two variables. Results: From 1024 collated sheets, 1007 are assessable; the median age of patients was 45.7 years (06-87 years), it's about 516 men and 491 women with a sex ratio M / F 1.05. The Diagnosis of CML is done by cytogenetic examination in 337 patients (33%), by Fish 214 patients (21%) and by molecular biology in 401 patients (39%). The prognostic classification (PC), according to the Sokal score, found a low risk in 18.7%, 55.5% as intermediate and a high risk in 25.8%. The Eutos score is less than 87 in 97% and more than 87 in 03%. A CHR at 03mois was found in 907 patients (90.1%). There is no correlation between the RHC at 03 months and the SOKAL PC (p = 0.23), by cons we found a significant correlation with the Eutos score (p <10-3). Molecular assessment at 03 and 06 months is performed in 222 patients and a bcr / abl ratio <10% was found in 66.5%. A molecular evaluation at 12 months showed an MMR in 55.4%. Cytogenetic evaluation (FISH) has found a 28.6% CCyR at 3 months, 45% at 6 months, 64.2% at 12 months (IRIS = 68%), 75.7% at 18 months (IRIS = 76.2%) and 85% at 24 months. Overall survival was 84% at 08 years and it is significantly correlated to Sokal score (p <10-6). A failure to TRT was found in 11.5% of the cases and a 10, 1% relapse rate, related to non-adherence to TRT in 50% of the cases and a lack of monitoring by a regular molecular control in the other half of the cases. Event-free survival at 08 years was 76%. A good clinical and biological tolerance is noted in 90% of the cases. Only 8% of patients were switched to a 2nd generation TKIs because of intolerance. A non-adherence to TRT was found in 14.4%. Conclusion: Imatinib, used in Algeria, is a very interesting molecule both efficiency side and tolerance level. However, we must ensure a molecular monitoring for a patients optimal follow up, and an adequate patient education for a better adherence. Disclosures No relevant conflicts of interest to declare.

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Characteristics and Outcomes of Unselected Adolescents and Young Adults Patients with Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era

Blood ◽

10.1182/blood.v124.21.1803.1803 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1803-1803

Author(s):

Stéphanie Bernardin ◽

Franck E. Nicolini ◽

Delphine Rea ◽

Mael Haiblig ◽

Martine Gardembas ◽

...

Keyword(s):

Overall Survival ◽

Young Adults ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Adolescents And Young Adults ◽

