Early circulating tumor (ct)DNA dynamics and efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9019-9019 ◽  
Author(s):  
Alice Tsang Shaw ◽  
Jean-Francois Martini ◽  
Benjamin Besse ◽  
Todd Michael Bauer ◽  
Chia-Chi Lin ◽  
...  
Keyword(s):  
Molecular Response ◽  
Dna Dynamics ◽  
Plasma Dna ◽  
End Of Treatment ◽  
Significant Difference ◽  
Previously Treated ◽  
Alk Positive ◽  
Ctdna Analysis ◽  
Ct Dna ◽  
Clinical Trial Information

9019 Background: Lorlatinib is a selective, potent, brain-penetrant, 3rd generation (gen) ALK/ROS1 TKI approved for pts with advanced ALK+ NSCLC previously treated with a 2nd gen ALK TKI. We recently showed that ALK mutation tumor genotyping after failure of a 2nd gen ALK TKI may identify pts more likely to respond to lorlatinib.1 To identify other molecular response correlates, we evaluated if early ctDNA dynamics predict clinical outcome on lorlatinib. Methods: In pts enrolled on the ongoing ph 2 study (NCT01970865), plasma samples were prospectively collected for ctDNA analysis at baseline (BL), cycle 3 day 1 (C3D1, or 6 weeks) and end of treatment. Plasma DNA was analyzed using Guardant360. Change in variant allele fraction (dVAF)2 of ALK alterations (fusions and/or mutations) was calculated as (mean VAFC3D1) – (mean VAFBL); dVAF < 0 indicated decreased ctDNA at C3D1. BOR, PFS and OS were evaluated according to dVAF. Results: Of 121 paired BL/C3D1 samples collected from 158 ALK+ pts previously treated with one or more 2nd gen ALK TKIs, 57 (47%) harbored a detectable ALK alteration at BL. At C3D1, mean VAF of ALK fusions and/or mutations was significantly decreased compared to BL (-1.07, p = 0.0014). Mean tumor volume was reduced by 26% in pts with dVAF < 0 (n = 40), but only by 12% in pts with dVAF ≥0 (n = 13) (p = 0.049). Mean dVAF at C3D1 was significantly decreased compared to BL for pts with CR/PR, while there was no significant difference with SD or PD/IND; mean dVAF -1.84, -0.74, and +0.35 in pts with CR/PR, SD, or PD/IND, respectively (p = 0.0011, 0.1444 and 0.3383). Median PFS was 6.6 months (mo) in pts with dVAF < 0 (n = 44) and 2.6 mo in pts with dVAF ≥0 (n = 13) (HR = 2.6, 95% CI: 1.2, 5.8). Median OS was 18.0 mo in pts with dVAF < 0 (n = 34) and 8.6 mo in pts with dVAF ≥0 (n = 13) (HR 2.0, 95% CI, HR 0.9–4.6). Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in ALK+ NSCLC, with decreased ctDNA at 6 wks associated with better response and longer PFS. Further studies are needed to validate these findings and to determine whether early intervention based on dynamic ctDNA monitoring may improve outcome. References: 1. Shaw, et al. J Clin Oncol. 2019. 2. Raja, et al. Clin Cancer Res. 2018. Clinical trial information: NCT01970865.

Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9011-9011
Author(s):  
Ross A. Soo ◽  
Jean-Francois Martini ◽  
Anthonie J. van der Wekken ◽  
Shunsuke Teraoka ◽  
Alice T. Shaw ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Molecular Response ◽  
Similar Response ◽  
Dna Dynamics ◽  
Paired Samples ◽  
Biomarker Analysis ◽  
Alk Positive ◽  
Ctdna Analysis

