Patients (Pts) with Ph+ Chronic Myeloid Leukemia In Chronic Phase (CML-CP) with a Suboptimal Molecular Response to Imatinib (IM) Can Achieve Deeper Responses When Switched to Nilotinib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2301-2301
Author(s):  
Carole Miller ◽  
Sikander Ailawadhi ◽  
Anand P. Jillella ◽  
Jerald P. Radich ◽  
Daniel J DeAngelo ◽  
...  
Keyword(s):  
Research Funding ◽  
Logarithmic Scale ◽  
Molecular Response ◽  
Response Dynamics ◽  
Transcript Levels ◽  
Protocol Deviation ◽  
Log Reduction ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Abstract 2301 Background: Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to IM and for frontline CML treatment. The achievement of a complete cytogenetic response (CCyR) and a major molecular response (MMR), defined as ≥ 3 log reduction of Bcr-Abl transcript levels from a standardized baseline (equivalent to ≤ 0.1% international scale [IS]) are favorable prognostic factors. Achieving CCyR and MMR are associated with significantly lower rates of disease progression (Saglio, G. et al. N Engl J Med 2010; 362:2251). This multi-center, open-label US study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in pts with CCyR but have demonstrated a suboptimal molecular response to IM. Methods: This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP pts (target enrollment n=50) who achieved CCyR but have a suboptimal molecular response to IM. Suboptimal molecular response was defined either as: (Group 1) pts treated ≥ 1 year with IM, but have not reached MMR; or (Group 2) pts with > 1 log increase in Bcr-Abl transcript levels from best response regardless of the IM treatment duration. Pts are treated with nilotinib 300 mg BID on study; if dose reductions are required, pts are treated with nilotinib 400 mg QD. Quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) analysis is performed by a central lab at baseline and then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR at baseline, monthly for the first 3 mos and then every 3 mos on study. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 mos on treatment with nilotinib. This analysis was performed on the 14 pts enrolled as of the data cut-off date of June 30, 2010. Results: Fourteen pts (Group 1:13; Group 2:1) have been treated with a median of 9.8 mos (range: 3.4–22.3 mos) on nilotinib. Thirteen pts entered the trial with a baseline CCyR. One pt (Group 1) was discontinued due to lack of evidence of CCyR at baseline (protocol deviation); however was included in the analysis since the pt had at least one post-baseline evaluation performed. Prior to enrollment, pts were treated with ≥ 400mg QD IM; the mean dose of prior IM treatment was 505 mg/day (range 377 – 786 mg/day). The median duration of prior IM treatment was 40.5 mos (range 15.3 – 115.8 mos). The median Bcr-Abl log reduction at baseline was 2.5 (0.32%IS). Overall 12/14 pts achieved MMR on study; 9 pts after 3 mos, 1 pt after 4.5 mos (measured at end of study due to a protocol deviation), and 2 pts after 9 mos. Overall, pts achieved a median 3.11 log reduction (0.078%IS) at Month (Mo) 3; median 3.33 log reduction (0.047%IS) at Mo 6, and a median 3.72 log reduction (0.019% IS) at Mo 9. Of the pts who were treated at least 12 mos, 6/7 (85.7%) reached MMR after switching to nilotinib and the median Bcr-Abl transcript log reduction at 12 mos was 3.66 (0.022% IS,1° endpoint). Nilotinib was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Five of 14 pts were dose reduced for nilotinib-related AEs. The median dose intensity was 536 mg (range 300 – 600 mg/day). One of each of the following Grade 3 AEs were reported: rash, pneumonia, squamous cell carcinoma, bladder prolapse, and uterine prolapse. Only the rash was suspected to be due to nilotinib. No Grade 4 AEs were reported. One pt experienced serious AEs; pancreatitis was suspected to be related to nilotinib and pneumonia was not suspected to be related to nilotinib. Nilotinib was interrupted and the pt recovered from both events. Four pts were discontinued from the study, 3 due to abnormal labs (Grade 2–3 ALT, Grade 2 bilirubin) and 1 due to a protocol deviation. The median Bcr-Abl log reduction of these 4 pts at end of study was 3.03 logs (0.096% IS). A protocol amendment has since instated a more liberal dose reduction guideline. No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation >500 msec was observed. Conclusions: Nilotinib treatment resulted in an improvement of molecular response in pts switched from IM and was well tolerated. Overall 12/14 (85.7%) of the pts who switched to nilotinib achieved MMR at the time of analysis, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.66 from the standardized baseline (0.022% IS). Disclosures: Miller: Novartis: Consultancy, Honoraria, Research Funding. Off Label Use: Nilotinib is being studied patients with suboptimal response in the context of a clinical trial. Ailawadhi: Novartis: Consultancy, Honoraria. Radich: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. DeAngelo: Novartis: Consultancy; BMS: Consultancy. Goldberg: Novartis: Consultancy, Honoraria, Research Funding. Williams: Novartis: Employment, Equity Ownership. Lin: Novartis: Employment. Akard: Novartis: Consultancy, Honoraria.