First Line ◽

Free Survival

Abstract Chronic myeloid leukemia (CML) is a myeloproliferative disorder with a median age of approximately 60 years (Hoglund M 2013). However, little is known about outcomes in CML in adolescents and young adults. In the literature there are few reports involving only patients enrolled in trials aged from 15 to 30 years (Cortes J 2012, Kalmanti L 2013). We report here the characteristics and outcomes in 78 unselected adolescents and young adults ranging from 18 to 25 years with newly diagnosed CML in chronic (n=73) or in accelerated phase (n=5) in the tyrosine kinase inhibitor (TKI) era from 13 Fi-LMC centers being in possession with local databases. The median follow-up is 56 months (0-144) after diagnosis. Sokal scores were low in 41 (56%) patients, intermediate in 10 (13%), and high in 13 (17%) and unknown in 9 (14%) patients. Five patients had a CCA/Ph+ but were in CP cytologically, at diagnosis. Initial TKI were imatinib alone (n=55) or in combination with IFN (n=3), nilotinib alone (n=5) or in combination (n=1), dasatinib alone (n=10) or in combination (n=1) or ponatinib (n=1). One patient died before treatment initiation from brain hemorrhage, and initial treatment is unknown in one patient. Only 38/76 (50%) of patients remained under TKI first-line at latest follow-up. The reasons of first-line discontinuation were blast crisis (n=3); according to ELN criteria, cytogenetic failures (n=10), molecular failures (n=5), molecular warnings (n=8), mutation (n=1); intolerance (n=6), FDA notification in EPIC study (n=1). The second-line therapies were imatinib (n=2), IFN in combination with aracytine (n=1), nilotinib (n=13), dasatinib (n=13), high-dose chemotherapy alone (n=1) or followed by allogeneic bone marrow transplantation (n=4). 13 patients discontinued their second line TKI for blastic transformations (n=2), cytogenetic failures (n=4), molecular failures (n=2), molecular warning (n=1), mutation (n=1) and intolerance (n=3). The third-line therapies were imatinib (n=1), nilotinib (n=2), dasatinib (n=5), ponatinib (n=1), chemotherapy alone (n=1), allo-transplantation (n=1). Only 25/78 (32%) of patients were included in a trial. Only one patient experimented a 4th line of TKI (ponatinib). We compared characteristics and outcome of the 2 groups of patients, enrolled in first line versus unenrolled (Table 1). There were significantly more men included than women. Accelerated phases and CCA/Ph+ were observed only in the unenrolled group. The overall survival is shown in Figure 1A. Blastic transformation, failure of TKI defined as ELN 2013 recommendations and death were used to calculate the EFS curve (Figure 1B). Finally, we designed a curve representing the probability to remain under first-line TKI: 2nd line TKI-Free Survival (Figure 1C). A complete analysis comparing characteristics and outcome between the 2 groups of patients, will be available for ASH presentation. Table 1: Characteristics of patients Total patients n=78 Enrolled patients n=24 Unenrolled patients n=54 P value Ratio H/F (n) 50/28 18/5 22/32 0.0025 Median age (years) 22 23 22 NS CCA/Ph+ (n) 5 0 5 - Phase (C/A) (n) 73/5 24/0 49/5 NS Sokal (L/I/H/U) (n) 41/10/13/9 16/2/5/1 25/8/8/8 NS Median FU (months) (Range) 56 (0-144) 41 (2-114) 63 (0-144) - Interval from D to 1st line TKI (days) 27 29 24 - 1st line TKI (I/N/D/P/NA)(n) 58/6/11/1/2 9/4/10/1/0 49/2/1/0/2 NS Median 1st line TKI duration (months) 27 26 28 - Discontinuations (n) 38 8 30 0.069 Discontinuation reasons (n) Blastic phase Cytogenetic failure Molecular failure Molecular warning Intolerance Pregnancy Sustained CMR FDA notification Mutation 3 10 5 8 6 2 2 1 1 0 3 3 0 0 0 1 1 0 3 7 2 8 6 2 1 0 1 TKI line Number (1/2/3/4)(n) 38/19/10/1 17/5/2/0 24/12/8/1 - Abbreviations: U unknown; FU follow up; D diagnosis; I imatinib; N Nilotinib; D dasatinib; P Ponatinib; TKI Tyrosine Kinase Inhibitor Figure 1: (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Figure 1:. (A) overall survival from diagnosis of enrolled and unenrolled patients. (B) EFS of enrolled and unenrolled patients. Patients in AP were excluded. (C) 2nd line TKI-Free Survival of enrolled and unenrolled patients corresponding to the probability to remain under first-line TKI. Disclosures Nicolini: Novartis: Consultancy. Gardembas:BMS: Honoraria. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Guerci-Bresler:Novartis, BMS, Pfizer: Honoraria. Roy:Novartis: Honoraria; BMS: Honoraria. Legros:Novartis, BMS: Honoraria.

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Bcr-Abl Mutations in Chronic Myeloid Leukemia - Impact on Survival and Treatment with Second Generation Inhibitors– A Study on Behalf of Latin American Leukemia Net (Lalnet)

Blood ◽

10.1182/blood.v118.21.1701.1701 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1701-1701

Author(s):

Katia B. Pagnano ◽

Israel Bendit ◽

Carla Boquimpani ◽

Carmino Antonio De Souza ◽

Eliana C M Miranda ◽

...

Keyword(s):

