scholarly journals Impact of Age on Efficacy, Safety, and Long-Term Outcome of Chronic Myeloid Leukemia (CML) Patients Treated in First-Line with Nilotinib: An Analysis of the Gimema CML Working Party

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3068-3068 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Mariella D'Adda ◽  
Fabio Stagno ◽  
...  
Keyword(s):  
Research Funding ◽  
Age Groups ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Group A ◽  
Group B ◽  
First Line Treatment

Abstract Background: In chronic phase (CP) chronic myeloid leukemia (CML) the disease characteristics at diagnosis, risk distribution, probability of transformation to accelerated/blast phase (AP/BP), and toxicities may vary according to age. Nilotinib has shown better efficacy compared to imatinib, but it has been associated to a higher incidence of arterial thrombotic events (ATEs). Little is known on the efficacy, safety and long-term outcome of nilotinib treated patients in different age groups. Aims: To investigate the efficacy and safety, particularly the cardiovascular safety, of first-line treatment with nilotinib according to age distribution. Methods: We analyzed 345 patients ≥ 18 years of age with CP CML enrolled in clinical trials of the GIMEMA CML WP investigating nilotinib as first-line treatment. Patients were treated with: nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123); nilotinib 300 mg BID (n=149). The median follow-up was 58 months. We divided the patients in 3 groups of age (table): 18-49 years (group A, 147 pts, median age: 39 years); 50-64 years (group B, 109 pts, median age 58 years); and ≥ 65 years (group C, 89 pts, median age 71 years). We analyzed in detail the response rates, events and outcome. Definitions: Major molecular response (MMR): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to AP/BP, or deaths. ATEs: peripheral arterial obstructive disease (PAOD), acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. Results: EUTOS high risk patients were: 8.8, 5.5, 1.1% in group A, B, and C, respectively (p=0.048). We did not observe significant differences in molecular response rates (table), including BCR-ABL/ABL <10% at 3 months, MMR and MR4 at 12 months, and cumulative incidences by 5 years of MR3 and MR4. Events leading to permanent nilotinib discontinuations occurred in 31%, 29%, and 42% of group A, B, and C, respectively (p=0.049). Overall, 29 ATEs were recorded, with higher rates, as expected, in elderly patients (group A: 2%; B: 11%; C: 15.7%; p=0.006); relative risk for ATEs in group B vs. A: 5; relative risk in group C vs. A: 6.7. ATEs were the reason for permanent nilotinib discontinuation in 2% of pts 18-49 years, 7.3% of pts 50-64 years, and 11.2% of pts > 65 years (p=0.015). Progressions to AP/BP were significantly more frequent in younger (18 - 49 years) patients (6.8%) compared to older (> 50 years) patients (1.5%), p= 0.019. Overall, 19 patients died (group A: 4.8%; B: 2.8%; C: 10%). In patients < 65 years all deaths (10) were leukemia-related, while in patients >65 years, all but one (8/9) deaths were leukemia-unrelated. The 6-year overall-survival was 94%, 97%, and 84% in pts 18-49 years, 50-64 years, and > 65 years of age (p=0.12) Summary/Conclusion: Nilotinib as first-line treatment of newly diagnosed CP CML patients showed high rates of molecular responses in all age groups. However, compared to older patients, significant more progressions occurred in younger (18-49 years) ones; the causes of death in this group were all leukemia-related. In contrast, in elderly patients (>65 years) the causes of death were almost all leukemia-unrelated. ATEs were rare (2%) in patients of 18-49 years, while high rates (> 10%) of ATEs were recorded in those of 50-64 years; as expected, ATEs occurred even more frequently in patients > 65 years. These data suggest that while in patients > 50 years more attention should be focused on the prevention of ATEs, in younger ones more efforts are needed to avoid the progression of CML to accelerated/blast phase. Disclosures Gugliotta: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Castagnetti:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Soverini:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Genentech: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy; Amgen: Consultancy; Genentech: Consultancy. Saglio:Ariad: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Baccarani:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Other: personal fees, Speakers Bureau; Ariad: Honoraria, Other: personal fees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

scholarly journals Prospective Parallel Randomized, Double-Blind, Double-Dummy Controlled Clinical Trial Comparing Clomiphene Citrate and Metformin as the First-Line Treatment for Ovulation Induction in Nonobese Anovulatory Women with Polycystic Ovary Syndrome

