Late Responders to Imatinib: Is Timing of Achievement of Complete Cytogenetic and Molecular Responses the Same in Previously Treated as Compared to the Newly Diagnosed CML Patients?

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4266-4266
Author(s):  
Vanesa Scholl ◽  
Roberta Bitencourt ◽  
Arthur Moellmann ◽  
Rocio Hassan ◽  
Moises Rocha ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Previous Treatment ◽  
Molecular Data ◽  
Newly Diagnosed ◽  
Gold Standard Method ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
The Moment ◽  
Off Time

Abstract Appropriate monitoring of the effect of tyrosine kinase (TK) therapy is a relevant issue for CML therapeutic strategy. Although cytogenetics is the gold-standard method for response evaluation, serial quantification of BCR-ABL levels by real time PCR (RQ-PCR) has shown accuracy in predicting therapeutic response. Optimal cytogenetic (CCyR) and molecular (MMR) responses for newly diagnosed chronic phase (CP) CML patients were defined within 12 and 18 months of Imatinib (IM) therapy. However, patients not achieving optimal responses (OpRes) within these times are classified as “late responders”. We evaluated a group of 142 patients (4 year follow up) treated with IM as 2nd line. Patients were classified in 3 groups according to previous treatment: IFN (n=90), SCT (n=11) and HU/IFN ≤3 months (n=41, considered as without treatment). BCR–ABL levels were measured every 3 months, at least 5 times/patient during follow-up. A laboratory-specific conversion factor of 1.33 was generated to convert the BCR-ABL/ABL% values to an International Scale (IS). At the moment, 90 patients are being followed (69 CP, 11 AP). Cytogenetics results were available in 80/90 cases, and 63/80 (79%) (55 CP, 8 AP) achieved CCyR. After 12 months of IM treatment, 30/63 cases (48%) obtained CCyR (early responders), and 33/63 (52%) were late responders. When 18 months were considered as a cut-off time to achieved OpRes, 46 (73%) were considered early and 17 (27%) late responders. Molecular data were available for 74 patients; 45/74 (61%) (40 CP, 5 AP) achieved MMR, and 20 (27%) also showed Complete MR. 10/45 cases (22%) were early responders, and 35/45 (78%) late at 18 months of IM. When evaluating at 24 months, 17 (38%) were early and 28 (62%) were late responders. When only CP patients that achieved CCyR (n=55) and MMR (n=40) were considered, these proportions were maintained. Attainment of CCyR/MMR was similar between patients with and without previous treatment (p=0,26;p=0,09). However, we found a delay in the timing of OpRes achievement in comparison with previous related work analyzing patients in 1st line IM. Thus, to achieve similar frequencies of CCyR/MMR obtained from the use of 1st line IM, previously treated patients needed an extension time of 6 months. Thus we suggest for the patients treated with IM as 2nd line a threshold of 18 months for CCyR and 24 for MMR for the establishment of the OpRes. This swap concept might be important in countries such as Brazil that postponed the introduction of IM as 1st line therapy for CML.

scholarly journals Comparison of first-line tuberculosis treatment outcomes between previously treated and new patients: a retrospective study in Machakos subcounty, Kenya

2020 ◽  
Author(s):  
Johannes Ndambuki ◽  
Joseph Nzomo ◽  
Lucy Muregi ◽  
Chris Mutuku ◽  
Francis Makokha ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Treatment Outcomes ◽  
Adverse Outcome ◽  
Previous Treatment ◽  
First Line ◽  
Adherence Support ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Lost To Follow Up

