- Email: [email protected]
Real-Life Discontinuation of TKIS
Abstracts 1
Department of Medical Biotechnology, VIT University, Vellore, Tamil
Nadu, India, Vellore, India; 2Department of Biomedical Sciences, VIT University, Vellore, Tamil Nadu, India, Vellore, India
Context: This study highlights the possibility of co-existence of microsatellite instability and chromosomal instability in samples with CML confirmed by t(9;22). Objective: The study was aimed to evaluate the association between microsatellite instability (MSI) and evolution of chronic myeloid leukemia (CML). Design: In order to establish variations in the (AC)n repeats of two known microsatellite markers on chromosomes 3p21.3 and 17p12-p11.1. PCR was carried out using normal and fluorescent primers and the PCR products were further subjected to bio-analysis and fragment analysis. Bio-analysis and fragment analysis of five CML patients and three healthy individuals was carried out in duplicates to understand the plausible underlying changes. The markers chosen for this study were D17S261 (Mfd41) and D3S643 (CI3-9). Setting: Sample collection was done at a referral center and research work was carried out at the institutional research laboratory. Genexplore Diagnostics and Research Centre Pvt. Ltd. which is in MoU with VIT University collected and confirmed CML as per the ethical guidelines. Main Outcome Measures: MSI was found in the clinical CML samples indicating variation in the number of (AC)n repeats for both the markers. Results: The presence and quantity of DNA was checked through agarose gel electrophoresis and NanoDrop spectrophotometer respectively. Results from fragment analysis indicated presence of MSI in patient samples and thus possible Loss of heterozygosity (LOH) in p53 and MLH1 tumor suppressor genes. Bio-analysis and fragment analysis results on comparison showed deviated results. Bio-analysis results did not show any significant variations in the (AC) repeats, but fragment analysis indicated presence of MSI in most of the patients as compared to the normal individuals for both the markers. Although bio-analysis was performed to check the presence of altered peak for the markers chosen, fragment analysis helped in confirmation of microsatellite instability. Conclusion: The findings suggest that microsatellite instability is an event that may also contribute towards CML progression and may induce resistance to various drugs.
CML-012 Real-Life Discontinuation of TKIS Debora Luzi
IFN alfa for further 47 months after stopping imatinib. Since discontinuation, patients were monitored by monthly quantitative PCR. Patients: Among 18 patients, 1 patient discontinued inside clinical trials, 6 patients intentionally and 11 because of toxicities (3 after myocardial infarction, 3 for pleura-pericardial effusions, 1 for severe pulmonary hypertension, 1 for worsening PAOD, 1 for secondary neoplasm, 1 after cerebrovascular event and 1 for thrombocytopenia). Fourteen of 18 patients discontinued in MR5-MR4.5, 1 in MR4, 1 in MMR, 1 in CCyR. Results: With median follow-up of 31.2 months (range 7-103), 14/18 patients (77%) are still off-therapy (Group1, G1), 9 in MR5, 1 in MR4.5, 1 in MR4, 1 in MMR and 2 in CCyR. In 4/18 patients (23%) (Group2, G2) median duration of relapse-free interval was 3.5 months (range 2-6). Except 2 cases, patients losing MMR were rescued with same or other TKI. Low SR at diagnosis was respectively documented in 71% and 25% of G1 or G2 cases. Furthermore, median IFN alfa exposure was 93 months in 57% and 16 months in 50% of G1 or G2 patients respectively. Twelve G1 patients (85%) stopped TKIs in MR5-MR4.5, 1 in MMR, 1 in CCyR. Three G2 patients (75%) discontinued in MR5 and 1 in MR4. Median duration of cumulative MR5, MR4.5, MR4 before discontinuation, was similar for both groups (45 vs 43 months). Notably, 11 patients (79%) of G1 and 2 (50%) of G2 achieved CCyR at 3 months of diagnosis. Median cumulative TKI exposure before discontinuation was 97,35 months for G1 and 84,25 months for G2. Conclusions: As expected, in our cohort, low SR at diagnosis, prior IFN and median cumulative TKI exposure before discontinuation were associated with longer relapse-free interval. Not the same for median duration of stable deep MR, probably suggesting the relevance of mechanisms additional to BCR-ABL inhibition in disease control.