2005 ◽  
Vol 90 (7) ◽  
pp. 4068-4074 ◽  
Author(s):  
Stefano Palomba ◽  
Francesco Orio ◽  
Angela Falbo ◽  
Francesco Manguso ◽  
Tiziana Russo ◽  
...  
Keyword(s):  
Polycystic Ovary ◽  
Clomiphene Citrate ◽  
Controlled Clinical Trial ◽  
Line Treatment ◽  
First Line ◽  
Ovary Syndrome ◽  
Double Blind ◽  
Group A ◽  
Group B ◽  
First Line Treatment

Abstract Context: Although metformin has been shown to be effective in the treatment of anovulation in women with polycystic ovary syndrome (PCOS), clomiphene citrate (CC) is still considered to be the first-line drug to induce ovulation in these patients. Objective: The goal of this study was to compare the effectiveness of metformin and CC administration as a first-line treatment in anovulatory women with PCOS. Design: We describe a prospective parallel randomized, double-blind, double-dummy controlled clinical trial. Setting: The study was conducted at the University “Magna Graecia” of Catanzaro, Catanzaro, Italy. Patients: One hundred nonobese primary infertile anovulatory women with PCOS participated. Interventions: We administered metformin cloridrate (850 mg twice daily) plus placebo (group A) or placebo plus CC (150 mg for 5 d from the third day of a progesterone withdrawal bleeding) (group B) for 6 months each. Mean outcome measures: The main outcome measures were ovulation, pregnancy, abortion, and live-birth rates. Results: The subjects of groups A (n = 45) and B (n = 47) were studied for a total of 205 and 221 cycles, respectively. The ovulation rate was not statistically different between either treatment group (62.9 vs. 67.0%, P = 0.38), whereas the pregnancy rate was significantly higher in group A than group B (15.1 vs. 7.2%, P = 0.009). The difference found between groups A and B regarding the abortion rate was significant (9.7 vs. 37.5%, P = 0.045), whereas a positive trend was observed for the live-birth rate (83.9 vs. 56.3%, P = 0.07). The cumulative pregnancy rate was significantly higher in group A than group B (68.9 vs. 34.0%, P &lt; 0.001). Conclusions: Six-month metformin administration is significantly more effective than six-cycle CC treatment in improving fertility in anovulatory nonobese PCOS women.

Peripheral Blood Flow-Cytometry Chronic Myeloid Leukemia Stem Cells Detection and Quantification during Tyrosine Kinase Inhibitors Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 942-942 ◽  
Author(s):  
Monica Bocchia ◽  
Lara Aprile ◽  
Santina Sirianni ◽  
Elisabetta Abruzzese ◽  
Antonella Gozzini ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Fish Analysis ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Qrt Pcr ◽  
First Line Treatment