Abstract Background Since 2016, patients with rifampicin-susceptible tuberculosis (TB) have been treated with the 6-month first-line regimen, regardless of treatment history. We assessed treatment outcomes of previously treated and new patients in Machakos subcounty, Kenya. Methods We performed a retrospective cohort study in patients started on first-line treatment between 2016 and 2017. Firth's logistic regression was used to estimate the effect of previous treatment on having a programmatic adverse outcome (either lost to follow-up, death, failure) and treatment failure vs treatment success (either cure or completion). Results Of 1024 new and 79 previously treated patients, 88.1% and 74.7% were treated successfully, 6.5% and 7.6% died, 4.2% and 10.1% were lost to follow-up and 1.2% and 7.6% had treatment failure, respectively. Previous treatment predicted having a programmatic adverse outcome (adjusted odds ratio [aOR] 2.4 [95% confidence interval {CI} 1.4 to 4.2]) and treatment failure (aOR 7.3 [95% CI 2.6 to 20.4]) but not mortality. Similar correlations were found in 334 new and previously treated patients with confirmed baseline rifampicin susceptibility. Conclusion Previously treated patients were more at risk of experiencing a poor treatment outcome, mainly lost to follow-up and treatment failure. Adherence support may reduce lost to follow-up. Rifampicin drug susceptibility testing coverage should increase. More robust retreatment regimens may reduce treatment failure.

Ten-Year Follow-Up of Inhibitor Induction in Previously Untreated Patients (PUPs) on Recombinate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4004-4004
Author(s):  
Louis M. Aledort ◽  
Gilbert C. White ◽  
Georges E. Rivard
Keyword(s):  
Factor Viii ◽  
High Titer ◽  
New Product ◽  
Regulatory Agencies ◽  
Time Data ◽  
Inhibitor Development ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Factor Concentrate

After contamination of factor concentrates with blood-borne viruses, U.S. FDA requirements for new product licensure was based on the safety and efficacy of new biologicals as determined in previously untreated patients (PUPs). While PUPs provided an excellent model for assessing contamination of new products HIV, hepatitis, and other blood-borne viruses, they were not a good model for risk of inhibitor development, since inhibitor development in one form or another was unpredictable and occurred in up to 30-35% of PUPs. More recently, the Factor VIII & IX Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis has recommended that inhibitor induction potential of new factor replacement products is best studied in previously treated patients (PTPs). At the conclusion of the five-year study of 73 PUPs on Recombinate (Baxter) [Bray GL, Gomperts ED, Courter SG et al. A multicenter study of recombinant factor VIII (recombinate): safety, efficacy, and inhibitor risk in previously untreated patients. Blood1994; 83: 2428–35.], the Data Safety and Monitoring Board (DSMB) independently initiated a five-year follow-up to determine how many new inhibitors occurred, and how many transient inhibitors recurred during this time. Data collection was a simple form to determine presence or absence of inhibitor yearly; if an inhibitor was reported to develop, did the subject remain on Recombinate or use other recombinant factor concentrate, and the inhibitor titer. Sixty-five of the original PUPs had data reported. For all 5 years, there were 21, for 4 years, 20, for 3 years, 5, for 2 years, 9, for 1 year, 10. For the 65 who have provided adequate data: Two subjects had a recurrence of their transient inhibitor with titers ranging from 0.78 to 1.3. They both stayed on Recombinate. They lost these inhibitors over the ensuing two years. Three subjects developed a new inhibitor. Their titers ranged from 0.9 to 4 Bethesda units. All stayed on Recombinate. None of these inhibitors were of high titer (>5.0 BU). These patients are PTPs, and on continued recombinant factor replacement, few new inhibitors occur, and those that did were low-titered, and some that disappear recur. Thus, five-year follow-up does not tell the whole story and continues to raise the issue of how many inhibitors are acceptable to regulatory agencies for licensure of a new product.

Correlations between BCR-ABL Ratio and Cytogenetic Response at Months 12 of the Randomized French SPIRIT Study on Behalf the Fi-LMC Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2150-2150
Author(s):  
Claude Preudhomme ◽  
Catherine Roche-Lestienne ◽  
Antoine Crinquette ◽  
Christophe Roumier ◽  
Virginie Eclache ◽  
...  
Keyword(s):  
Conversion Factor ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Cytogenetic Response ◽  
Statistical Test ◽  
First Year ◽  
Newly Diagnosed ◽  
Molecular Monitoring ◽  
Cytogenetic Monitoring

