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

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.

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Assessment of the early reach ability of major molecular response (MMR) in chronic phase of CML Egyption patients on first(1st) and second(2nd) generation TKI(as regard 1st and 2nd line of treatment

QJM ◽

10.1093/qjmed/hcaa052.034 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

M O Azzazi ◽

R M M Said ◽

M Abdallah ◽

A Elshazly ◽

A A M Allam

Keyword(s):

First Generation ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

University Hospital ◽

Molecular Response ◽

Newly Diagnosed ◽

Major Molecular Response ◽

2Nd Generation ◽

Group 2 ◽

Group 1

Abstract Background Nilotinib has been shown to be a more potent inhibitor of BCR-ABL than imatinib. We evaluated the efficacy and safety of nilotinib, as compared with imatinib, in patients with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia (CML) in the chronic phase Aim of the work Comparsion between the early reach ability of major molecular response (MMR) in chronic phase of CML patients on first(1st) and second(2nd) generation TKI(as regard 1st and 2nd line of treatmen t Patients and methods major molecular response (MMR) was assessed by quantative PCRfor BCR –ABL in 100 paients with newly diagnosed CML d ivided to three groups, group 1 included 40 patients on first generation tKI(imitinib), group 2 included 40 patients shifted from 1st generation (imitinib) to 2nd generation (nilotinib) and groups 3 included 20 patients on 2nd generation (nilotinib) from the start. The patients were recruited from clinical hematology department at Ain shams university hospital over the period from1/2018 to1/2019 Results in CML patients, rate of MMRat 12 months of treatment on 2nd generation TKI (nilotinib) as 1st line was higher than other groups (p = 0.025*), rate of EMR was higher in patients on nilotinib 300 mg than on imitinib 400 mg(p = <0.001) in CMl patients started on imitinib 400mg with additional cyto genetics abnormalities had high numbers of failure of MMR(p = 0.001) in comparsion to patients on nilotinib either 1st line or shifted. in CMl patients started on nilotinib 300mg had rising of liver functions than patients on imitinib(p = 0.002 in CMl patients started on nilotinib 3oomg as 1st line had high numbers of ECG chnges than patients on imitinib4oomg(p = 0.005) in CMl patientswith high sockal score started on imitinib 400mg had high number s of failure of MMR in comparsion to patients on nilotinib 300 mg(p < 0.001) in CMl patients, rateof CCR at6 and 12month had higher in patients started on nilotinib 300mgthan imitinib 400mg (p = 0.020) Conclusion treatment with first-line nilotinib is a better clinical strategy than starting with imatinib followed by switching to nilotinib for inadequate responses

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Loss of the Y Chromosome Predicts Lower Complete Cytogenetic Remission Rate in Patients (pts) with Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood.v120.21.4804.4804 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4804-4804

Author(s):

Mohamed Abdelfatah ◽

Adel Al-Alwan ◽

Zeyad Kanaan ◽

Mark R Litzow ◽

Alexandra Wolanskyj ◽

...

Keyword(s):

