Jak-2 and Nfkbia Gene Expression Play a Strategic Role in Chronic Myeloid Leukemia (CML) Molecular Response during Early Nilotinib Treatment: The PhilosoPhi34 Data

Abstract Background Targeted therapy with Tyrosine-Kinase-Inhibitors (TKIs) totally modified the course of treatment of Chronic Myeloid Leukemia (CML). The objectives and the needs of treatment have been modified during the last years and the discontinuation of therapy is now a feasible aim. However, a lot of biological data acquired in the last twenty years, showed that degree and mechanisms of Leukemic Stem Cells (LSCs) clearance during TKI treatment are not clearly established as well as the predictive criteria for a stable and prolonged Treatment Free Remission (TFR). The multicentre, prospective, single-arm PhilosoPhi34 study (EudraCT: 2012-005062-34) was designed by the Rete Ematologica Lombarda (REL), to verify the in-vivo activity and time-course of first-line Nilotinib (NIL) therapy on Bone Marrow (BM) CD34+/lin-Ph+ cells clearance. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells at diagnosis and at 12 months (mos) of treatment, for the first 30 evaluable pts, was included. Preliminary GEP data suggested a correlation between different NFKBIA expression at diagnosis and at 12 mos and the achievement of a deeper Molecular Response (MR) (Pungolino et al, AJH 2018). We report here some results of GEP analysis on all enrolled evaluable pts and their possible correlation with clinical data. Methods BM cells were collected and stored at diagnosis and at 12 mos of treatment. CD34+/lin- cells were purified with a Diamond CD34 Isolation Kit Miltenyi (97% of purity). For GEP analysis we used Affymetrix HG-U133 Plus 2.0 microarray and Genechip platform (Affymetrix) and the Affymetrix GeneChip Scanner 3000. Data was pre-processed and normalized using the Robust Multi-array Average (RMA) algorithm. The Significant Analysis of Microarrays (SAM) was used to identify genes with statistically significant changes in expression. P-values were corrected for multiple testing using false discovery rate, for differentially expressed genes confirmation. We chose to analyse different expression of NFKBIA (the inhibitor of NF-kB onco-gene) in order to confirm the preliminary data reported on the first 30 analysed pts. Pts were monitored according to ELN-recommendation. Biological data were correlated with MR at 3, 12 and 36 mos of therapy. We use Fishers test to compare unbalanced group. Results Out of the 87 enrolled pts, 80 completed the first 12 mos of treatment and 78 (1 failure and 77 CCyR) were evaluable for GEP analysis. We observed 2726 genes symbol differentially expressed of which 1868 are coding genes. Among these, JAK-2 showed a down regulation at 12 mos (p: .024). JAK-2 expression ranged from 2.62 to 4.95 at diagnosis and from 1.48 to 5.58 at 12 mos. Only 26/78 pts increased JAK-2 expression that was > 4 in 1/26 pts, at diagnosis; 2/26 (7.69%) pts showed a H Sokal. Other 52/78 pts decreased JAK-2 expression that was ≥ 4 in 21/52 pts, at diagnosis; 10/52 (19.23%) pts and 6/21 (28,57%) pts showed a H Sokal. Similarly, when we compared low JAK-2 expression (< 3.5) vs vary high expression (≥ 4) 2/21 vs 6/22 pts had H Sokal (9.52% vs 27.27%; p: .0057). Considering the role of JAK-2 and NFKBIA in cell regulation and survival, we evaluated how the combination of their different expression impact on MR (i.e. NFKBIA increased expression/JAK-2 decreased expression vs NFKBIA decreased expression/JAK-2 increased expression). Data are reported in Table 1 and 2. Conclusion GEP analysis showed a down regulation of JAK-2 expression after 12 mos of first line NIL treatment, in 78 early chronic phase CML pts. Data suggest that high expression of JAK-2, at diagnosis, correlate with H Sokal score. However, H Sokal pts with a JAK-2 down regulation, obtain during treatment similar MR compared to L Sokal pts. Additionally, the study confirms our preliminary observation on 30 pts , concerning the role of NKBIA up - regulation in increasing percentage of earlier and deeper MR . The better condition of NFKBIA and JAK-2 expression (up regulation of NFKBIA and down regulation of JAK-2) is associated with a higher percentage of early MR3 and optimal responses over time, despite the higher number of H Sokal pts in this group. A study with NIL as first line treatment combined with low dose of JAK-2 inhibitor and a natural inhibitor of NF-kB (such as curcuma), during the first year of treatment, to increase the deeper MR rate and the probability of TFR is warrented. Disclosures Rossi: Sandoz: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Teva: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Novartis: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Blood ◽