Nilotinib-Associated Molecular Responses Achieved in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients with a Suboptimal Molecular Response to Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2206-2206
Author(s):  
Allen S. Yang ◽  
Anand Jillella ◽  
Carole B. Miller ◽  
Luke P. Akard ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
Research Funding ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Log Reduction ◽  
Group 2 ◽  
Grade 3 ◽  
The Impact ◽  
Group 1

Abstract Abstract 2206 Poster Board II-183 Background Nilotinib is a potent, highly selective Bcr-Abl kinase inhibitor approved for adult patients with Ph+ CML in chronic and accelerated phase who are resistant or intolerant to imatinib. The achievement of a major molecular response (MMR), defined as a 3 log reduction of the Bcr-Abl transcript level from the baseline mean, is a favorable prognostic factor for the disease at any time point. This multi-center, open-label study was designed to assess the impact of nilotinib on Bcr-Abl molecular response dynamics in patients who have achieved complete cytogenetic response but have demonstrated a suboptimal molecular response to imatinib. Methods This study evaluates the change in Bcr-Abl kinetics in 2 groups of CML-CP patients (n=160) who achieve CCyR but have a suboptimal molecular response to imatinib defined either as: (Group 1) treated > 1 year with imatinib, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1 log increase in Bcr-Abl transcript levels regardless of the imatinib treatment duration. At study entry, patients are treated with nilotinib 300 mg b.i.d. The primary endpoint is to measure the change on a logarithmic scale of Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR after 12 months on treatment with nilotinib. Since there is a paucity of efficacy data published for suboptimal responders to imatinib, this preliminary analysis was performed on a small cohort of patients enrolled as of the data cut-off date of July 21, 2009. Results 11 CML-CP suboptimal molecular responding patients have been treated with a median of 2.6 months on nilotinib. One patient entered the study as a Group 2 patient and ten entered into Group 1. 1 patient was deemed ineligible due to lack of evidence of CCyR at baseline. The remaining 10 entered the trial with a baseline CCyR. Prior to enrollment, patients were treated with at least 400mg QD imatinib; the mean dose of prior imatinib treatment was 463 mg/day (range 377 – 573 mg/day). The median duration of prior imatinib treatment was 39.5 months (range 14.0-106.4 mo). 1 patient was previously treated with interferon. 8 patients have been treated for >3 months. Out of these 8 patients, 2 have been treated for > 6 months and 1 patient has been treated for > 9 months. Aside from these 8 patients, another 3 did not yet reach end of Month 3 at the time of analysis. Six out of 8 evaluable patients (75%) achieved MMR; 4 patients after three months on nilotinib, 1 patient after 4.5 months on nilotinib (measured at end of study), and 1 patient after 9 months on nilotinib. Overall, patients achieved a median log reduction of PCR transcript levels of 3.1 (range 2.1-4.5) from the standardized baseline (based on the IS) at the end of Month 3. 4 out of 11 patients were dose reduced for nilotinib related adverse events (AEs). No grade 4 AEs were reported. 1 patient experienced a grade 3 headache and two cases of grade 3 elevated ALT were reported. Brief dose interruptions were sufficient to manage most AEs. The median dose intensity was 600 (range 400-600 mg/day). No patients discontinued from the study due to an AE as of the data cut-off date. No patients who experienced QTcF changes had differences >34 msec from baseline. No QTcF prolongation >500 msec was observed. Conclusions Nilotinib treatment results in high rates of molecular response in CML-CP patients with suboptimal molecular responses to imatinib. 75% of the evaluable patients who switched to nilotinib achieved MMR at the time of analysis, and all evaluable patients achieved a median > 3 log reduction of PCR transcripts from the standardized baseline within 3 months of starting therapy. No patients were discontinued due to AEs. Outcomes for additional patients enrolled and longer term follow-up will become available. Disclosures: Yang: Bristol Myers Squibb: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Esai: Speakers Bureau; Therepi: Equity Ownership. Off Label Use: Nilotinib for suboptimal responders to imatinib therapy. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Akard:Novartis: Consultancy, Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Speakers Bureau. Goldberg:Novartis Pharmaceuticals: Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Radich:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2771-2771 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Carole B. Miller ◽  
Anand P. Jillella ◽  
Nebu Koshy ◽  
Brian Tudor ◽  
...  
Keyword(s):  
Research Funding ◽  
Molecular Response ◽  
Employment Equity ◽  
Transcript Levels ◽  
Log Reduction ◽  
End Point ◽  
Day Range ◽  
Equity Ownership ◽  
Group 2 ◽  
Group 1