Overall Survival ◽

Y Chromosome ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Blast Phase ◽

Male Patients ◽

Cytogenetic Remission ◽

Group 2 ◽

Group 1

Abstract Abstract 4804 Background: Chronic myeloid leukemia (CML) is one of the classic myeloproliferative neoplasms characterized by a reciprocal translocation of BCR and ABL t(9;22)(q34;q11). Tyrosine kinase inhibitors (TKI) have revolutionized the management of CML in inducing rapid and prolonged responses. However; clonal evolution (CE) is considered a poor prognostic factor and a criterion for accelerated phase (AP) CML by the World Health Organization (WHO). Deletion of chromosome Y (−Y) is frequently considered an age-related abnormality and the exact prognostic value has not yet been determined. Aim: To determine if –Y carries an impact on the clinical outcome of male pts with CML. Methods: All male patients diagnosed with chronic phase CML in our institution between 1993 and 2011 were screened for -Y. Data were collected in a retrospective manner and compared (using t-test) to male patients with sole BCR-ABL translocation after excluding patients with advanced stages (accelerated phase, blast phase). Demographics, laboratory tests, cytogenetic analysis, molecular testing and survival data were abstracted. Kaplan-Meier estimates of overall survival were used via JMP software v9.0. Institutional Review Board (IRB) approval was obtained for this study in accordance with the Helsinki Declaration. Results: 20 of 162 (12%) males with CML were found to have –Y abnormality (group 1). CML male patients with sole Philadelphia chromosome abnormality were the control cohort (group 2). In group1; the median age was 57 years, BMI 27.7, hemoglobin 12.2 g/dL, white blood cell count (WBC) 32.8 x109/L, platelet 270 x109/L, and peripheral blood blasts 1%. Sokal risk was low in 30%, intermediate in 65% and high in 5% of pts. Nine pts (45%) were treated with interferon (IFN) prior to TKI. In group 2; the median age was 54 years, hemoglobin 12 g/dL, WBC 57 x109/L, and platelet 282 x109/L. Sokal risk was low in 37%, intermediate in 47%, and high in 16%. 46 of 142 patients (32%) had received previous interferon therapy. All patients in both groups had chronic phase CML at the time of diagnosis, with a median bone marrow cellularity of 95%. In group 1, 14 of 20 pts (70%) received imatinib, all of whom achieved a complete hematological response (CHR), 7 of 14 pts (50%) had partial cytogenetic response, 2 of 14 pts (14%) achieved a complete cytogenic response (CCyR);1 (7%) pt achieved CCyR within 12 months and an additional 1 (7%) by 18 months). Two pts of 12 (16%) achieved at least a major molecular response (MMR); one of whom (8%) achieved a complete molecular response (CMR). In comparison, 107of 142 pts (75%) in group 2 received imatinib, all of whom achieved CHR. Twenty-one pts (20%) achieved partial cytogenetic remission. CCyR was more frequently achieved than group 1 (48/107 pts (45%), p 0.026); 24 pts (22%) achieved CCyR within 12 months of therapy and an additional 10 pts by 18-months. MMR and/or CMR was higher in group 2 compared to group 1 (34 /101 (34%), p 0.18); 16 (16%) of which were CMR. In group 1; 6 (30%) pts had disease progression; 4 of 20 pts (20%) progressed to blast phase (BP) and 2 pts (10%) progressed to AP, compared to 32 (22%) pts in group 2 (p 0.17); 22 (15%) of whom progressed to BP and 10 (7%) patients progressed to AP. Median overall survival was 110 months in group 1 compared to 155 months in group 2 (log rank p=0.48). On multivariate analysis, CCyR was an independent factor for a better OS (p 0.03), but not –Y (p 0.7). Conclusion: Loss of the Y chromosome in chronic myelogenous leukemia is an infrequent phenomenon (12%). Although patients with –Y had a statistically significant less chance to achieve CCyR, loss of the Y chromosome did not affect the progression rate or overall survival. Larger scale studies are needed to confirm our observations Disclosures: No relevant conflicts of interest to declare.

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Impact of Myelofibrosis at Presentation on Outcomes in Chronic Myeloid Leukemia in Chronic Phase

Blood ◽

10.1182/blood-2018-99-118182 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1747-1747

Author(s):

Ravichandran Ambalathandi ◽

Rajani Priya Yedla ◽

Nageswara Reddy Palukuri ◽

Stalin Chowdary Bala ◽

Meher Lakshmi Konatam ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chronic Phase ◽