10.1182/blood-2018-99-119182 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 458-458 ◽

Cited By ~ 1

Author(s):

Gabriele Gugliotta ◽

Fausto Castagnetti ◽

Massimo Breccia ◽

Alessandra Iurlo ◽

Mariella D'Adda ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Advisory Board ◽

Molecular Response ◽

First Line ◽

Advisory Committees ◽

Deep Molecular Response ◽

First Line Treatment

Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

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First-Line Second Generation Tyrosine Kinase Inhibitors in Newly Diagnosed Accelerated Phase Chronic Myeloid Leukemia Patients.

Blood ◽

10.1182/blood-2018-99-113058 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 48-48 ◽

Cited By ~ 2

Author(s):

Marie Balsat ◽

Vincent Alcazer ◽

Gabriel Etienne ◽

Gaelle Fossard ◽

Francoise Huguet ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Board Of Directors ◽

Tyrosine Kinase Inhibitors ◽

Myeloid Leukemia ◽

Kinase Inhibitors ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Free Survival

Abstract Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts <30%, basophils in PB ≥20%, or persistent thrombocytopenia <100×109/L (unrelated to therapy) and/or chromosomal abnormalities in addition to the Ph at diagnosis (ACA-AP). Pts initiated nilotinib at 6-800 mg BID or dasatinib at 100-140 mg QD with further dose adaptations according to toxicities or response. Overall survival (OS), progression-free survival (PFS) and failure-free survival [FFS= progression to blast crisis, death, loss of any previous response (CHR, CCyR, or MMR) discontinuation of TKI2 for toxicity], were analysed since TKI2 initiation in intention-to-treat. Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p <0.001], PB blasts [median: 12.05 (7.5-15) vs. 1.5 (0-4)%, p<.001], as well as PB blasts+promyelocytes [median 14 (11-20) vs. 4 (1-7)%, p<.001]. Hemoglobin levels were significantly lower in the HEM-AP group [median 93 (6-113.5) vs 120 (100-134) g/L, p<0.001]. Neither WBC counts, platelets counts, nor BCR-ABL/ABL load differed significantly between the 2 groups. In the ACA-AP group, 10 (30%) pts harbored major route ACA and 23 (70%) pts harbored minor route ACA of whom 3 pts with i(17q) and 1 with 7q abnormalities. In the ACA-AP group, Sokal score was low in 42%, intermediate in 32% and high in 26% of pts (2 pts unknown). Dasatinib was initiated in 19/33 pts (57.5%) in the HEM-AP group and in 8/33 pts (24%) in the ACA-AP group. Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p<0.001) and the % of BM blasts+promyelocytes (HR=1.14, 95%CI: 1.06-1.22, p<0.001). We identified too few significant factors in univariate analysis to perform a multivariate analysis. Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.

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Conventional Real Time Quantitative Polymerase Chain Reaction Method Yields Similar Level of Sensitivity to Digital Droplet Polymerase Chain Reaction for Detection of BCR-ABL p210 Transcripts in Patients with Chronic Phase Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-131207 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3382-3382 ◽

Cited By ~ 1

Author(s):

Hannah Asghari ◽

Chetasi Talati ◽

Alexandra Achille ◽

John J. Powers ◽

Eva Sahakian ◽

...