Abstract Introduction: In chronic myeloid leukemia (CML), tyrosine Kinase Inhibitors (TKIs) treatment is a potentially life-time therapy for the majority of patients (pts), as few of them, only after achieving a deep and stable molecular response, may discontinue TKIs without recurrence of disease. Available data suggest that relapse after TKIs discontinuation is due to the persistence of leukemic stem cells (LSCs) intrinsically resistant to TKIs. Survival of CML LSCs may be the consequence of activation of several pathways BCR-ABL1 independent. qRT-PCR, the most sensitive assay to monitor disease status in CML pts, may be inappropriate to quantify residual quiescent CML LSCs that are transcriptionally silent. Therefore, the possibility to easily quantify LSCs during TKIs treatment is a great opportunity to better understand the behavior of residual LSCs and potentially to identify those pts candidates to safely discontinue TKIs. Recently, Valent et al described that CD34+/CD38-/Lin- CML LSCs specifically co-express dipeptidylpeptidase IV (CD26) and that CD26 is a potential biomarker for the quantification and isolation of CML LSCs, in bone marrow samples of CML patients. Furthermore, Culen et al. quantified CD26+ LSCs bone marrow compartment in 31 CML patients at diagnosis and their number appears to correlate with response to TKIs treatment. In the present study we wanted to explore the feasibility, rate and potential implication of detecting CD26+ LSCs in peripheral blood (PB) from CML pts during TKI treatment. Methods: CML pts during first line treatment with any approved TKIs, referring to several Italian Hematology Centers, entered this non interventional cross sectional study after signing a proper informed consent. During a routine follow up visit, in which pts were checked for molecular response by standard PB qRT-PCR BCR-ABL1 analysis, additional 3 mls of PB were collected in EDTA and sent within 24 hours to Siena Hematology Lab to detect CD34+/CD38-/CD26+ LSCs by multicolor flow cytometry. After red blood cells lysis, cells were incubated with anti CD45 (BD Biosciences), CD34 (581), CD38 (HIT2), CD26 (M-A261) (BD Pharmigen). After washing, acquisition and analysis were performed by FACSCanto II (BD Biosciences, NR Nannini) using DIVA 8 software (BD, Biosciences). CD45+ cells acquired for each sample ranged from 500,000 to 1,000,000. Isotype controls were included in each staining. In 5 pts a FISH analysis of PB sorted CML LSCs population was also performed. Results: to validate our assay we first performed a FISH analysis of both PB sorted CD34+/CD38-/CD26+ and CD34+/CD38-/CD26- in 5 CML patients at 3-6 months after starting treatment, confirming Ph+ cells only in the CD26+ fraction. Afterward, we checked for circulating CML LSCs a total of 202 CML pts in first line treatment with TKIs for a median of 39 months (range 1-175). Type of TKI, length of treatment, molecular response and quantification of LSCs are summarized in Table 1. PB CML LSCs were detectable in 146/202 (72.3%) pts with a median number of CD26+ of 0,0165 cells/µL (range 0,0018-0,66). Kendall rank correlation coefficient used to analyze the relation between the measurable variables showed no correlation between BCR-ABL/ABLIS ratio (median 0,004 range 0-61) and number of residual LSCs (r 0.118 p=0.097). In 56/202 (27.7%) pts CD26+ LSCs were undetectable, yet we found no correlation with the concomitant degree of molecular response. Conclusions: this study represents the first attempt to measure in a large cohort of CML patients residual circulating LSCs during TKIs treatment. In our hands PB LSCs flow-cytometry assay appeared feasible, specific and sensitive and thus suitable for routine monitoring. As expected, the majority of CML patients, even in deep molecular response, still harbor residual LSCs and the number of PB CD26+ did not correlate with the number of BCR-ABL1 copies. This evidence suggests that the molecular response refers to transcriptionally active CML progenitor cells and not to quiescent, TKIs resistant, CML LSCs. Prospective studies evaluating the behavior of PB CML LSCs during different TKIs treatment, as well as studies monitoring PB CD26+ in CML pts that discontinued TKIs treatment are ongoing. Our goal is to rule out the impact, if any, of a "stem cell response" in addition to the standard molecular response in the management of CML patients mainly to identify those pts candidates for a safe TKI discontinuation. Disclosures Bocchia: Janssen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Aprile:Novartis: Honoraria. Castagnetti:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4000-4000 ◽  
Author(s):  
E. Van Cutsem ◽  
M. Nowacki ◽  
I. Lang ◽  
S. Cascinu ◽  
I. Shchepotin ◽  
...  
Keyword(s):  
Response Rate ◽  
Performance Status ◽  
Phase Iii ◽  
Line Treatment ◽  
First Line ◽  
Ecog Performance Status ◽  
Skin Reactions ◽  
Group A ◽  
Group B ◽  
First Line Treatment