Abstract Abstract 2771 Background: NIL is a potent, highly selective Bcr-Abl kinase inhibitor approved for newly diagnosed adult pts with Philadelphia-chromosome positive (Ph+) CML-CP and in Ph+ CML-CP and accelerated-phase pts who are resistant or intolerant to IM. Achieving complete cytogenetic response (CCyR) and major molecular response (MMR, 3-log reduction of Bcr-Abl transcript level from the baseline mean) are favorable prognostic factors for CML. This multicenter, open-label study (ENABL) was designed to explore nilotinib Bcr-Abl effects in pts with CCyR but who have suboptimal molecular response to IM. Methods: This study evaluates change in Bcr-Abl trends in 2 groups of CML-CP pts (total n = 18) who achieved CCyR but have suboptimal molecular response to IM defined as: (Group 1) treated ≥ 1 year with IM, but Bcr-Abl transcript levels did not reach ≤ 0.1% on the international scale (IS) (MMR); or (Group 2) > 1-log increase in Bcr-Abl transcript levels from best response regardless of IM treatment duration. Pts are treated with NIL 300 mg twice daily for ≥ 1 year. RQ-PCR analysis is performed by a central lab at screening, then every 3 months (mos) for Group 1. Group 2 pts are monitored by RQ-PCR monthly for the first 3 mos, then every 3 mos. The 1° end point is change in Bcr-Abl transcript levels from a standardized baseline value by RQ-PCR at 12 mos. The data cutoff date for this analysis was June 30, 2011. Results: Eighteen pts (Group 1, n = 17; Group 2, n = 1) have been treated with NIL for a median of 17 mos on study (range 3–34 mos). Thirteen pts have been treated for ≥ 6 mos and 10 for ≥ 12 mos. One pt was deemed ineligible due to lack of evidence of CCyR at baseline but is included in the analysis because there was at least 1 post-baseline evaluation performed. The remaining 17 pts had CCyR at baseline. Before enrollment, pts were treated with at least 400 mg once-daily IM; the mean dose of prior IM treatment was 487 mg/day (range 342–786 mg/day). Median duration of prior IM treatment was 3.4 yrs (range 1.3–10.2 yrs). Three pts had prior interferon treatment. All 18 pts were treated for ≥ 3 mos and had ≥ 1 post-baseline RQ-PCR result. Overall, 15 of 18 evaluable pts (83%) achieved MMR during treatment; 10 pts by 3 mos, 1 pt by 4.5 mos (measured at end of study), 1 pt by 6 mos, 2 pts by 9 mos, and 1 pt by 30 mos (Figure 1). The 3 pts who did not reach MMR at any point were only followed for up to 3 mos before discontinuing from the trial but showed a decreasing Bcr-Abl trend. Overall, pts achieved a median log reduction of PCR transcript levels of 3.1 (0.08% IS) at 3 mos; median 3.3-log reduction (0.05% IS) at 6 mos, and median 3.5-log reduction (0.035% IS) at 9 mos. Four pts had > 4-log (≤ 0.01% IS) reduction in Bcr-Abl; of these, 2 pts reached > 4.5-log (≤ 0.0032% IS) reduction in Bcr-Abl at least once during the study. Median Bcr-Abl transcript log reduction at 12 mos was 3.6 (0.025% IS, 1° end point) for 10 evaluable pts. All these pts reached MMR during NIL treatment; 9 pts by 12 mos, 1 pt after 30 mos. NIL was well tolerated and brief dose interruptions were sufficient to manage most adverse events (AEs). Seven of 18 pts were dose reduced for NIL-related AEs and re-escalated if the patient recovered from the AEs. Patients were permitted to dose escalate to 400 mg b.i.d. per physician's discretion if MMR was not achieved after 6 mos (n = 1). The Grade 3 AEs reported include 2 cases of rash and 1 case each of pneumonia, squamous cell carcinoma, bladder prolapse, uterine prolapse, bradycardia, hypertension, hyperbilirubinemia and hypophosphatemia. The rashes and bradycardia were suspected to be related to NIL. No Grade 4 AEs were reported. The median dose intensity was 600 mg/day (range 300–683 mg/day). Five pts were discontinued from the study (3 due to abnormal laboratory values, 1 due to an AE, and 1 due to protocol violation). No pts who experienced QTcF changes had differences > 33 msec from baseline. No QTcF prolongation > 500 msec was observed. Conclusions: NIL treatment results in high molecular response rates in CML-CP pts with suboptimal molecular responses to IM. Overall 83% of pts who switched to NIL achieved MMR, and the median Bcr-Abl log reduction for pts who reached 12 mos on study was 3.6 (0.025% IS). The IRIS study has shown that MMR rates increase with time in pts treated with IM (Hughes Blood 2010); however, this study appears to demonstrate that MMR is achieved relatively quickly in suboptimal molecular IM-treated pts when switched to NIL. Disclosures: Ailawadhi: Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Miller:Incyte: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Akard:Eisai: Speakers Bureau; Bristol Myers-Squibb: Speakers Bureau; Novartis: Speakers Bureau; Millenium: Speakers Bureau; Chemgenex: Consultancy. Ericson:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lin:Novartis: Employment, Equity Ownership. Radich:Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. DeAngelo:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy.

scholarly journals Deep Molecular Response in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated With Nilotinib: ENESTnext Update

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1796-1796
Author(s):  
Michael J. Mauro ◽  
Shaker Dakhil ◽  
Jorge E. Cortes ◽  
David A. Rizzieri ◽  
Christopher H Keir ◽  
...  
Keyword(s):  
Research Funding ◽  
Digital Pcr ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Pcr Assay ◽  
Transcript Levels ◽  
Time Points ◽  
Log Reduction ◽  
Equity Ownership