Bone Marrow Examination ◽

Molecular Response ◽

Newly Diagnosed ◽

Major Molecular Response ◽

Event Free Survival ◽

Free Survival ◽

Grade 3 ◽

One Year

Abstract Background: Presence of myelofibrosis on bone marrow examination is considered as poor prognostic factor in patients with chronic myelogenous leukemia (CML). Scant data is available on myelofibrosis, especially in the era of tyrosine kinase therapy. The present study was designed to analyze impact of myelofibrosis on outcomes in newly diagnosed patients with chronic myeloid leukemia in chronic phase (CML-CP). Aims and objectives: The primary objective of this analysis was to study event free survival (EFS) and major molecular response rates (MMR) at one year in patients with CML-CP with myelofibrosis. Secondary objectives were to study the parameters impacting outcomes in patients with CML-CP with myelofibrosis Materials and methods: Study period: 2010 to 2016 Type of study: retrospective analysis. The diagnosis of CML-CP was done by demonstration of BCR-ABL translocation by polymerase chain reaction or fluorescence in situ hybridization. Event free survival was defined as the time from start of therapy to death, transformation to accelerated or blast phase, hematologic resistance or toxicity intolerance. Statistical analysis was done using SPSS software, version 25. Overall survival curves were plotted using the Kaplan-Meier method. Grade of myelofibrosis, EUTOS risk, age and compliance were analyzed on multivariate analyses. Results: Data of 147 patients with CML-CP with myelofibrosis at presentation was retrospectively collected, of which 79(53.7%) were males and 68(46.3%) were females. The baseline characters were tabulated in Table 1. Abdominal fullness (60.5%) was the most common symptom at presentation followed by fatigue (48.9%), weight loss (36.7%), fever (25.1%) and bleeding manifestations (12.9%). EUTOS risk was low in 94(64%) patients and high in 53 (36%) patients. Myelofibrosis grade 1, 2, 3 and 4 were seen in 20(13.6%), 36(24.5%), 38(25.9%) and 27(18.3%) patients respectively. Grade of myelofibrosis was not available in 26(17.7%) patients. Of 147 patients, outcome parameters were available in 92 patients. Of 92 patients, 34(37%) attained MMR at 1 year. At a median follow up of 46 months, event free survival was 60.9%. Of 92 patients, MMR at one year differed significantly in patients with grade 1 and 2 myelofibrosis (48.8%) compared to patients with grade 3 and 4 myelofibrosis (26.5%) (p=0.02). Event free survival was higher in patients with grade 1 and 2 myelofibrosis (76.7%) compared to patients with grade 3 and 4 myelofibrosis (46.9%) (p=0.005). Drug induced myelosuppression was seen in 27(29.3%) patients, of which 7(26%) patients received dose reduction. Phase transformation was seen in 6 patients, of which 1(16.7%) and 5(83.3%) patients were transformed to accelerated phase and blastic phase respectively. On multivariate analysis, only grade of myelofibrosis had significant impact on event free survival(p=0.013). Conclusion: In patients with newly diagnosed CML-CP, major molecular response was significantly lower for those with higher grade of myelofibrosis. Grade of myelofibrosis at presentation had significant impact on outcomes in CML-CP. Hence, bone marrow examination for presence and grade of myelofibrosis helps in prognosticating CML-CP patients. Disclosures No relevant conflicts of interest to declare.

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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 ◽

10.1182/blood.v116.21.2301.2301 ◽

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.

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The Persistence of p190 BCR-ABL Transcripts Is Associated with Lower Probability of Molecular Response to Imatinib in Early and Late Chronic Phase CML Patients.

Blood ◽

10.1182/blood.v106.11.3282.3282 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3282-3282

Author(s):

Anna Garuti ◽

Adalberto Ibatici ◽

Gabriella Cirmena ◽

Maurizio Miglino ◽

Riccardo Varaldo ◽

...

Keyword(s):