4000 Background: Cetuximab in combination with irinotecan-based regimens has proven activity in previously-treated patients (pts) with mCRC. The present trial investigated the effectiveness of cetuximab in combination with standard FOLFIRI compared with FOLFIRI alone in the first-line treatment of pts with epidermal growth factor receptor (EGFR)-expressing mCRC. Methods: Pts were randomized 1:1 to receive either cetuximab (400 mg/m2 initial dose then 250 mg/m2/week [w]) plus FOLFIRI q 2 w (irinotecan 180 mg/m2, FA 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2,400 mg/m2 over 46 hours) (Group A) or FOLFIRI alone (Group B). The primary endpoint was progression-free survival (PFS), with secondary endpoints of overall survival (OS), response rate (RR), disease control rate and safety. 633 events were required to statistically differentiate PFS between groups with 80% power. Results: Between August 2004 and October 2005, 1,217 pts were randomized, 608 to Group A and 609 to Group B (60% male, median age 61 [19–84], ECOG performance status: 0=54%; 1=43.5%; 2=3.5%). Median PFS was significantly longer for Group A compared to Group B (8,9 months [8 - 9,5] for Group A vs. 8 months [7.6 - 9] for Group B, p=0.036). Response Rate was also significantly increased by cetuximab (46.9% vs. 38.7%, p=0.005). Treatment was generally well tolerated with neutropenia (26.7% Group A, 23.3% Group B), diarrhea (15.2% and 10.5% respectively) and skin reactions (18.7% and 0.2% respectively) being the most common grade 3/4 adverse events. Conclusions: Cetuximab in combination with FOLFIRI significantly increases response rate and significantly prolongs PFS in the first-line treatment of pts with mCRC, reducing the relative risk of progression by approximately 15%. Treatment-related side effects of cetuximab in combination with FOLFIRI were as expected, with diarrhea being moderately and skin reactions significantly more frequent as compared to FOLFIRI alone. [Table: see text]

scholarly journals Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 458-458 ◽  
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Alessandra Iurlo ◽  
Mariella D'Adda ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Advisory Board ◽  
Molecular Response ◽  
First Line ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

scholarly journals Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

Haematologica ◽  
2015 ◽  
Vol 100 (9) ◽  
pp. 1146-1150 ◽  
Author(s):  
G. Gugliotta ◽  
F. Castagnetti ◽  
M. Breccia ◽  
L. Levato ◽  
M. D'Adda ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Line Treatment ◽  
Phase 2 ◽  
First Line ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Phase 2 Trial ◽  
First Line Treatment

Prognostic Factors and Long Term Outcome of 138 Adults with Systemic Anaplastic Large-Cell Lymphoma: a Retrospective Study by the Groupe d'Etude Des Lymphomes De l'Adulte (GELA)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 322-322 ◽  
Author(s):  
David Sibon ◽  
Marion Fournier ◽  
Josette Briere ◽  
Laurence Lamant ◽  
Corinne Haioun ◽  
...  
Keyword(s):  
Cell Lymphoma ◽  
Large Cell ◽  
Line Treatment ◽  
First Line ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Entire Cohort ◽  
Large Cell Lymphoma ◽  
First Line Treatment