CML-027 RT-qPCR and RT-Digital PCR: a Comparison of Different Platforms for the Evaluation of Residual Disease in Chronic Myeloid Leukaemia Mary Alikian ,1,2 Alexandra Whale,3 Susanna Akiki,4 Kim Piechocki,4 Celia Torrado,2 Thet Myint,1 Simon Cowen,5 Michael Griffiths,4 Jane Apperley,2,7 Helen White,6 Jim F. Huggett,3 Letizia Foroni2,7
S.C. Oncoematologia, Azienda Ospedaliero-Universitaria Santa Ma-
1
ria, Terni, Italy
smith Hospital, London, United Kingdom; 2Centre for Haematology,
Imperial Molecular Pathology, Imperial Healthcare Trust, Hammer-
Faculty of Medicine, Imperial College London, London, United
Background: About 60% patients with CML in deep persistent molecular remission (MR4, MR4.5 or MR5), relapse after TKI discontinuation. Here we reported our real-life single center experience. Objective: To evaluate impact of baseline factors associated with higher probability of Treatment-Free Remission (TFR) [low SokalRisk (SR), prior IFN, longer total duration of TKI exposure, duration of stable deep MR before discontinuation] on patients’ outcome. Methods: We reviewed charts of 18 CML patients among 60 treated at our institution between March 1989 and April 2016, who discontinued TKIs [imatinib (n¼7), nilotinib (n¼8), dasatinib (n¼2) or ponatinib (n¼1)] as first line (N¼7) or salvage therapy (N¼11) from September 2008 to April 2016. One patient, still in MR5, received
Kingdom; 3Molecular and Cell Biology Team, LGC, Queens Road, Teddington, London, United Kingdom; 4West Midlands Regional Genetics Laboratories, Birmingham Women’s NHS Foundation Trust, Birmingham, United Kingdom; 5Statistics Team, LGC, Queens Road, Teddington, London, United Kingdom; 6National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, United Kingdom; 7Clinical haematology, Imperial College Healthcare NHS Trust, London, United Kingdom
Background: Tyrosine Kinase Inhibitors (TKIs) are part of the successful clinical management of patients with Chronic Myeloid Leukaemia (CML). However, optimal clinical management of CML
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S55
Department of Medical Biotechnology, VIT University, Vellore, Tamil
Nadu, India, Vellore, India; 2Department of Biomedical Sciences, VIT University, Vellore, Tamil Nadu, India, Vellore, India
Context: This study highlights the possibility of co-existence of microsatellite instability and chromosomal instability in samples with CML confirmed by t(9;22). Objective: The study was aimed to evaluate the association between microsatellite instability (MSI) and evolution of chronic myeloid leukemia (CML). Design: In order to establish variations in the (AC)n repeats of two known microsatellite markers on chromosomes 3p21.3 and 17p12-p11.1. PCR was carried out using normal and fluorescent primers and the PCR products were further subjected to bio-analysis and fragment analysis. Bio-analysis and fragment analysis of five CML patients and three healthy individuals was carried out in duplicates to understand the plausible underlying changes. The markers chosen for this study were D17S261 (Mfd41) and D3S643 (CI3-9). Setting: Sample collection was done at a referral center and research work was carried out at the institutional research laboratory. Genexplore Diagnostics and Research Centre Pvt. Ltd. which is in MoU with VIT University collected and confirmed CML as per the ethical guidelines. Main Outcome Measures: MSI was found in the clinical CML samples indicating variation in the number of (AC)n repeats for both the markers. Results: The presence and quantity of DNA was checked through agarose gel electrophoresis and NanoDrop spectrophotometer respectively. Results from fragment analysis indicated presence of MSI in patient samples and thus possible Loss of heterozygosity (LOH) in p53 and MLH1 tumor suppressor genes. Bio-analysis and fragment analysis results on comparison showed deviated results. Bio-analysis results did not show any significant variations in the (AC) repeats, but fragment analysis indicated presence of MSI in most of the patients as compared to the normal individuals for both the markers. Although bio-analysis was performed to check the presence of altered peak for the markers chosen, fragment analysis helped in confirmation of microsatellite instability. Conclusion: The findings suggest that microsatellite instability is an event that may also contribute towards CML progression and may induce resistance to various drugs.