Prognostic Significance ◽

Chronic Phase ◽

Cytogenetic Response ◽

Lower Probability ◽

Molecular Response ◽

Qrt Pcr ◽

Complete Cytogenetic Response ◽

Group 2 ◽

Group 1

Abstract Background. It has been demonstrated that about 70% of patients with CML in chronic phase (CP) at diagnosis co-expressed p210 and p190 BCR/ABL transcripts, although at a much lower level (Blood1996;87:5213–17). In previous studies, the co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was considered as indicative of higher tumor burden. However, the clinical relevance of p190 BCR-ABL mRNA monitoring in CML pts under Imatinib on bone marrow (BM) samples is not known. Materials and Methods. BM samples were obtained from 83 pts with CP-CML treated with Imatinib at a daily oral dose ranging between 300–500mg. These included 192 samples from 43 pts with late CP-CML (post-IFN failure) and 140 samples from 40 pts with early CP-CML who received Imatinib as first line therapy. Median follow-up was 18 (3–58) and 39 (12–58) months for early and late CP-CML, respectively. As part of a diagnostic work-up, BM samples from each patient were assessed for expression of both p210 and p190 BCR/ABL levels by real-time quantitative reverse transcription PCR (QRT-PCR) using a TAQ-Man system (ABI Prism 7700 Perkin Elmer) for BCR-ABL and ABL genes. The median number of BM assessment was 3 (2–6) for early CP-CML and 4 (2–10) for late CP-CML. A major molecular response (MMR) was defined as BCR-ABL/ABL ratios less than 0.05%. A specific nested RT-PCR screening was assessed for detection of p210 (b2a2, b3a2) and p190 (e1a2) BCR-ABL transcripts to confirm the negative data of p210 and p190 in QRT-PCR. Results. A MMR was obtained in 20 pts (50%) and 20 pts (46%) in early and late CP-CML respectively. However, early CP-CML pts showed a significantly greater reduction in p210 BCR-ABL levels compared to late CP-CML after 12 months of Imatinib therapy (p=0.006), indicating a different kinetic of molecular response. Co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was 73% for early CP-CML, whereas it was not available for late CP-CML. To test whether the persistence of p190 BCR-ABL transcript was predictive of MMR, we divided CML pts in 2 groups, those with 0 or 1 p190 BCR-ABL positive samples (group 1) and those with 2 or more positive samples (group 2) during the follow-up. We found that CP-CML pts of the group 2 showed a significant lower probability to obtain MMR molecular response compared to pts of group 1 both for late and early CML patients respectively [17/24 (71%) vs 5/19 (26%) with p=0.0039)], [15/21 (71%) vs 6/18 (33%) with p=0.017)]. This correlation holds also for complete cytogenetic response (data not shown). Conclusions. In this study, approximately 50% of pts reached a MMR; half of them had undetectable values of p210 BCR-ABL transcripts. However, in a proportion of pts with complete cytogenetic response and low level of p210 BCR-ABL transcript, the expression of p190 is still detectable. The persistence of p190 signal despite the 2–3log fall in p210 BCR-ABL levels, may be of prognostic significance and may disclose unfolded concepts of biological relevance.

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Poor response to second-line kinase inhibitors in chronic myeloid leukemia patients with multiple low-level mutations, irrespective of their resistance profile

Blood ◽

10.1182/blood-2011-08-375535 ◽

2012 ◽

Vol 119 (10) ◽

pp. 2234-2238 ◽

Cited By ~ 53

Author(s):

Wendy T. Parker ◽

Musei Ho ◽

Hamish S. Scott ◽

Timothy P. Hughes ◽

Susan Branford

Keyword(s):

Mass Spectrometry ◽

Chronic Myeloid Leukemia ◽

Mutation Analysis ◽

Myeloid Leukemia ◽

Direct Sequencing ◽

Chronic Phase ◽

Molecular Response ◽

Second Line ◽

Poor Risk ◽

Imatinib Resistant

Abstract Specific imatinib-resistant BCR-ABL1 mutations (Y253H, E255K/V, T315I, F317L, and F359V/C) predict failure of second-line nilotinib or dasatinib therapy in patients with chronic myeloid leukemia; however, such therapy also fails in approximately 40% of patients in the chronic phase of this disease who do not have these resistant mutations. We investigated whether sensitive mutation analysis could identify other poor-risk subgroups. Analysis was performed by direct sequencing and sensitive mass spectrometry on 220 imatinib-resistant patients before they began nilotinib or dasatinib therapy. Patients with resistant mutations by either method (n = 45) were excluded because inferior response was known. Of the remaining 175 patients, 19% had multiple mutations by mass spectrometry versus 9% by sequencing. Compared with 0 or 1 mutation, the presence of multiple mutations was associated with lower rates of complete cytogenetic response (50% vs 21%, P = .003) and major molecular response (31% vs 6%, P = .005) and a higher rate of new resistant mutations (25% vs 56%, P = .0009). Sensitive mutation analysis identified a poor-risk subgroup (15.5% of all patients) with multiple mutations not identified by standard screening.