Abstract Abstract 322 Background: anaplastic large-cell lymphoma (ALCL) is a T-cell lymphoma characterized by peculiar morphologic features and strong expression of CD30. Based on the anaplastic lymphoma kinase (ALK) protein expression, the current WHO classification distinguishes ALK+ and ALK- systemic ALCL as separate disease entities. ALK+ ALCL has classically a better prognosis than ALK- ALCL, however the independant prognostic value of ALK expression remains debated and the long term outcome of adults with systemic ALCL is not known. Patients and Method: eligibility criteria for this study included patients with confirmed diagnosis of systemic ALCL after immunohistopathological review and defined ALK expression status. Patients were retrieved from the GELA LNH87-LNH93-LNH98 prospective clinical trials. Most patients received an anthracyline-based regimen as first line treatment. Result: of the 138 included patients with systemic ALCL, 64 (46%) were ALK+ and 74 (54%) were ALK-. The median follow-up duration was 8 years. At diagnosis patients with ALK+ ALCL were younger than those with ALK- ALCL (median age 31 vs 56 years) with significantly more patients < 40 years in ALK+ group (66% vs 23%, p<0.0001). There was a predominance of males in both types (64%). The performance status (PS) was poor (≥2) in 16% (ALK+) vs 33% (ALK-) (p=0.019). The IPI score was high (3-5) in 24% (ALK+) vs 48% (ALK-) (p=0.03). Beta2microglobulin (level available in 90/138 patients) was ≥ 3 mg/L in 12% (ALK+) vs 33% (ALK-) (p=0.016). Ann Arbor stage, elevated LDH, number of extranodal sites > 1, bulky disease (mass > 10 cm), B symptoms, blood cell counts, hypoalbuminemia < 35 g/L and gammaglobulin level had a similar distribution in ALK+ and ALK- patients. The overall response rate to first line treatment was better in ALK+ than in ALK- patients (89% vs 76%, p=0.0417). Eleven patients died during first line treatment, all in the ALK- group. All these patients had disseminated disease. Fourteen (22%) patients relapsed in ALK+ group vs 26 (35%) patients in ALK- group. After 3 years, there was no relapse in ALK+ group, whereas 3/26 relapses in ALK- group (2 relapses after 5 years). The 8-year progression-free survival (PFS) was 54% (95% CI 45–63%) for the entire cohort, 72% (95% CI 58–83%) in ALK+ vs 39% (95% CI 27–51%) in ALK- patients (p=0.0005), and 8-year overall survival (OS) was 64% (95% CI 55–72%) for the entire cohort, 82% (95% CI 69–89%) in ALK+ vs 49% (95% CI 37–61%) (p<0.0001). Clinical and laboratory features were tested in univariate analysis for their impact on PFS and OS in the whole cohort and in ALK+ and ALK- groups. IPI (and its 5 factors taken individually), age < 40 years, ALK status, mediastinal, lung, liver and spleen involvement, hypoalbuminemia < 35 g/L and beta2microglobulin ≥ 3 mg/L had a significant impact on PFS and OS. Interestingly, in patients < 40 years old, there was no impact of ALK status on PFS/OS. In multivariate analysis taking into account factors of IPI (with a cut-off at 40 years for age) and ALK status, only number of extranodal sites, age and ALK status remained significant predictors of PFS and OS. Adding beta2microglobulin to these 6 factors resulted in a model in which only beta2microglobulin (p= 0.0003 for PFS and p=0.0004 for OS) and age (p= 0.04 for PFS and p=0.03 for OS) had a significant impact on PFS and OS, beta2microglobulin being the most discriminant factor (Figure). Not all the ALK- ALCL had a poor prognosis, and reciprocally not all the ALK+ ALCL had a favorable outcome. Conclusion: this long term study of ALCL emphasizes the prominent impact of age and beta2microglobulin both in ALK+ and ALK- ALCL in PFS and OS. These two factors could be useful for improving the prognostic assessment of patients with ALCL. They could also be of help in stratifying patients in prospective trials. Disclosures: No relevant conflicts of interest to declare.

Impact Of Major Molecular Response On Overall Survival and Its Time Of Achievement On Complete Molecular Response Incidence In Chronic Myeloid Leukemia Patients Treated By Tyrosine Kinase Inhibitors In First Chronic Phase

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2721-2721
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Helene Labussiere ◽  
Lila Gilis ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Sokal Score ◽  
Hasford Score ◽  
First Line Treatment