9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF <0 indicated decreased ctDNA at week 4. Objective tumor response and PFS were evaluated according to dVAF. These analyses were repeated vs ctDNA results at week 24. Additional correlation analyses between depth of molecular response and/or ctDNA clearance and clinical outcomes are ongoing. Results: Paired samples were available at SC and week 4 from 232 of 255 pts included in the ctDNA analysis: 118/130 (90.8%) in the lorlatinib arm and 114/125 (91.2%) in the crizotinib arm. ALK alterations were detected in 122/232 (52.6%) pts at SC (62/118 [52.5%] from the lorlatinib arm) but only 19/232 (8.2%) at week 4 (8/118 [6.8%] from the lorlatinib arm). Mean VAF of ALK alterations at week 4 was significantly decreased compared with SC in both treatment arms (lorlatinib -1.54, crizotinib -1.25; both P<0.0001; P=0.4239 between arms). In the lorlatinib arm, mean VAF at week 4 was significantly decreased compared with SC in pts with a complete or partial response (dVAF -1.53; n=47; P<0.0001), or stable disease (dVAF -1.37; n=12; P=0.0304). Similar results were observed in the crizotinib arm. In pts with dVAF <0 for ALK alterations, mean percent change from screening in tumor size was -40.8% with lorlatinib (n=59) and -38.7% with crizotinib (n=58). Only 2 pts had dVAF ≥0, both from the crizotinib arm. Median PFS for pts with dVAF <0 for ALK alterations was not reached in the lorlatinib arm (n=62), and was 7.4 months (95% CI, 7.2–9.3) in the crizotinib arm (n=58). Similar response and PFS data were observed in the analysis of dVAF for ALK alterations at week 24. Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. Reference: Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Clinical trial information: NCT03052608.

Effect of iFISH defined 1q21 amplification/gain in multiple myeloma patients treated on total therapy protocols.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8023-8023
Author(s):  
Maurizio Zangari ◽  
Meera Mohan ◽  
Niels Weinhold ◽  
Leo Rasche ◽  
Jeffrey Sawyer ◽  
...  
Keyword(s):  
Prognostic Value ◽  
Gene Locus ◽  
Newly Diagnosed ◽  
Lambda Light Chain ◽  
Study Enrollment ◽  
Significant Difference ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Total Therapy ◽  
Clinical Trial Information

8023 Background: The amplification of the proximal 1q21 region has been reported by interphase FISH (iFISH) in about 40% of newly diagnosed patients, and in 70% of MM patients at relapse. We hereby report the prognostic value of 1q21 amplification/gain by iFISH at enrollment in subjects treated on total therapy (TT) 4, 5 and 6 protocols. Methods: TT4 protocol enrolled newly diagnosed patients with LR disease as defined GEP 70 model ≤ 0.66. TT5 was designed for newly diagnosed patients with HR MM.TT6 enrolled previously treated patients with both HR and LR disease. iFISH was performed on bone marrow samples obtained at the time of study enrollment. FISH probes were generated from specific BAC DNA clone for CKS1B gene locus (1q21) gene locus. MM cells were identified post hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of MM cells. The iFISH signals in 100 of MM cells were recorded. A 20% cutoff point was used for detection of significant abnormalities i.e. gain of 1q21 (≥ 3 copies). Results: 607 patients were included in this analysis. With a median age of 61 years, 39% had high risk and 88% low risk disease. 1q21 abnormalities were present in 55% of patients at enrollment. 591 patients (97%) received at least one HDT ASCT. The analysis included 382 TT4 patients with a median PFS of 7.2 years and OS not yet reached. 75 patients enrolled on TT5 protocol experienced median PFS of 2.2 years and median OS of 5.6 years.150 TT6 enrolled patients experienced median PFS of 4.1 years and median OS of 7.5 years. Statistically significant difference in PFS (p < 0.0001) and OS (p < 0.0001) was observed between 1q21 defined groups (figure 1). No differences in survival were observed based on the 1q21 copy number > 3. Conclusions: This retrospective analysis clearly showed that 1q21 amplification/gain detected by interphase iFISH in different stages of disease can identify patients with significant shorter progressive free and overall survival even if exposed to total therapy regimens. Clinical trial information: NCT00734877, NCT00869232.