Abstract Background: The BCR-ABL tyrosine kinase inhibitor nilotinib elicits faster and deeper molecular responses (MRs) vs imatinib in patients with CML-CP. Achievement of sustained deep MR is associated with improved long-term outcomes and is a key criterion for entry into treatment-free remission (TFR) studies. Given the importance of accurately measuring deep MR in patients with CML, increasingly sensitive techniques are needed for monitoring minimal residual disease. In ENESTnext, MR to nilotinib was assessed using conventional methodology (real-time quantitative reverse transcriptase polymerase chain reaction [RQ-PCR]) and a novel microfluidic digital PCR assay that is > 1 log more sensitive than standard RQ-PCR. Methods: In this single-arm, open-label, multicenter study (NCT01227577), adults with CML-CP diagnosed within 6 months of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. Dose escalation to nilotinib 400 mg BID for patients with suboptimal response or treatment failure (per modified European LeukemiaNet 2009 recommendations) was permitted per physician discretion. RQ-PCR evaluation of peripheral blood samples was performed by a central laboratory (monthly for the first 3 months and every 3 months thereafter) according to the International Scale (IS). The primary endpoint is the rate of confirmed (≥ 2 samples taken 3 months apart) MR4.5 (≥ 4.5-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.0032%) with 2 years of nilotinib therapy; complete cytogenetic response (CCyR) and major MR (MMR; 3-log reduction of BCR-ABL transcript levels; BCR-ABLIS ≤ 0.1%) were evaluated as secondary endpoints. Per protocol, assessment of cytogenetic response was not required at specified time points for all patients on study. In an exploratory analysis, samples from patients with confirmed MR4.5by conventional RQ-PCR were also evaluated using the more sensitive Fluidigm digital PCR platform. The data cutoff date for this analysis was April 30, 2014. Results: A total of 128 patients were enrolled (median age, 56.5 years [range, 21.0-89.0 years]); 64 patients (50.0%) were male and 103 (80.5%) were Caucasian. As of the data cutoff, 45 patients (35.2%) had completed the study, 49 (38.3%) remained on treatment, and 34 (26.6%) had discontinued early. With a median treatment duration of 12.7 months, 88 (68.8%), 94 (73.4%), and 32 (25.0%) patients achieved CCyR, MMR, and MR4.5, respectively, at any time (Table). Of 32 patients who achieved MR4.5, 14 achieved MR4.5 by 6 months. A total of 169 samples from 32 patients with confirmed MR4.5 by conventional RQ-PCR were analyzed by digital PCR. Using the digital PCR platform, 6 of these patients initially had detectable BCR-ABL transcripts that subsequently became undetectable with continued nilotinib therapy. Of the remaining 26 patients, 12 had BCR-ABL transcripts that were initially undetectable and remained undetectable by digital PCR, 12 had detectable BCR-ABL transcripts that remained detectable, and 2 had undetectable BCR-ABL transcripts that became detectable. The most common (≥ 4 patients) grade 3/4 adverse events (AEs) regardless of relationship to study drug were increased lipase (n = 14), thrombocytopenia (n = 11), neutropenia (n = 8), hypophosphatemia (n = 5), anemia (n = 4), and nausea (n = 4). Reasons for study discontinuation were AEs (n = 15), unsatisfactory therapeutic effect (n = 5), withdrawn consent (n = 4), death (n = 3; causes of death were other malignancy, pneumonia, and not specified/no AE [n = 1 each]), protocol deviation (n = 3), abnormal laboratory values (n = 2), loss to follow-up (n = 1), and administrative problems (n = 1). Conclusions: Frontline treatment with nilotinib 300 mg BID in patients with newly diagnosed CML-CP led to rapid achievement of MR4.5 as assessed with conventional RQ-PCR. As > 40% of samples with at least MR4.5according to standard RQ-PCR were positive using the digital PCR assay, this tool may have potential in evaluating MR to determine eligibility for TFR studies. Table Response CCyRa MMR MR4.5 Patients with response, n (%) 88 (68.8) 94 (73.4) 32 (25.0) Time to response, n (%) < 3 mo 26 (20.3) 21 (16.4) 2 (1.6) 3 to < 6 mo 42 (32.8) 41 (32.0) 12 (9.4) 6 to < 12 mo 16 (12.5) 22 (17.2) 11 (8.6) 12 to < 18 mo 4 (3.1) 9 (7.0) 7 (5.5) ≥ 18 mo 0 1 (0.8) 0 a Cytogenetic response was not assessed in all patients at all time points. Disclosures Mauro: Novartis Oncology: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Rizzieri:Sanofi: Consultancy; Celgene: Consultancy, Speakers Bureau. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis Pharmaceuticals: Employment. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; MolecularMD: Consultancy, Equity Ownership. Goldberg:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Pfizer: Research Funding. Kuriakose:Teva: Speakers Bureau; Alexion: Speakers Bureau. Radich:Novartis: Consultancy, Research Funding; Ariad: Consultancy.

scholarly journals The Impact of Comorbidity on Quality of Life in Chronic Myeloid Leukemia Patients with Deep Molecular Response Who Stopped Therapy By Tyrosine Kinase Inhibitors: Results of the RU-SKI Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2925-2925
Author(s):  
Tatyana Ionova ◽  
Tatiana Nikitina ◽  
Natalia Porfirieva ◽  
Anna Petrova ◽  
Ekaterina Yu. Chelysheva ◽  
...  
Keyword(s):  
Social Functioning ◽  
Physical Functioning ◽  
Kinase Inhibitors ◽  
Molecular Response ◽  
Sf 36 ◽  
Before And After ◽  
Group 2 ◽  
Comorbidity Status ◽  
The Impact ◽  
Group 1