Abstract Most patients with CML treated with Tyrosine Kinase Inhibitors (TKIs) achieve a major molecular response (MMR), that is, the absence of detectable Philadelphia chromosome. Even after this threshold is achieved, the disease burden continues to progressively decrease with continued treatment. Therefore, more sensitive polymerase chain reaction (PCR)–based molecular methods are required to detect and quantify levels of minimal residual disease leading to complete molecular response (CMR), especially at long time points after TKI initiation. Low levels of minimal residual disease, as measured by real-time quantitative PCR, have been shown to be an excellent surrogate marker for long-term prognosis. The objective of the present study is to describe the different clinical and therapeutic characteristics of chronic myeloid leukemia (CML) patients consecutively treated in first chronic phase (CP1) using tyrosine-kinase inhibitors (TKI) as first line treatment, followed at our centre between years 2001 and 2011, and at a second time to assess response to TKI with the incidence of major molecular response (MMR) and then its evolution to reach complete molecular response (CMR). Among 253 consecutive CML patients treated in CP1 at our centre, we analysed 183 (72%) who received TKI as first line treatment, 117 males and 66 females with a median age at diagnosis of 50 years (17-81)]. Among 135 patients evaluated for Sokal score, 41 (30%) were low, 63 (47%) were intermediate and 31 (23%) were high. According to hasford score (125 evaluated), 57 (46)% were low, 61 (49%) intermediate and 7 (5%) were high. First line treatment was imatinib for 161 (88%) patients, dasatinib for 14 (8%) patients and nilotinib for 8 (4%) patients. Overall, 167 (91%) patients obtained MMR [134 (80%) after first line treatment, 26 (16%) after second line treatment and 7 (4%) after third line treatment] within a median time of 13 months (range: 2-88); and 16 (9%) patients never reached MMR. Non-MMR patients, were as follow: 53% had high sokal score 33% intermediate and 14% low; 6% had high hasford score, 47% intermediate and 47% low; they received a median of 3 TKI-based treatment lines during a median follow-up of 37 months; 6 (37.5%) of them died after disease progression and 10 still under treatment. The median time to obtain MMR was correlated with sokal score: 9 months (range: 2-84) in patients with low score; 13 months (range: 3-78) in patients with intermediate score and 17 months (range: 3-63) in patients with high score, p=0.03, same according to hasford score with 11 months, 13 and 20 months respectively, p=0.05. Among MMR patients, 18 (11%) lost their MMR after a median time of 28 months (range: 3-65) while 57 (34%) achieved a CMR after a median time of 36 months (range: 0-73) from MMR. Interestingly, response enhancement from MMR to CMR was significantly impacted by the time to have a MMR, thus the 5 years incidence of CMR was 67% in patients who had MMR in ≤ 3 months, 56% in patients with MMR > 3 and ≤ 12 months, 28% in patients with MMR > 12 and ≤ 24 months, and 12% in patients with MMR > 24 months, p=0.01 (Figure 1). After a median follow-up of 62 months (range: 6-135), patients who were in MMR at 24 months had 5 years probability of overall survival of 99% compared to 64% for those who did not have it at that time nor later, p <0.001 (Figure 2).Figure 1CMR incidence according to time to obtain MMRFigure 1. CMR incidence according to time to obtain MMRFigure 2Overall survival for patients in MMR at 24 months vs. those never in MMRFigure 2. Overall survival for patients in MMR at 24 months vs. those never in MMR We showed that MMR is a very significant factor predicting patient overall survival independently of treatment line number and delay of its achievement. In addition, we demonstrated that patients with low Sokal and Hasford scores have significant faster time to achieve MMR and that CMR incidence was significantly related to shorter time to obtain MMR. Disclosures: Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding.

The Molecular Response at 3 Months, Measured Using a Genxpert Platform, Predicts Further Outcomes in Chronic Myeloid Patients, but the Cutoff Differs from the 10% Cutoff Commonly Used with the EUTOS Method

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1906-1906
Author(s):  
Valentín García Gutiérrez ◽  
María Teresa Gómez-Casares ◽  
Jose Manuel Puerta ◽  
Juan Manuel Alonso ◽  
Santiago Osorio ◽  
...  
Keyword(s):  
Research Funding ◽  
Second Generation ◽  
World Health ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Optimal Response ◽  
Automated Method ◽  
First Line Treatment

Abstract Backgroung: In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels ≤10% measured using conventional RQ-PCR (IS) have consistently been correlated with further outcomes. Monitoring molecular responses using the Xpert BCR-ABL1 MonitorTM PCR system has demonstrated an optimal correlation with standardized RT-qPCR (IS), however, it is not known whether both methods are also equivalent when measuring BCR-ABL1 levels higher than 10%. We previously showed how the cutoff of 10% was not correlate with subsequent responses when using Xpert BCR-ABL1 in a cohort of 125 consecutive CML patients treated with imatinib (58%) and second generation TKI (2GTKI) (42%) as frontline treatment. By contrast, by using a receiver operating characteristic curve, a new cutoff of 1.5% was correlated with probabilities to achieve complete cytogenetic response (CCR) and major molecular response (MMR. The aim of this study is to validate the new cutoff of 1.5% at 3 months in patients treated with second generation 2GTKI. Methods: We have studied 57 new consecutive CML-CP patients treated 2GTKI from from Andalusian CML Group Registry. BCR-ABL1 transcript quantification was performed using the automated method Xpert BCR-ABL1 Monitor™, Cepheid, aligned to the 0.1% BCR-ABL1 ratio according to the standards of the World Health Organization. The samples were not centrally collected. All analyses were performed on an intention-to-treat basis unless otherwise stated. The proportions of patients who achieved MMR and CCyR after first-line treatment for 1 year and the response at 3 months were compared by applying Pearson's chi-square test or Fisher's exact test The study was approved by the Ethics Committee. Results: The median age at diagnosed was 48 years (18-74). The ratio of men to women was 59/41, and the risk groups according to Sokal Score were 48%, 30% and 22% for low, intermediate and high risk, respectively. Median follow up was 38 months (3-56). First-line treatment consisted of nilotinib and dasatinib in 58% and 42% of patients, respectively. Overall, the probability of achieving CCyR and MMR at 12 months was 92% (48/52) and 82% (39/47), respectively. Ten patients (17%) required treatment changes as a result of resistance (n=3), not achieving MMR (n=3) or intolerance (n=4). No patients progressed to advanced phases, and only 1 patient died during follow-up (not CML related). The overall median value of BCR-ABL1 at 3 months was 0.16%. Consistent with the original cohort of patients treated with first-line 2GTKI, all patients achieved a BCR-ABL1 level ≤10% at 3 months; therefore, this cutoff did not predict further evolution. We classified this new cohort based on the new cutoff observed in the primary population (BCR-ABL1 level at 3 months ≤1.5%); 77% of patients achieved BCR-ABL1 levels ≤1.5%, whereas 23% of patients did not. This cutoff also predicted the probability to obtain MMR by 12 months (91% vs. 44% (p=0.025). Conclusions: We have shown that when using the current version of GeneXpert, a BCR-ABL1cutoff of 10% at 3 months may underestimate the probability of not achieving an ulterior optimal response. We have shown that a new cutoff of 1.5% at 3 months can better identify patients with lower risk to achieve an optimal response at 12 months. This information should be taken into considerations when using this practical and widespread platform to monitor CML patients. Disclosures García Gutiérrez: Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Ramirez:Bristol-Myers-Squibb: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria. Steegmann:BMS: Honoraria, Other: Research funding for the Spanish CML Group; Pfizer: Honoraria, Other: Research funding for the Spanish CML Group; Novartis: Honoraria, Other: Research funding for the Spanish CML Group; Ariad: Honoraria, Other: Research funding for the Spanish CML Group.