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Induction and maintenance for chronic myeloid leukemia-chronic phase: A novel treatment strategy.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19526 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19526-e19526

Author(s):

Aditi Jain ◽

Manoranjan Mahapatra ◽

Tulika Seth ◽

Anil Irom ◽

Sudha Sazawal

Keyword(s):

Chronic Phase ◽

Standard Of Care ◽

P Value ◽

Molecular Response ◽

Molecular Responses ◽

T315i Mutation ◽

Group 3 ◽

Group 2 ◽

Group 1

e19526 Background: Imatinib remains the standard of care for CML-CP in many countries because of its affordability and safety with long term use. Given that upfront Nilotinib has higher rates of major molecular response and early deep responses predict long term responses, we hypothesized that upfront Nilotinib as induction followed by Imatinib maintenance may help to capitalize on the efficacy of Nilotinib without sacrificing the safety and efficacy of Imatinib. Methods: CML CP patients were divided into 3 groups at the time of diagnosis. Group 1 received Imatinib 400mg OD upfront, Group 2 and 3 received Nilotinib 300 mg BD for 1st 3 and 6 months respectively then switched over to Imatinib 400 OD. Quantitative real time PCR for BCR-ABL (RQ PCR for BCR-ABL) was done at 3, 6,12, 18, 24, 30, and 36 months to assess response. 3 early molecular responses were defined for analysis. EMR 1 was defined as Bcr-abl RQPCR < 10% at 3 months, EMR 2 as < 1% at 6 months and EMR 3 as < 0.1% at 6 months. Results: Patients on Nilotinib induction had deeper responses than patients on Imatinib at 3 and 6 months. However, subsequent molecular responses were similar in all 3 groups. The rates of Early Molecular responses were significantly better in the Nilotinib group compared to the Imatinib group. Significantly lesser patients in Group 1 had EMR 1 compared to Groups 2 and 3 [80.49% vs 100% vs 95.56%, p value 0.001]. Results were similar for EMR 2 and 3 [EMR 2: 34.15% vs 42.11% vs 60%, p value 0.017, EMR 3: 25.71% vs 25.53% vs 44.44%, p value Group 1 vs Group 3: 0.030]. TKI failure/progression rates were significantly better amongst patients who achieved EMR vs those who did not achieve EMR for EMR 2 and 3 but not EMR 1. For EMR 2, 42.68% who did not achieve EMR eventually had TKI failure compared to 18.03% of those who achieved EMR (p value 0.002). Similarly, 32.95% who failed to achieve EMR 3 progressed vs 11.9% of those who achieved EMR 3 (p value 0.011). 3 patients in group 1 and 1 patient in group 2 developed T315I mutation while none did in Group 3. Conclusions: The early advantage achieved with Nilotinib Induction was not sustained after switching to Imatinib maintenance. Nevertheless, target responses were still achieved and similar failure rates were present in all 3 groups. Patients who attained an EMR < 1 % at 3 months or < 0.1% at 6 months tend to have higher EFS and lower rates of TKI failure/progression irrespective of the treatment arm.

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Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Blood ◽

10.1182/blood.v124.21.1816.1816 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1816-1816 ◽

Cited By ~ 1

Author(s):

Soo Young Choi ◽

Sung-Eun Lee ◽

Yun jeong Oh ◽

Soo-Hyun Kim ◽

Richard C. Woodman ◽

...

Keyword(s):

Conflicts Of Interest ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Group 3 ◽

Group 2 ◽

Group 1

Abstract Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE. The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or intolerance to treatment were allowed to switch to other treatment. Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3). With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10). Up to now, all patients in three groups have maintained CCyR without progression or resistance. 10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD. Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614). Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia. Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. Disclosures No relevant conflicts of interest to declare.