Visual effects in anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) patients treated with crizotinib.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7596-7596 ◽  
Author(s):  
Ravi Salgia ◽  
Benjamin J. Solomon ◽  
Alice Tsang Shaw ◽  
D. Ross Camidge ◽  
Tracey L. Evans ◽  
...  
Keyword(s):  
Symptom Assessment ◽  
Point Scale ◽  
Visual Effects ◽  
Minimal Impact ◽  
Anaplastic Lymphoma ◽  
End Of Treatment ◽  
The Us ◽  
Previously Treated ◽  
Alk Positive ◽  
Nsclc Patients

7596 Background: Crizotinib is an ALK inhibitor indicated in the US for advanced ALK-positive NSCLC. Visual effects reported by patients treated with crizotinib were characterized using the Visual Symptom Assessment Questionnaire (VSAQ). Methods: Patients with previously treated, advanced ALK-positive NSCLC were administered 250 mg BID crizotinib in an ongoing phase II study (PROFILE1005, NCT00932451; Pfizer). Patients completed the VSAQ at day 1 of each 21 day cycle and at end of treatment. The VSAQ has a recall period of 3 weeks and consists of 7 questions assessing presence, frequency, timing, duration and degree of bother of visual effects and their impact on Activities of Daily Living (ADL). The visual effects assessed included appearance of overlapping shadows/after images, flashing lights and streamers/strings/floaters, difficulty adapting to lights and seeing at night. Patients rated degree of bother on a 5-point scale ranging from ‘not at all’ to ‘extremely’. Impact on ADL was measured using a 10-point scale (0: no effect; 10: completely prevented ADL). Frequency analyses were performed. Results: As of June 1 2011, visual effects as identified by VSAQ were reported by 63% (114/182) of patients at cycle 2 (C2), 57% at C3 (85/149), 52% at C4 (64/123) and 41% at C5 (46/112). The most commonly experienced visual events were appearance of flashing lights (C2:81%; C3:82%; C4:84%; C5: 76%), streamers/strings/floaters (C2: 83%; C3:78%; C4: 81%; C5:87%) and overlapping shadows/after images (C2:70%; C3:77%; C4:87%; C5:84%). Most patients reported each event to last ≤1 minute (C2:61%; C3:71%; C4:77%; C5: 70%). Majority of patients reported event frequency at each cycle of < 7 days/wk (50–78%). Patients reported that the visual effects occurred mostly in the morning (52–62%) and/or evening (62–73%). Majority of patients reported that visual effects were not at all or a little bothersome (C2:62%; C3:61%; C4:66%; C5:65%). Majority of patients indicated no or minimal impact on ADL (C2:80%; C3:80%; C4:83%; C5:87%). Conclusions: Visual effects identified by VSAQ in patients treated with crizotinib were frequent, but were reported to be transient with no or minimal impact on ADL.

Subgroup analysis of crizotinib versus either pemetrexed (PEM) or docetaxel (DOC) in the phase III study (PROFILE 1007) of advanced ALK-positive non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8105-8105
Author(s):  
Benjamin J. Solomon ◽  
Scott N. Gettinger ◽  
Gregory J. Riely ◽  
Shirish M. Gadgeel ◽  
Hiroshi Nokihara ◽  
...  
Keyword(s):  
Risk Ratio ◽  
Standard Of Care ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Vision Disorder ◽  
Phase Iii Study ◽  
Previously Treated ◽  
Alk Positive ◽  
To Receive ◽  
Clinical Trial Information