Abstract In September 2003, the French CML study group (Fi-LMC) activated the four armed randomized SPIRIT trial comparing imatinib 400mg with imatinib 600mg, imatinib 400mg + ara-C and imatinib 400mg + pegylated interferon in newly diagnosed CML in chronic phase. The molecular monitoring was centralized and performed, according to the EAC protocol, in duplicate on the same BCR-ABL cDNA among two French laboratories (Bordeaux and Lille). Data were expressed as BCR-ABL/ABLx100 on the new internationally agreed scale (IS) using a conversion factor of 1.33 and 0.80 for Bordeaux and Lille respectively. A good correlation between the two laboratories was observed. During the first year of follow-up the quantification was performed each three months (M0 to M12). In May 2006, 297 of the 492 enrolled pts had a follow up of more than 12 months, and 263 pts were analysed at M12. Using the IS, the median values of the BCR-ABL/ABL normalized ratios were 90%, 6,4%, 0.68%, 0.32% and 0.16% at M0, M3, M6, M9, and M12 respectively. At M12, 15%, 29%, 27%, 17% and 12% of the pts presented a BCR-ABL/ABL ratio lower than 0.01%, 0.1% ,1%, 10%, and 100% respectively. Overall, 71% of the pts presented a ratio lower than 1%. Conventional cytogenetic data were available for 193 pts at M12: 156 pts (80%) were in complete cytogenetic response (CCR), 25 pts (13%) were in major cytogenetic response (MCR) and 12 pts (6.2%) were in minor or a lack of cytogenetic response. Among pts with a BCR-ABL transcript ratio lower than 1%, all except four were in CCR. The last 4 cases were in MCR associated with BCR-ABL ratios of: 0.96% for one pt, 0.08% and 0.12% for 2 pts (who further reached CCR at 6 and 18 months) and 0.128% for the last one. Percentages of Philadelphia positive metaphase (Ph+) were 4%, 6%, 5 % and 15% respectively. Among the 30 pts with a BCR-ABL ratio > 5%, none were in CCR and only 18 pts were in MCR. Among the 27 pts presenting a BCR-ABL ratio in the 1%–5% intervals, 20 pts were in CCR and 7 pts were in MCR (5 pts with Ph+ lower than 10% and two pts with 16% and 20% Ph+). In conclusion, our findings suggest that a ROC statistical test will be able to determine critical BCR-ABL/ABL ratios associated to CCR in our study. Nevertheless, at M12 the percentage of available data was superior using molecular than cytogenetic monitoring, suggesting that molecular monitoring expressed with the new international scale is probably sufficient fore more than 85 % of the pts treated by IM solely or in association.

Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Kimmo Porkka ◽  
Michele Baccarani ◽  
Andreas Hochhaus ◽  
Hagop Kantarjian ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Chronic Phase ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Management Interventions ◽  
Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

Predicting survival in renal cell carcinoma: The role of quality-of-life assessment.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 460-460
Author(s):  
Digant Gupta ◽  
Donald Peter Braun ◽  
Christopher G. Lis ◽  
Edgar Donald Staren
Keyword(s):  
Quality Of Life ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Prognostic Significance ◽  
Life Assessment ◽  
Newly Diagnosed ◽  
Previously Treated Patients ◽  
Previously Treated