Five-year survival analysis of interferon-a plus sorafenib versus sorafenib monotherapy as first-line treatment for metastatic clear cell renal cell carcinoma.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 486-486
Author(s):  
Ye Ding-Wei ◽  
Zhang Hai-Lang
Keyword(s):  
Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Line Treatment ◽  
First Line ◽  
Cell Renal Cell Carcinoma ◽  
Group A ◽  
Group B ◽  
First Line Treatment

486 Background: We compared the short- and long-term efficacy and safety of interferon-a plus sorafenib with sorafenib monotherapy as first-line treatment in metastatic clear cell renal cell carcinoma (mRCC) patients. Methods: mRCC patients who had not received systemic treatment were administered either interferon-a (300 MIU IM every other day) plus sorafenib (400 mg bid n=24, Group A) or sorafenib monotherapy (400 mg bid; n=24, Group B). Objective responses (OR; RECIST criterion ver 1.0) and differences in OR, progression-free survival (PFS), overall survival (OS) and toxicity were compared. Results: Sixty eight percent males were present in both the groups with comparable baseline demographic characteristics. After a median follow-up of 68 months, the OR was comparable (p=0.726) in Group A vs B; complete remission (1 vs 0 cases), partial remission (6 vs 7 cases), stable disease (14 vs 15 cases), and progressive disease (3 vs 3 cases). No significant difference was observed in the median PFS (p=0.965) and median OS (p=0.223) between both groups [9.4 months (95% CI: 5.8-17.4), Group A vs 14.0 months (95% CI: 9.9-18.0), Group B] and [32.9 months (95% CI: 8.2-87.1), Group A vs 20.4 months (95% CI: 16.2-24.6), Group B], respectively. The 5-year survival rate was higher in Group A vs B (46% vs 25%). Toxicity symptoms like fever (13 vs 3 cases), fatigue (15 vs 9 cases) and neutropenia (6 vs 1 cases) were more pronounced in Group A vs B. The incidence of hand and foot skin reactions, alopecia, rash, hypertension, liver dysfunction, hypophosphatemia, anemia, and other toxicities was similar in both groups. There were 14 (58.3%) and 8 (33.3%) cases of dosage reduction or suspension in Groups A and B, respectively. Conclusions: Short-term effect of interferon-a plus sorafenib as first-line treatment for mRCC was comparable to sorafenib monotherapy in terms of OR and PFS. Although higher toxicity was reported for interferon-a plus sorafenib, the combination holds promise for improving long-term OS.

Sign in / Sign up

Export Citation Format

Share Document