8105 Background: PROFILE 1007 compared the efficacy and safety of crizotinib with that of standard-of-care chemotherapy in patients with ALK+ NSCLC. Although the study was not designed for formal assessment of patient outcomes on crizotinib vs. PEM or crizotinib vs. DOC, due to later interest, we performed retrospective efficacy and safety analyses of patient subgroups treated with crizotinib or each chemotherapy individually. Methods: Patients with stage IIIB/IV ALK+ NSCLC previously treated with 1 prior platinum-based regimen were randomized to receive crizotinib 250 mg PO BID or chemotherapy (PEM 500 mg/m2 or DOC 75 mg/m2, IV q3 wk). Patients with progressive disease on chemotherapy were offered crizotinib treatment in a separate study. In these subgroup analyses, PFS and ORR based on independent radiologic review, and safety were evaluated. Results: Of 347 patients randomized, 172 received crizotinib, 99 PEM, 72 DOC, and 4 no treatment. At data cutoff (Mar 2012), 85 crizotinib patients, 21 PEM patients, and 7 DOC patients were receiving treatment. Median treatment duration was longer in the crizotinib arm (7.1 mo) than in either the PEM (4.1 mo) or DOC (2.1 mo) treatment subgroups. Median PFS was significantly longer on crizotinib (7.7 mo) than on either PEM (4.2 mo; HR, 0.59; P=0.0004) or DOC (2.6 mo; HR, 0.30; P<0.0001). 1-year PFS rates were 31% on crizotinib, 16% on PEM, and 6% on DOC. The ORR on crizotinib (66%) was significantly higher than on either PEM (29%; risk ratio, 2.31; P<0.0001) or DOC (7%; risk ratio, 9.65; P<0.0001). The most common all-causality adverse events with crizotinib were diarrhea (60%), vision disorder (60%), and nausea (55%); with PEM, nausea (38%), fatigue (36%), and decreased appetite (26%); and with DOC, alopecia (47%), neutropenia (43%), and nausea (36%). Conclusions: Crizotinib’s superior efficacy over chemotherapy, with a distinct but generally tolerable and manageable side effect profile in patients with advanced ALK+ NSCLC, was also observed in separate comparisons with either PEM or DOC. In patients receiving chemotherapy, median PFS, 1-year PFS rates, and ORR were all numerically higher on PEM than on DOC. Clinical trial information: NCT00932893.

In Vitro Shoot Regeneration from Callus Derived from Marubakaido Apple Rootstock under Different Aluminium Concentrations

HortScience ◽  
1998 ◽  
Vol 33 (3) ◽  
pp. 460e-460 ◽  
Author(s):  
Marisa F. de Oliveira ◽  
Gerson R. de L. Fortes ◽  
João B. da Silva
Keyword(s):  
Shoot Regeneration ◽  
Dichlorophenoxyacetic Acid ◽  
Apple Rootstock ◽  
Under Five ◽  
Significant Difference ◽  
Previously Treated ◽  
2,4 Dichlorophenoxyacetic Acid ◽  
In Vitro Shoot Regeneration

The aim of this work was to evaluate the organogenesis of Marubakaido apple rootstock under different aluminium concentratons. The explants were calli derived from apple internodes treated with either 2,4-dichlorophenoxyacetic acid or pichloram at 0.5 and 1.0 μM and under five different aluminium concentrations (0, 5, 10, 15, 20 mg/L). These calli were then treated with aluminium at 0, 5, 10, 15, and 20 mg/L. It was observed shoot regeneration only for those calli previously treated with pichloram. There were no significant difference among the aluminium concentrations.

scholarly journals Safety and efficacy of directly acting antivirals (sofosbuvir and daclatasvir) in treatment of chronic HCV in HIV-HCV co-infected Egyptian patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Inas E L-Khedr Mohamed ◽  
Kadry Mohamed EL-Saeed ◽  
Mahmoud Hassan Al-Sadik ◽  
Christina Alphonse Anwar
Keyword(s):  
Complete Blood Count ◽  
Virologic Response ◽  
Safety And Efficacy ◽  
Treatment Regimens ◽  
End Of Treatment ◽  
Increased Risk ◽  
Significant Difference ◽  
Egyptian Patients ◽  
Infected Adult ◽  
Chronic Hcv

Abstract Background Cure of chronic hepatitis C (HCV) in HIV/HCV co-infected patients is a priority due to their increased risk of complications. Daclatasvir and sofosbuvir treatment regimens with or without ribavirin are considered an important chance for better HCV treatment in patients with HIV/HCV co-infection. This study aimed at the assessment of safety and efficacy of sofosbuvir-daclatasvir treatment regimens in HIV/HCV co-infected Egyptian patients. Results Thirty HIV/HCV co-infected adult patients were included. All patients completed the study duration without major problems or drug interactions, HCV PCR was negative for all patients at the end of treatment, yet 12 weeks after ending treatment, only one patient (3.33%) had HCV relapse. Liver enzymes showed a significant decrease by the end of treatment and 12 weeks after end of treatment in comparison with their values before treatment (P-value = 0.0001). CD4 counts as well showed significant increase. There was non-significant change in serum albumin, total bilirubin, alfa fetoprotein, complete blood count (CBC), coagulation profile, random blood sugar, or serum creatinine. Ultrasonographic findings did not show significant difference. Conclusion Combination of daclatasvir and sofosbuvir have showed 96.67% sustained virologic response at 12 weeks after treatment (SVR 12) among HIV/HCV co-infected patients, with a good safety profile. Moreover, the treated patients showed a significant increase in CD4 lymphocytic count.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21207-e21207
Author(s):  
Zhehai Wang ◽  
Xiao Han ◽  
Jun Guo ◽  
Ming Jia ◽  
Changbin Zhu ◽  
...  
Keyword(s):  
Disease Progression ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Synergetic Effect ◽  
Circulating Tumor Dna ◽  
First Line ◽  
Long Term Outcome ◽  
Significant Difference ◽  
Previously Treated ◽  
Tumor Dna