CML-012 Real-Life Discontinuation of TKIS Debora Luzi
IFN alfa for further 47 months after stopping imatinib. Since discontinuation, patients were monitored by monthly quantitative PCR. Patients: Among 18 patients, 1 patient discontinued inside clinical trials, 6 patients intentionally and 11 because of toxicities (3 after myocardial infarction, 3 for pleura-pericardial effusions, 1 for severe pulmonary hypertension, 1 for worsening PAOD, 1 for secondary neoplasm, 1 after cerebrovascular event and 1 for thrombocytopenia). Fourteen of 18 patients discontinued in MR5-MR4.5, 1 in MR4, 1 in MMR, 1 in CCyR. Results: With median follow-up of 31.2 months (range 7-103), 14/18 patients (77%) are still off-therapy (Group1, G1), 9 in MR5, 1 in MR4.5, 1 in MR4, 1 in MMR and 2 in CCyR. In 4/18 patients (23%) (Group2, G2) median duration of relapse-free interval was 3.5 months (range 2-6). Except 2 cases, patients losing MMR were rescued with same or other TKI. Low SR at diagnosis was respectively documented in 71% and 25% of G1 or G2 cases. Furthermore, median IFN alfa exposure was 93 months in 57% and 16 months in 50% of G1 or G2 patients respectively. Twelve G1 patients (85%) stopped TKIs in MR5-MR4.5, 1 in MMR, 1 in CCyR. Three G2 patients (75%) discontinued in MR5 and 1 in MR4. Median duration of cumulative MR5, MR4.5, MR4 before discontinuation, was similar for both groups (45 vs 43 months). Notably, 11 patients (79%) of G1 and 2 (50%) of G2 achieved CCyR at 3 months of diagnosis. Median cumulative TKI exposure before discontinuation was 97,35 months for G1 and 84,25 months for G2. Conclusions: As expected, in our cohort, low SR at diagnosis, prior IFN and median cumulative TKI exposure before discontinuation were associated with longer relapse-free interval. Not the same for median duration of stable deep MR, probably suggesting the relevance of mechanisms additional to BCR-ABL inhibition in disease control.
CML-027 RT-qPCR and RT-Digital PCR: a Comparison of Different Platforms for the Evaluation of Residual Disease in Chronic Myeloid Leukaemia Mary Alikian ,1,2 Alexandra Whale,3 Susanna Akiki,4 Kim Piechocki,4 Celia Torrado,2 Thet Myint,1 Simon Cowen,5 Michael Griffiths,4 Jane Apperley,2,7 Helen White,6 Jim F. Huggett,3 Letizia Foroni2,7
S.C. Oncoematologia, Azienda Ospedaliero-Universitaria Santa Ma-
1
ria, Terni, Italy
smith Hospital, London, United Kingdom; 2Centre for Haematology,
Imperial Molecular Pathology, Imperial Healthcare Trust, Hammer-
Faculty of Medicine, Imperial College London, London, United
Background: About 60% patients with CML in deep persistent molecular remission (MR4, MR4.5 or MR5), relapse after TKI discontinuation. Here we reported our real-life single center experience. Objective: To evaluate impact of baseline factors associated with higher probability of Treatment-Free Remission (TFR) [low SokalRisk (SR), prior IFN, longer total duration of TKI exposure, duration of stable deep MR before discontinuation] on patients’ outcome. Methods: We reviewed charts of 18 CML patients among 60 treated at our institution between March 1989 and April 2016, who discontinued TKIs [imatinib (n¼7), nilotinib (n¼8), dasatinib (n¼2) or ponatinib (n¼1)] as first line (N¼7) or salvage therapy (N¼11) from September 2008 to April 2016. One patient, still in MR5, received
Kingdom; 3Molecular and Cell Biology Team, LGC, Queens Road, Teddington, London, United Kingdom; 4West Midlands Regional Genetics Laboratories, Birmingham Women’s NHS Foundation Trust, Birmingham, United Kingdom; 5Statistics Team, LGC, Queens Road, Teddington, London, United Kingdom; 6National Genetics Reference Laboratory (Wessex), Salisbury District Hospital, Salisbury, United Kingdom; 7Clinical haematology, Imperial College Healthcare NHS Trust, London, United Kingdom
Background: Tyrosine Kinase Inhibitors (TKIs) are part of the successful clinical management of patients with Chronic Myeloid Leukaemia (CML). However, optimal clinical management of CML
Clinical Lymphoma, Myeloma & Leukemia September 2016
- S55