Background The data on quality of life (QoL) in chronic myeloid leukemia (CML) patients (pts) with deep molecular response (DMR) in the treatment-free remission (TFR) studies are limited. The influence of comorbidities on QoL in CML pts before and after tyrosine kinase inhibitors (TKIs) discontinuation has not been studied. Aim We aimed to study the impact of comorbidities on QoL in CML pts before and after the stop therapy by TKIs. Patients and methods The chronic phase (CP) CML pts who had received therapy by any TKI ≥3 years (yrs) with sustained DMR (BCR-ABL ≤0.01% IS) during ≥2 yrs were enrolled into the prospective TFR study RU-SKI. A regular qPCR with BCR-ABL IS evaluation was performed after TKI cessation. TKI were resumed in pts with major molecular response loss (MMR loss, BCR-ABL>0,1%). The QoL was evaluated by RAND SF-36 questionnaire at baseline before TKI stop and at 1, 3, 6, 12 mo during TFR. Eight functional scales were assessed: physical functioning, role limitations physical, bodily pain, general health perceptions, energy/vitality, social functioning, role limitations emotional, mental health. The Integral QoL Index (IQoLI) was calculated based on the scales. Mann-Whitney test, paired Wilcoxon test χ2 were used for the statistical analysis. Molecular relapse free survival (MRFS) was evaluated by Kaplan-Meier method, log-rank test was used for comparison. Results The analysis was performed in the group of 97 CML pts. Median (Me) age was 47±14.5 (yrs), 48.5% were males. The TKI before treatment cessation were as follows: imatinib and second-generation (2G) TKIs in 67 (70%) and 30 (30%) pts accordingly; 9 (30%) pts received 2G TKIs in 1st line and 21 (70%) pts in 2nd line. Me time of observation was 25 mo (range 12-42). Comorbidities were present in 81 pts (82%) at baseline. The most frequent comorbidities were cardiovascular (38.4%), gastroenterological (29.3%) and musculoskeletal disorders (27.3%). First we compared baseline QoL in 2 pts groups: group 1 - pts with acute comorbidity status at baseline (n=42), group 2 - pts with stable comorbidity status (n=29) and with no comorbidity (n=16). QoL in group 1 was significantly worse by all functional scales, except mental health (p<0.05). The IQoLI at baseline was significantly lower in group 1 vs group 2: 0.477 vs 0.589 (p<0.001). Then we evaluated QoL at 3 mo after TKI stop in 72 available pts, as acute status comorbidity remained in 30 pts. The majority of pts exhibited QoL improvement or stabilization by all SF-36 scales. The most pronounced positive changes were observed by SF-36 scales in pts with acute comorbidity status (group 1).The proportion of pts with QoL improvement at 3 mo after TKI stop was higher in group 1 as compared to group 2 by physical functioning (57% vs 29%), role physical functioning (30% vs 5%) and social functioning (40% vs 24%), p<0.05. Increasing of social functioning was statistically significant: ∆20.2 in group 1 vs ∆12.6 in group 2 (p=0.005). The proportion of pts with QoL worsening at 3 mo after TKI stop was similar in both groups. MRFS at 24 mo was 62% (CI 46-77%) and 45% (CI 32-58%) in groups 1 and 2 respectively, with no significant differences between the groups (p=0.107). Conclusion CML pts with DMR and acute comorbidity status had a worse QoL before TKI therapy cessation compared to pts without comorbidity or with comorbidity in remission. The majority of pts exhibited QoL improvement or stabilization in early terms after TKI stop. Pts with acute comorbidity status had more pronounced positive QoL changes after treatment cessation than other pts. Possible explanation is that TKI therapy could increase the clinical symptoms manifestation by overlapping with the treatment toxicity effects. The molecular relapse rate was similar in pts with and without acute comorbidity status. Thus, comorbidity is not a factor which may have negative impact on the outcomes of stop TKI therapy in CML pts. Disclosures Ionova: Takeda, BMS: Other: Principal Investigator of IISR, Research Funding. Chelysheva:Novartis: Consultancy, Honoraria; Fusion Pharma: Consultancy. Shukhov:Novartis: Consultancy; Pfizer: Consultancy. Turkina:Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; fusion pharma: Consultancy; Novartis: Consultancy, Speakers Bureau.

Molecular Response According to Type of Preexisting BCR-ABL Mutations after Second Line Dasatinib Therapy in Chronic Phase CML Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 319-319 ◽  
Author(s):  
Martin C. Mueller ◽  
Philipp Erben ◽  
Thomas Ernst ◽  
Michelle Giehl ◽  
Thomas Schenk ◽  
...  
Keyword(s):  
Mutation Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Response Dynamics ◽  
Imatinib Resistant ◽  
Group 2 ◽  
One Year ◽  
New Mutations ◽  
Group 1

Abstract Dasatinib (SPRYCEL®) has demonstrated significant efficacy in a high proportion of imatinib-resistant or -intolerant chronic phase CML patients (pts) concerning achievement of hematologic and cytogenetic responses. We sought to establish a relationship between type of preexisting BCR-ABL mutations associated with imatinib resistance and achievement of major molecular response (MMR, BCR-ABL ≤0.1% according to International Scale, IS) after 12 months of dasatinib therapy in pts with chronic phase CML. We have investigated 1,605 peripheral blood samples from 202 pts (n=62 imatinib-intolerant, n=140 imatinib-resistant; 52% male, median age 60 yrs, range 21–78) who had been enrolled in an international phase II study (START-C study, CA180–013) investigating the activity of 70mg dasatinib BID after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. During follow up, pts were monitored in 3-monthly intervals by RQ-PCR for BCR-ABL mRNA transcripts and by mutation analysis to determine the quantitative course of the preexisting mutation or the emergence of new mutations. Prior to dasatinib therapy, 34 different BCR-ABL mutations involving 29 amino acids were detected in 85/202 pts (42%) with a striking predominance in imatinib-resistant (77/140 pts, 55%) over imatinib-intolerant pts (8/62 pts, 13%). 75 pts showed one, 8 pts two and 2 pts three mutations. RQ-PCR data after 12 months of therapy was available from 154 pts (76%), samples from 48 pts (24%) were not available for monitoring after one year due to progressive disease. MMR was achieved in 28 imatinib-intolerant (45%) and 19 imatinib-resistant pts (14%, p<0.0001). The overall rate of imatinib-resistant pts with mutations was comparable in pts achieving MMR (group 1) vs pts not achieving MMR within 12 months (group 2; 53% vs 57%, p=0.80). Several mutations in imatinib-resistant pts are associated with differential response (group 1 vs group 2 response) and are presented with their IC50 values to dasatinib: H396R (n=0 vs n=6; IC50 0.6–1.3nM), M351T (n=1 vs n=7; 1.1nM), G250E/V (n=1 vs n=8; 1.8nM), Y253H (n=0 vs n=5; 1.3–10nM), L387M (n=0 vs n=2; 2nM), F359I/V (n=0 vs n=4; 2.2nM), E255K/V (n=1 vs n=4; 5.6–13nM), F317L (n=0 vs n=3; 7.4–18nM), T315I (n=0 vs n=3; >1,000nM). Of 85 pts without sufficient molecular response to dasatinib (BCR-ABL IS >5%) after 12 months (median, range 9–15) mutation analysis revealed the emergence of new mutations in 17 formerly imatinib-resistant pts (T315I, n=2; T315A, n=1; F317L, n=6; V299L, n=2; M351T, n=2; L248V, n=1; G250E, n=1; K271R, n=1; Y320C, n=1). We conclude that dasatinib is capable of inducing high rates of major molecular response after one year treatment particularly in imatinib-intolerant pts. Response dynamics depend on the individual type of mutation which may be a basis for individual dose adjustment according to the mutation pattern.