Overall Survival ◽

Latin American ◽

Myeloid Leukemia ◽

Second Generation ◽

Mutation Detection ◽

Blast Crisis ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival

Abstract Abstract 1701 Mutations within the BCR-ABL domain are the most frequent mechanism of imatinib (IM) resistance. The second generation inhibitors (SGI) are indicated for imatinib intolerance or resistance and the initials trials showed similar response rates in IM resistant patients after IM failure, independent of mutation status, with exception of T315I. The aim of this work was to report the frequency of BCR-ABL mutations in chronic myeloid leukemia (CML) patients of a Latin American population and to evaluate the clinical impact of the presence and type of mutations in overall survival (OS), progression free survival (PFS) and in the response to second generation inhibitors (SGI). Methods: retrospective analysis of 17 centers from Latin America. A total of 529 CML patients with mutation analysis performed in samples collected between 2002 and 2011 were included. Mutations were detected by direct sequencing from bone marrow or peripheral blood samples, collected from CML patients. After imatinib resistance, patients were treated with SGI (69%) or other treatments. Overall survival (OS) was calculated from date of mutation detection until last follow-up or death, and progression-free survival (PFS) from date of mutation detection until progression to accelerated phase or blast crisis, last follow-up or death. Survival curves were calculated using the log-rang test (SPSS 14.0 software).Results: the median age of patients at diagnosis was 45 years (5–87). 81% were in chronic phase (CP), 13% in accelerated phase (AP), 6% in blast crisis (BC). According to Sokal score, patients were stratified in low (36%), intermediate (30%) and high risk (34%); 36% had previously used Interferon. The median time from diagnosis until Imatinib treatment was 8 months (0–310) and from Imatinib start until mutation detection was 31 months (1–104). Mutations were found in 188 patients, in the following sites: P-loop (75/40%), nucleotide contact site (34/18%), catalytic domain (44/23%), A-loop (11/6%) and others (24/13%). The most frequent mutations detected were: T315I (30/16%), F359V/C/I (27/14%), M244V (18/9.6%), E255K/V (17/9%), G250E (17/9%), Y253H/F/Y (15/8%), M351T/L (12/6%); Ten patients presented concomitant mutations. On dasatinib treatment 29 mutations (27% T315I) were detected whereas 18 during nilotinib (16.5% T315I). Overall survival in the total group was 61% (95%CI: 51–71%) with a median time of 12 months. There was a significant difference in OS and PFS between non-mutated and mutated patients (76% vs 44% and 64% vs 44% respectively (P= 0.008 and P= 0.001). There was no difference in survival comparing P-loop mutations and others, excluding T315I. Patients with T315I mutations had a poorer outcome in comparison with other mutations (OS 21% vs 62%; PFS 35% vs 55%) (P= 0.04 and 0.06, respectively). In the group with BCR-AL mutations, OS was superior in patients that received a SGI in comparison with other treatments after resistance (50% vs 36% P= 0.007). One hundred patients (19%) died due to: disease progression (72), infections (8), graft versus host disease (2), central nervous system bleeding (2), cardiac failure (1), second neoplasia (1). 14 causes were not reported. Conclusions: Patients with BCR-ABL mutations had an inferior OS and PFS. T315I mutations were associated to a poor outcome. Treatment with SGI prolonged survival of patients after imatinib failure. Disclosures: Pagnano: Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Pasquini:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Spector:Novartis: Membership on an entity's Board of Directors or advisory committees.

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Carboplatin and paclitaxel as first-line treatment of unresectable or metastatic esophageal or gastric cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.140 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 140-140

Author(s):

Gopi Kesaria Prithviraj ◽

Kathryn Anissa Baksh ◽

William J. Fulp ◽

Ken Meredith ◽

Sarah E. Hoffe ◽

...

Keyword(s):

Gastric Cancer ◽

Overall Survival ◽

Progression Free Survival ◽

Complete Response ◽

Response To Therapy ◽

First Line ◽

Total Study Population ◽

Free Survival ◽

Grade Iii

140 Background: Survival in patients with metastatic esophageal and gastric cancer is dismal. No standard treatment has been established. Carboplatin/paclitaxel is active in both advanced gastric and esophageal cancer. Here we present the data of our single center retrospective analysis. Methods: Between 1998-2013, a total of 134 patients with metastatic esophageal and gastric adenocarcinoma treated with carboplatin/paclitaxel (carboplatin predominantly AUC 5 and paclitaxel predominantly 175 mg/m2) every 3 weeks as first-line therapy were identified. Baseline characteristics, response to therapy, toxicities, and survival in this patient population were evaluated. Overall survival was defined as date from biopsy to death or last follow-up and progression-free survival was defined at time from cycle 1 to death, progression, or last follow-up. Kaplan-Meier curves were fit to estimate overall and progression-free survival. Results: Of the 134 patients evaluated, the median age at diagnosis was 65 years. Overall response rate (ORR) was 62.6% (complete response (CR)- 11%, partial response (PR)- 28%, stable disease (SD)-33%). Median overall survival from date of initial diagnosis was 1.29 years (95% confidence interval [CI] 1.06-1.5). Median progression-free survival from date of initiation of carboplatin and paclitaxel was 0.44 years (95% CI 0.34-0.5). Grade III toxicity occurred in 18.7% of patients. The most common grade III toxicity was neuropathy, present in 3.7% of total study population. Conclusions: In patients with metastatic or unresectable esophageal or gastric cancer, the combination of carboplatin and paclitaxel is well tolerated with comparable overall survival and progression-free survival to existing regimens in this population.

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