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

scholarly journals Response to combination of sofosbuvir and daclatasvir in chronic hepatitis C infection.

2020 ◽  
Vol 27 (12) ◽  
pp. 2596-2600
Author(s):  
Irfan Ahmad ◽  
Muhammad Israr ul Haq ◽  
Ghulam Abbas
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Treatment Response ◽  
Chronic Hepatitis C ◽  
Hepatitis C Infection ◽  
Open Label ◽  
College Hospital ◽  
End Of Treatment ◽  
Significant Difference ◽  
Chronic Hepatitis C Patients

Objectives: To determine efficacy of sofosbuvir and daclatasvir in the treatment of chronic hepatitis C infection. Study Design: Open label uncontrolled interventional study. Setting: Hepatitis Clinic, Sheikh Zayed Medical College/Hospital, Rahim Yar Khan. Period: June to December 2018. Material & Methods: Five hundred treatment naïve chronic hepatitis C patients including those with compensated cirrhosis were included in the study. They were given sofosbuvir 400 mg daily and daclatasvir 60 mg daily. Weight based ribavirin was added if patient has evidence of cirrhosis. Treatment duration was 12 weeks for non-cirrhotic and 24 weeks for cirrhotics. End of treatment response (ETR) was recorded. Results: Mean age of the included patients was 41±11.69 with range from 8 to 82 years, while 217 (43.4 %) patients were male and 283 (56.6 %) were female. Cirrhosis was present in 59 (11.8 %) patients; among these 35.6 % were in Child A and 64.4 % in early Child B. End of treatment response occurred in 491 (98.2 %) patients and there was no significant difference in ETR between male and female patients, and between cirrhotic and non-cirrhotic. Similarly, there was no significant difference in age between those having ETR and those having no ETR. Fatigue was experienced by 13.2 % and headache by 4.2 % patients. Conclusion: The combination of sofosbuvir and daclatasvir has high response rate in chronic hepatitis C patients of our population.

scholarly journals Non-Intensive Continuous Treatment with a Tyrosine Kinase Inhibitor (TKI) Followed By Allo-HSCT Is an Effective Therapeutic Strategy for Adult Ph-Positive Acute Lymphoblastic Leukemia: Outcomes of the Russian Prospective Multicenter RALL Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4395-4395
Author(s):  
Olga A. Gavrilina ◽  
Elena N. Parovichnikova ◽  
Vera V. Troitskaya ◽  
Zalina Kh. Akhmerzaeva ◽  
Sergey N. Bondarenko ◽  
...  
Keyword(s):  
Risk Factors ◽  
Lymphoblastic Leukemia ◽  
Significant Risk ◽  
Continuous Treatment ◽  
Molecular Response ◽  
Monosomy 7 ◽  
Long Term Outcome ◽  
Landmark Analysis ◽  
Significant Difference ◽  
New Generation