Switching to a Second Generation TKI in Chronic Myeloid Leukemia Patients with Late Suboptimal Response with Imatinib Obtained Better Molecular Responses That the “Watch and Wait” Approach. an Experience of a Multicenter Registry in Patients Outside Clinical Trials

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3768-3768
Author(s):  
J Valentin Garcia-Gutierrez ◽  
Begoña Maestro ◽  
Luis Felipe Casado ◽  
Manuel Perez-Encinas ◽  
Isabel Massague ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Second Generation ◽  
Molecular Response ◽  
Treatment Change ◽  
Molecular Responses ◽  
Group 2 ◽  
Group 1

Abstract Abstract 3768 Introduction: Tyrosine kinase inhibitors (TKIs) have dramatically changed chronic myeloid leukemia prognostic. The European Leukemia Net guidelines are widely used for patients treated with TKIs. While strategies for patients with optimal response and failure after imatinib are clear, there are doubts about the best treatment option for patients with suboptimal response (SubR), specially for late SubR (patients with complete cytogenetic response (CCyR) but not mayor molecular response (MMR) after 18 months of treatment). Patients with MMR seem to have better outcomes than patients with CCyR but not MMR, but at this time, there are few data showing the benefits of treatment change in this group of patients. Aims: To identify the benefits of treatment change in patients with late SubR, outside clinical trials, in the setting of a multicenter hospital-based registry. Patients and methods: We have studied retrospectively a group of 488 CML chronic phase patients treated with imatinib as first TKI, identifying 96 patients (19%) with SubR criteria (following the ELN recommendations) after 18 months of treatment. These patients have been classified according to the strategy followed by their physician after SubR identification. Group 1 includes 65 patients (67%) continuing with imatinib (either initial dose or higher dose) and group 2 includes 31patients (33%) that were changed to second generation TKI (2GTKI: dasatinib or nilotinib). Sokal risk index was high in 17% and 9%; intermediate 44 % and 41%; and low in 39% and 50 % for group 1 and 2, respectively. 31% and 30% of patients had received interferon prior to imatinib. Molecular response was analyzed after 12 months of identifying late SubR (for group 1) or after switching to 2GTKI, for group 2. Results: The use of 2G TKIs resulted in significant benefit to patients in terms of improving molecular responses. Complete molecular responses (CMR) and MMR rates were 3.8% vs 27% and 41.5% vs 69% for group 1 and 2 respectively (p=0.006). Time for the achievements the best molecular responses was significantly lower for patients receiving second generation TKI (4.1 vs 20.2 months, p=0.004). Probabilities of treatment failure, defined as loss of CCR, were also higher in patients remaining with imatinib (15.4% vs 5.7% (p=0.12). Progression free survival was 93.8% vs 97.2% (p=0.18) for group 1 and 2 respectively. Changing treatment for late SubR patients was also safe, and only 17% of patients needed to switch to another TKI due to intolerance. Conclusions: In CML patients treated with Imatinib with late SubR, and outside clinical trials, switching to second generation TKI increased probabilities of achievement a deeper molecular response, with a good safety profile. Disclosures: Casado: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Steegmann:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau.

Single-Arm, Open-Label, Multicenter Study Of Deep Molecular Response (MR4.5) With Nilotinib In Adult Patients (pts) With Newly Diagnosed Philadelphia Chromosome–Positive Chronic Myeloid Leukemia In Chronic Phase (CML-CP): ENESTnext Study Update

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4015-4015 ◽  
Author(s):  
Michael Mauro ◽  
Jerald Radich ◽  
Jorge E. Cortes ◽  
Shaker Dakhil ◽  
Christopher Keir ◽  
...  
Keyword(s):  
Copy Number ◽  
Research Funding ◽  
Digital Pcr ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Pcr Assay ◽  
Transcript Levels ◽  
Log Reduction ◽  
Deep Molecular Response ◽  
The Mean