460 Background: Assessment of quality of life (QoL) with validated instruments has been increasing in the clinical oncology community, but to date few studies have examined its prognostic significance in renal cell carcinoma (RCC). We investigated the association between QoL at presentation and survival in RCC. Methods: A consecutive series of 138 RCC patients treated between January 2001 and December 2009. QoL was evaluated at baseline using EORTC-QLQ-C30 which incorporates 1 global, 5 functional and 8 symptom scales. Scores range from 0-100 with higher scores in the global/functional scales and lower scores in the symptom scales indicating better QoL. Patient survival was the primary endpoint. Cox regression was performed to evaluate the prognostic significance of QoL. Results: Mean age at diagnosis was 53.8 years. 51 patients were newly diagnosed at our hospital, while 87 were previously treated elsewhere. Stage at diagnosis was I, 32; II, 19; III, 32; and IV, 55. Median overall survival was 17.2 months (95% CI: 10.1-24.2 months). QoL scales predictive of survival upon univariate analysis were physical (p=0.003), role (p=0.02), social (p=0.03), fatigue (p=0.02), pain (p=0.03), and constipation (p=0.04). Upon multivariate analyses, after adjusting for age, gender, stage, and treatment history, physical (HR=0.89; 95% CI=0.78, 0.99; p=0.04), social (HR=0.91; 95% CI=0.83, 0.99; p=0.04), fatigue (HR=1.10; 95% CI=1.01, 1.19; p=0.03) and constipation (HR=1.11; 95% CI=1.02, 1.20; p=0.01) scales were significantly associated with survival, such that patients with higher (better) physical and social scores and lower (better) fatigue and constipation scores had better survival. For newly diagnosed patients, physical scale was significant, while for previously treated patients, physical, fatigue, and constipation scales were significant. Conclusions: Baseline QoL elements that reflect specific functional and symptomatic attributes provide useful prognostic information in RCC. Significantly, this held true for physical function for both newly diagnosed and previously treated patients. Such determinations should be considered when designing clinical trials with survival endpoints and may aid decision-making in clinical practice.

Phase II study of the FGFR inhibitor AZD4547 in previously treated patients with FGF pathway-activated stage IV squamous cell lung cancer (SqNSCLC): LUNG-MAP sub-study SWOG S1400D.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9055-9055 ◽  
Author(s):  
Charu Aggarwal ◽  
Mary Weber Redman ◽  
Primo Lara ◽  
Hossein Borghaei ◽  
Philip C. Hoffman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Grade 5 ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

9055 Background: LungMAP is a National Clinical Trials Network umbrella trial for previously-treated SqNSCLC. S1400D is a phase II biomarker-driven therapeutic sub-study evaluating the FGFR inhibitor AZD4547 in patients (pts) with FGFR positive chemo-refractory SqNSCLC. Methods: Eligible pts had tumor FGFR alteration and/or mutation by next generation sequencing (Foundation Medicine), measurable disease, Zubrod PS 0-2, progression after 1 line of systemic therapy, and adequate end organ function. Receipt of prior immunotherapy was allowed. Eligible pts received AZD4547 80 mg bid orally. Primary endpoint was overall response rate (ORR) by RECIST; secondary endpoints included progression-free survival (PFS) and duration of response (DoR). Originally designed as a randomized trial of AZD4547 versus docetaxel, it was redesigned to be a single arm AZD4547 trial with the emergence of immunotherapy as standard 2ndline therapy. Forty pts were required to rule out an ORR of < = 15% if the true ORR was > 35% (90% power, alpha 0.05). Results: 93 pts (13% of pts screened on S1400) were assigned to S1400D; 43 were enrolled with 28 receiving AZD4547. Pt characteristics: median age 66.3 y (49-88), female (n = 8, 29%), & Caucasian (n = 25; 89%). Biomarker profile: FGFR1 amplification (n = 38; 86%); FGFR3 S249C (n = 4; 9%); FGFR3 amplification (n = 3; 7%); and FGFR3 fusion (n = 2; 5%). Nine pts (26%) had more than one biomarker alteration. The study was closed at interim analysis for futility in October 2016. Treatment related Grade 3 AEs were seen in 5 pts (dyspnea, fatigue, hyponatremia, lung infection & retinopathy); 1 pt had Grade 4 sepsis. There were no Grade 5 AEs. Median follow up among alive pts was 4.3 months (mos). Of 25 response evaluable pts, one with FGFR3 S249C had unconfirmed PR (4%, 95% CI 1-20%) with DoR of 1.5 mos. Median PFS was 2.7 mos (95% CI 1.4 - 4.3 mos). Conclusions: This is the first Phase II trial to evaluate AZD4547 as a targeted approach in pts with previously treated FGFR-altered SqNSCLC. AZD4547 had an acceptable safety profile but minimal activity in this biomarker-enriched cohort. Evaluation of other targeted agents in LUNG-MAP is currently ongoing. Clinical trial information: NCT02965378.

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