Abstract Introduction. As Ph-positive (Ph+) ALL in adults remains less favorable in prognosis than other ALL, and by expert opinion needs non-intensive chemotherapy protocols and new generation TKI with the majority of pts undergoing allo-HSCT, the results of treatment based on the different approach: de-escalated but continuous treatment with the change of TKI according to the molecular response and allo-HSCT may be of interest and provide new insights to the treatment of Ph+ ALL. Aim. To evaluate survival and outcomes in different risk groups in pts with Ph+ ALL in the RALL-study (Ph+ALL-2009, Ph+ALL-2012 and Ph+ALL-2012m protocols). Patients and methods. Between January 2010 and June 2021, 74 new Ph+ ALL cases were diagnosed in 6 centers of the RALL-group and 63 of them were evaluable for analysis (median age 37 years (17-73), m/f 32(43%)/42(57%), CNS disease in 13(21%) pts, WBC&gt;30*10 9/l in 27(43%) pts, bcr/abl transcript p190/p210/p190+210 in 31(60%)/12(23%)/9(17%) cases). Standard cytogenetic was performed in all 63 pts, 1 had no mitosis, 6(10%) monosomy 7 and 2 (3%) complex karyotypes were detected. All pts were treated according to RALL protocols with continuous Imatinib. Ph+ALL-2009 protocol included 600 mg Imatinib with prednisone, VNCR, L-asp, Dauno, Cph, followed by 6-MP and MTX. Imatinib had to be changed to Dasatinib (140 mg) after non-achievement of molecular complete response (MolCR) on day 70. MolCR was defined as bcr/abl chimeric transcript &lt;0,01% by PCR with 10 -4 sensitivity. In protocols Ph+ALL-2012 and Ph+ALLm, we de-intensified chemotherapy: reduced Dauno, Cph and L-asp doses, accordingly. All pts were considered as candidates for allogeneic HSCT in CR1 if HLA-identical donor was available. 36 (57%) pts underwent HSCT in the first-line therapy: 2(6%) autologous, 9 (25%) matched related, 20 (56%) matched unrelated and 5 (13%) haplo-HSCT. Results. Hematological complete remission (CR) was achieved in 60 (95%) of 63 pts (1 early death and 2 refractory cases occurred). On day 70, MolCR was achieved in 21(38%) of 56 pts. Death on therapy in CR (within 5 months of induction/consolidation) was registered in 4 (6%) cases. The major causes of the non-relapsed mortality in unrelated allo-HSCT (n=9) were aGVHD and severe infections, at a median +4 months after HSCT. The 5-year overall survival (OS) and disease-free survival (DFS) for all 63 pts were 58% and 45%, respectively. The long-term outcome on different protocols (Ph+ALL-2009, Ph+ALL-2012 and Ph+ALL-2012m) were similar: 3-year OS - 55% vs 51% vs 75% (p=0,27), 3-year DFS - 56% vs 44% vs 50% (p=0,54), respectively. The 5-year OS was 65% vs 61% (p=0,84), and DFS was 57% vs 31% (p=0,24) in transplanted vs non-transplanted patients by landmark analysis with a median 5,3 month of CR. Landmark analysis of 5-year OS for transplanted and non-transplanted pts depending on age showed no significant difference for both groups: &gt;45y 40% vs 80%; and ≤45y 70% vs 49%, respectively (p=0,1625), although data for 5-year OS was still not mature at the time of analysis. DFS was significantly different in transplanted vs. non-transplanted pts: &gt;45y 40% vs 71%; ≤45y 61% vs 0%; respectively (p=0,0439). In a multivariate analysis for Ph+ ALL among common risk factors (age &gt; 45y, WBC&gt;30, LDH&gt;2N, immunophenotype, late MolCR &gt;70d, CNS leukemia) WBC&gt;30, HSCT were significant risk factors for OS and DFS. Conclusions. Our data demonstrate that de-intensification of chemotherapy does not affect the efficacy of Ph+ ALL therapy in the era of TKIs. We confirmed that patients older than 45y old could be treated by chemotherapy with TKI (new generation TKI if needed) only, but all pts younger than 45y should be considered for HSCT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Which One, Generic Vs Original Glivec Is More Effective in Patients with Chronic Myeloid Leukemia?