Abstract Background Pivotal treatment-free remission (TFR) trials require prolonged deep molecular response (MR), often MR4.5, for study entry (Mahon et al. 2010), which has led to increasing focus on MR4.5 as a treatment goal for pts with CML-CP. New tyrosine kinase inhibitors (TKIs), such as nilotinib, more potently inhibit BCR-ABL and elicit significantly deeper and faster MRs than imatinib (Larson et al. 2012), requiring more sensitive techniques to monitor residual disease. In ENESTnext (registered as NCT01227577), MR was evaluated using standard reverse transcriptase quantitative polymerase chain reaction (RQ-PCR) and a microfluidic “digital” PCR assay, which is >1-log more sensitive than conventional methods. Methods Pts diagnosed with CML-CP within 6 mo of enrollment were treated with nilotinib 300 mg twice daily (BID) for up to 2 years. RQ-PCR was performed on peripheral blood samples by a central laboratory according to the International Scale (IS). Samples were taken monthly in mo 1-3 and every 3 mo thereafter. The primary endpoint was the rate of confirmed MR4.5 at 2 years, defined as ≥ 2 samples taken 3 mo apart with ≥ 4.5-log reduction of BCR-ABL transcript levels (≤ 0.0032%IS) with a minimum of 25,614 ABL control copies. Pts with suboptimal response or failing treatment (per European LeukemiaNet 2009 recommendations) could dose escalate to nilotinib 400 mg BID per physician discretion. Complete cytogenetic response (CCyR) and major MR (MMR, 3-log reduction of BCR-ABL transcript levels [≤ 0.1%IS]) were also assessed. In an exploratory analysis, samples identified as MR4.5 using conventional RQ-PCR were also evaluated using the Fluidigm digital PCR platform (Oehler et al. 2009). BCR-ABL copy number was estimated by Poisson distribution; samples were positive if copy number was > 0. The data cutoff date for this analysis was April 30, 2013. Results Of 128 pts, 64 (50%) were male and 103 (80%) were white. The mean age was 55.6 y (range, 21.0-89.0). Pts were treated for a median of 8.5 mo (range 0.1-24.1); median daily nilotinib dose was 600 mg. As of the data cut, 87, 36, 23 and 18 pts have been treated for ≥ 6, ≥ 12, ≥ 18 and ≥ 22 mo, respectively. Cumulative incidence of MR4.5, MMR and CCyR was 22 (17%), 76 (59%) and 72 (56%) pts, respectively. In the 22 pts who achieved MR4.5, the mean time to first MR4.5 was 6.4 mo (range, 1.0-22.7). Digital PCR was performed on 57 samples from these 22 pts; 15/22 pts had ≥ 2 samples from different time points. Of these, 8 were initially positive for BCR-ABL and became negative, 5 were initially negative and remained negative and 2 were initially positive and remained positive. Achieving BCR-ABL negativity using digital PCR generally occurred rapidly (within 3 mo of MR4.5). The most common (≥ 2 pts) grade 3 adverse events (AEs) were nausea (n = 4), headache (n = 3), elevated lipase level (n = 12), thrombocytopenia (n = 6), neutropenia (n = 6), hypophosphatemia (n = 5), anemia (n = 4) and increased amylase level (n = 3). Grade 4 AEs were myocardial infarction (n = 2), device-related infection (n = 1), elevated lipase level (n = 4), thrombocytopenia (n = 3), neutropenia (n = 2) and hyponatremia (n = 1). To date, 22 (17%) pts have discontinued treatment. Reasons included AEs (n = 11), withdrawn consent (n = 3), protocol deviation (n = 2), unsatisfactory therapeutic effect (n = 2), abnormal laboratory values (n = 2), abnormal test procedure result (n = 1) and loss to follow-up (n = 1). Conclusions Treatment with nilotinib 300 mg BID in pts with newly diagnosed CML-CP resulted in rapid and substantial rates of MR4.5 using conventional RQ-PCR, with a safety profile similar to that reported in previous studies. The digital PCR assay detected residual BCR-ABL in approximately 50% of samples with at least MR4.5 by RQ-PCR, and showed declining BCR-ABL levels with continued therapy. Thus, use of digital PCR may help better identify appropriate candidates for TFR studies. Based on results from the ENESTnd trial (Larson et al. 2012), MR4.5 rates are expected to increase over time. Other studies have demonstrated that pts who achieve early, deep MR have improved long-term outcomes (Marin et al. 2012). Evaluation of longer-term outcomes for patients with negative digital PCR results is ongoing. Disclosures: Mauro: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Off Label Use: This abstract describes a clinical trial evaluating the investigational agent midostaurin for use in patients with advanced systemic mastocytosis. Radich:novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Keir:Novartis: Employment, Equity Ownership. Yi:Novartis: Employment. Goldberg:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

CD34 immunostain increases sensitivity of the diagnosis of fetal vascular malperfusion in placentas from ex-utero intrapartum treatment

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Jerzy Stanek
Keyword(s):  
Statistical Significance ◽  
Treatment Procedure ◽  
Fetal Survival ◽  
Ex Utero Intrapartum Treatment ◽  
Life Threatening ◽  
Group 2 ◽  
Cd34 Immunostain ◽  
The Impact ◽  
Diaphragmatic Hernias ◽  
Group 1