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Intracoronary Injection of Autologous CD34+ Cells Improves One-Year Left Ventricular Systolic Function in Patients with Diffuse Coronary Artery Disease and Preserved Cardiac Performance—A Randomized, Open-Label, Controlled Phase II Clinical Trial

Journal of Clinical Medicine ◽

10.3390/jcm9041043 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1043 ◽

Cited By ~ 2

Author(s):

Pei-Hsun Sung ◽

Yi-Chen Li ◽

Mel S. Lee ◽

Hao-Yi Hsiao ◽

Ming-Chun Ma ◽

...

Keyword(s):

Systolic Function ◽

Coronary Intervention ◽

Left Ventricular ◽

Diffuse Coronary Artery Disease ◽

Cd34 Cells ◽

Group 2 ◽

Artery Disease ◽

One Year ◽

Lv Systolic Function ◽

Group 1

This phase II randomized controlled trial tested whether intracoronary autologous CD34+ cell therapy could further improve left ventricular (LV) systolic function in patients with diffuse coronary artery disease (CAD) with relatively preserved LV ejection fraction (defined as LVEF >40%) unsuitable for coronary intervention. Between December 2013 and November 2017, 60 consecutive patients were randomly allocated into group 1 (CD34+ cells, 3.0 × 107/vessel/n = 30) and group 2 (optimal medical therapy; n = 30). All patients were followed for one year, and preclinical and clinical parameters were compared between two groups. Three-dimensional echocardiography demonstrated no significant difference in LVEF between groups 1 and 2 (54.9% vs. 51.0%, respectively, p = 0.295) at 12 months. However, compared with baseline, 12-month LVEF was significantly increased in group 1 (p < 0.001) but not in group 2 (p = 0.297). From baseline, there were gradual increases in LVEF in group 1 compared to those in group 2 at 1-month, 3-months, 6-months and 12 months (+1.6%, +2.2%, +2.9% and +4.6% in the group 1 vs. −1.6%, −1.5%, −1.4% and −0.9% in the group 2; all p < 0.05). Additionally, one-year angiogenesis (2.8 ± 0.9 vs. 1.3 ± 1.1), angina (0.4 ± 0.8 vs. 1.8 ± 0.9) and HF (0.7 ± 0.8 vs. 1.8 ± 0.6) scores were significantly improved in group 1 compared to those in group 2 (all p < 0.001). In conclusion, autologous CD34+ cell therapy gradually and effectively improved LV systolic function in patients with diffuse CAD and preserved LVEF who were non-candidates for coronary intervention (Trial registration: ISRCTN26002902 on the website of ISRCTN registry).

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Effect of anterior capsular polishing on the incidence of YAG capsulotomy

Annals of King Edward Medical University ◽

10.21649/akemu.v11i3.1021 ◽

2016 ◽

Vol 11 (3) ◽

Author(s):

Muhammad A Ahad ◽

Mohammad Rashad Qamar ◽

Sameh K Hindi ◽

Martin N Kid

Keyword(s):

Outcome Measure ◽

Early Postoperative Period ◽

Controlled Study ◽

Control Group ◽

Anterior Capsule ◽

Main Outcome Measure ◽

Group I ◽

Group 2 ◽

One Year ◽

Group 1

Purpose: To study the effect of anterior capsule polishing during phacoemulsification on the incidence of post operative YAG laser capsulotomy. Method: A retrospective controlled study of 159 patients who underwent uncomplicated phacoemulsification with anterior capsular polishing between October 1998 and March 2000. 169 age matched patients who underwent phacoemulsification but without anterior capsule polishing served as controls. Main outcome measure: Incidence of visually significant YAG capsulotomy, which improved the Snellen acuity for more than 1 line or at least 1 line with subjective improvements in symptoms. Results: 2.51 % of patients with anterior capsular polishing (Group 1) had YAG capsulotomy compared to 7.1% of patients in control group at one year. However, after two years, 11.3% of patients in Group I had YAG capsulotomy compared to 12.4% in Group 2. Conclusion: Anterior capsular polishing during cataract surgery may delay the opacification of posterior capsule during the early postoperative period. But does not decrease the incidence of YAG capsulotomy after two years.

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