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4156-4156
Author(s):  
Ekin Kircali ◽  
Guldane Cengiz Seval ◽  
Sinem Civriz Bozdag ◽  
Selami Kocak Toprak ◽  
Meltem Kurt Yuksel ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Chronic Phase ◽  
Response Rates ◽  
Molecular Response ◽  
Optimal Response ◽  
Generic Group ◽  
Significant Difference ◽  
Generic Groups ◽  
Support Research

Introduction:Generic imatinib formulations are increasingly being used as more affordable alternatives worldwide and a few studies have evaluated the safety and efficacy of these formulations prospectively. We have retrospectively analyzed our CML cohort in terms of first line treatment of Glivec versus generic imatinib. This study aims to evaluate the safety and efficacy of generic imatinib products in chronic phase chronic myeloid leukemia as first line treatment. Methods:We have retrospectively analyzed our CML cohort from January 2000 to December 2018 treated with either Glivec or one of generic imatinib formulations. All of our patients (with 1 exception) were initiated imatinib in chronic phase in less than 56 days from diagnosis. All of our patients were followed in accordance with European Leukemia Net (ELN) 2013 recommendations and national hematology association CML guidelines and response definitions were applied according to ELN 2013 criteria. Event free survival (EFS) was defined as the time between treatment initiation and either loss of hematological response, progression to accelerated phase (AP) or blastic phase (BP), or death from any cause. Progression free survival was defined as the time between treatment initiation and transformation to AP, BP or death while on imatinib. For statistical analyses SPSS version 21.0 was used. All p values < 0.05 were considered statistically significant. Results:A total of 192 patients were analyzed comparing 102 (53.1 %) patients on Glivec with 90 patients on (476.9 %) generic formulations. 99 (51.6 %) were female patients. The median age of our population was median 46 years (14-88 years) for Glivec and median 51 years (19-79 years) for generic group (p=0.01). Risk stratifications according to Sokal, Hasford and ELTS scores were run for both Glivec and generic formulation groups. Most of the patients had low risk according to Sokal (137, 71.4%) and Hasford (116, 60.4 %) but intermediate risk according to ELTS (113, 58.9 %) scoring systems. There was no statistically significant difference in the gender distribution, Sokal, Hasford, ELTS scores and ECOG between the two groups. The median time to initiate imatinib treatment was 23.5 (1- 156) days for Glivec group and 13 (1- 51) days generic group (p< 0.05). But the late onset of the treatment was not associated with treatment failure or death. The median follow up was 119.8 (3.7- 250.5) months for Glivec group and 43.6 (2- 150) months for generic groups, respectively (p< 0.05). This difference might be explained by the fact that Glivec has been on the market for about two decades. Similar rates of grade> 2 hematological and non- hematological toxicity were seen in Glivec (4.9 %) and generic groups (3.3 %), respectively (p> 0.05). The rates of treatment failure at 3 months were significantly higher in generic formulation (6.7 %) group than Glivec (2.9 %) group (p< 0.05). Also, the rates of treatment failure at 6 months were significantly higher in generic formulation (3.3 %) group than Glivec (0.9 %) group (p< 0.05). Optimal molecular response rate at 3 months was 76.5 % (n=78) for Glivec and 32.2 % (n=29) for generic groups (p< 0.001). Also, optimal molecular response rate at 6 months was 69.6 % (n=71) for Glivec and 45.6 % (n=41) for generic groups (p= 0.01). Median EFS was found significantly higher for Glivec group compared to generic group (168 mos (95% CI: 159-177 mos) vs 74.6 mos (95% CI: 56-93); p<0.001) (Figure). Conclusion: We found that complete hematological response rates at 3 and 6 months were similar in both groups, but in early phase of treatment the optimal response rates of Glivec group was statistical significantly higher than generic group. Generic group presented with a lower rate of optimal response at 3 months but 13.4 % improvement in optimal response rates was observed at six months. No significant difference in safety concerns was observed between the groups. We recommend that these results from single center should be clarified in a prospective, randomized study including larger population. Figure Disclosures Özcan: AbbVie: Other: Travel support, Research Funding; MSD: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Other: Travel support; BMS: Other: Travel support; Jazz: Other: Travel support; Sanofi: Other: Travel support; Abdi Ibrahim: Other: Travel support; Janssen: Other: Travel support, Research Funding; Bayer: Research Funding; Celgene Corporation: Research Funding, Travel support; Takeda: Honoraria, Other: Travel support, Research Funding; Archigen: Research Funding; Roche: Other: Travel support, Research Funding. Beksac:Celgene: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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