AbstractShort CommunicationsEXIT (ex-utero intrapartum treatment) procedure is a fetal survival-increasing modification of cesarean section. Previously we found an increase incidence of fetal vascular malperfusion (FVM) in placentas from EXIT procedures which indicates the underlying stasis of fetal blood flow in such cases. This retrospective analysis analyzes the impact of the recently introduced CD34 immunostain for the FVM diagnosis in placentas from EXIT procedures.Objectives and MethodsA total of 105 placentas from EXIT procedures (48 to airway, 43 to ECMO and 14 to resection) were studied. In 73 older cases, the placental histological diagnosis of segmental FVM was made on H&E stained placental sections only (segmental villous avascularity) (Group 1), while in 32 most recent cases, the CD34 component of a double E-cadherin/CD34 immunostain slides was also routinely used to detect the early FVM (endothelial fragmentation, villous hypovascularity) (Group 2). 23 clinical and 47 independent placental phenotypes were compared by χ2 or ANOVA, where appropriate.ResultsThere was no statistical significance between the groups in rates of segmental villous avascularity (29 vs. 34%), but performing CD34 immunostain resulted in adding and/or upgrading 12 more cases of segmental FVM in Group 2, thus increasing the sensitivity of placental examination for FVM by 37%. There were no other statistically significantly differences in clinical (except for congenital diaphragmatic hernias statistically significantly more common in Group 2, 34 vs 56%, p=0.03) and placental phenotypes, proving the otherwise comparability of the groups.ConclusionsThe use of CD34 immunostain increases the sensitivity of placental examination for FVM by 1/3, which may improve the neonatal management by revealing the increased likelihood of the potentially life-threatening neonatal complications.

scholarly journals The negative effects of COVID-19 and national lockdown on emergency surgery morbidity due to delayed access

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Francesco A. Ciarleglio ◽  
Marta Rigoni ◽  
Liliana Mereu ◽  
Cai Tommaso ◽  
Alessandro Carrara ◽  
...  
Keyword(s):  
Emergency Department ◽  
Blood Transfusion ◽  
Emergency Surgery ◽  
Surgical Care ◽  
Close Correlation ◽  
Negative Effects ◽  
Group 2 ◽  
Retrospective Comparative Study ◽  
The Impact ◽  
Group 1

Abstract Background The aim of this retrospective comparative study was to assess the impact of COVID-19 and delayed emergency department access on emergency surgery outcomes, by comparing the main clinical outcomes in the period March–May 2019 (group 1) with the same period during the national COVID-19 lockdown in Italy (March–May 2020, group 2). Methods A comparison (groups 1 versus 2) and subgroup analysis were performed between patients’ demographic, medical history, surgical, clinical and management characteristics. Results Two-hundred forty-six patients were included, 137 in group 1 and 109 in group 2 (p = 0.03). No significant differences were observed in the peri-operative characteristics of the two groups. A declared delay in access to hospital and preoperative SARS-CoV-2 infection rates were 15.5% and 5.8%, respectively in group 2. The overall morbidity (OR = 2.22, 95% CI 1.08–4.55, p = 0.03) and 30-day mortality (OR = 1.34, 95% CI 0.33–5.50, =0.68) were significantly higher in group 2. The delayed access cohort showed a close correlation with increased morbidity (OR = 3.19, 95% CI 0.89–11.44, p = 0.07), blood transfusion (OR = 5.13, 95% CI 1.05–25.15, p = 0.04) and 30-day mortality risk (OR = 8.00, 95% CI 1.01–63.23, p = 0.05). SARS-CoV-2-positive patients had higher risk of blood transfusion (20% vs 7.8%, p = 0.37) and ICU admissions (20% vs 2.6%, p = 0.17) and a longer median LOS (9 days vs 4 days, p = 0.11). Conclusions This article provides enhanced understanding of the effects of the COVID-19 pandemic on patient access to emergency surgical care. Our findings suggest that COVID-19 changed the quality of surgical care with poorer prognosis and higher morbidity rates. Delayed emergency department access and a “filter effect” induced by a fear of COVID-19 infection in the population resulted in only the most severe cases reaching the emergency department in time.

scholarly journals QOL-49. THE IMPACT OF OTOTOXICITY AND VISUAL IMPAIRMENT ON EDUCATION IN CHILDREN TREATED FOR CNS TUMOURS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii440-iii440
Author(s):  
Harriet Dulson ◽  
Rachel McAndrew ◽  
Mark Brougham
Keyword(s):  
Visual Impairment ◽  
Impaired Hearing ◽  
Cranial Radiotherapy ◽  
Radiotherapy Group ◽  
Platinum Based Chemotherapy ◽  
Cns Tumours ◽  
Group 3 ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract INTRODUCTION Children treated for CNS tumours experience a very high burden of adverse effects. Platinum-based chemotherapy and cranial radiotherapy can cause ototoxicity, which may be particularly problematic in patients who have impaired vision and cognition as a result of their tumour and associated treatment. This study assessed the prevalence of impaired hearing and vision and how this may impact upon education. METHODS 53 patients diagnosed with solid tumours in Edinburgh, UK between August 2013–2018 were included in the study. Patients were split into three groups according to treatment received: Group 1 – cisplatin-based chemotherapy and cranial radiotherapy; Group 2 - platinum-based chemotherapy, no cranial radiotherapy; Group 3 – benign brain tumours treated with surgery only. Data was collected retrospectively from patient notes. RESULTS Overall 69.5% of those treated with platinum-based chemotherapy experienced ototoxicity as assessed by Brock grading and 5.9% of patients had reduced visual acuity. Patients in Group 1 had the highest prevalence of both. 44.4% of patients in Group 1 needed increased educational support following treatment, either with extra support in the classroom or being unable to continue in mainstream school. 12.5% of Group 2 patients required such support and 31.3% in Group 3. CONCLUSIONS Children with CNS tumours frequently require support for future education but those treated with both platinum-based chemotherapy and cranial radiotherapy are at particular risk, which may be compounded by co-existent ototoxicity and visual impairment. It is essential to provide appropriate support for this patient cohort in order to maximise their educational potential.

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