Keyword(s):

Clinical Trial ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Molecular Response ◽

Rt Pcr ◽

Chain Reaction ◽

Advisory Committees ◽

Polymerase Chain ◽

Tki Discontinuation

Introduction: Several studies have investigated the utility of digital droplet polymerase chain reaction (ddPCR) in the detection of p210 BCR-ABL fusion transcripts in chronic myeloid leukemia (CML), and have suggested greater sensitivity compared to real-time quantitative PCR (RT-qPCR). There is limited data regarding the utility and sensitivity of ddPCR in patients with chronic phase CML (CP-CML) who are candidates for tyrosine kinase inhibitor (TKI) discontinuation. We aimed to investigate the capability of ddPCR to detect p210 BCR-ABL transcript levels in CP-CML patients and compare the sensitivity to RT-qPCR. Methods: We analyzed 103 different peripheral blood (n=98) and bone marrow (n=5) samples from 36 patients with CP-CML treated at Moffitt Cancer Center between 2013 and 2018. Samples were from patients who either met clinical criteria for TKI discontinuation or were enrolled in a phase I dose-escalation study evaluating combination therapy with nilotinib plus ruxolitinib who had at least a complete cytogenetic response (CCyR) to TKI therapy with detectable BCR-ABL transcripts by RT-PCR at the time of enrollment(1, 2). BCR-ABL levels were assessed by RT-qPCR at the time of collection with level of transcript reported as % International Standard (%IS). Samples collected from 2013 to 2014 were reported as p210 to ABL and converted to %IS per lab-specific conversion factor. Stored purified RNA samples were obtained retrospectively and ddPCR was performed using the QX-200 Droplet Digital PCR System and QXDx BCR-ABL %IS Kit (Bio-Rad). Droplets were analyzed by QXDx BCR-ABL reporter software to determine p210 transcript level (%IS). Analysis for RNA degradation of stored samples was performed via High Sensitivity RNA ScreenTape (Agilent). Samples that did not pass quality check upon performing ddPCR were excluded from further analysis. Correlation coefficient was calculated with p-value of <0.05 being significant. Results: Of the 36 patients, 28 were in the TKI discontinuation cohort and 10 were enrolled in the clinical trial of nilotinib plus ruxolitinib. Two patients who participated in the clinical trial subsequently also met criteria for TKI discontinuation. In the TKI discontinuation cohort, 46% of patients (n=13) lost major molecular response (MMR) with a median time to loss of MMR of 88 days. We observed a statistically significant correlation between RT-qPCR and ddPCR levels when comparing %IS (correlation coefficient R2=0.42; p<0.0001) as well as calculated molecular response (MR) logarithm values of all available samples (R2=0.67; p <0.0001) (Figure 1). There was a weaker correlation between patients determined to have MMR by RT-qPCR (MR≥3.0) compared to ddPCR (R2=0.55; p <0.0001) (Figure 2). A total of 91 different samples were consistent with MMR when tested by RT-PCR. Of these samples, 85.7% (n=78) were consistent with MMR when tested by ddPCR and the remaining 14.3% (n=13) appeared to have higher detectable levels of p210 transcripts (MR<3.0). When investigating deeper molecular responses, 62 samples were consistent with MR≥4.0 by RT-PCR, and 20.9% (n=13) of these samples did not achieve a deep molecular response (MR<4.0) when tested by ddPCR. Of note, 5 representative samples were also evaluated for potential RNA degradation and 3 were noted to have significant degradation present. Conclusion: Compared to RT-PCR, ddPCR represents a viable method for detection of p210 transcripts for patients with CP-CML. The two methods yield similar efficacy when detecting varying levels of molecular response, however further research is warranted for the ability to detect deeper molecular responses for patients in MMR. Our study is limited by inherent retrospective bias and quality of RNA in stored samples. 1. National Comprehensive Cancer Network. Chronic Myeloid Leukemia (Version 1.2019). 2. Sweet K, Hazlehurst L, Sahakian E, Powers J, Nodzon L, Kayali F, et al. A phase I clinical trial of ruxolitinib in combination with nilotinib in chronic myeloid leukemia patients with molecular evidence of disease. Leuk Res. 2018;74:89-96. Disclosures Talati: Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. Shelton:Bio-Rad: Employment. Nodzon:Pharmacyclics: Consultancy; Abbvie: Other: Speaker Fees; Genentech: Consultancy, Other: Speaker Fees; Pfizer: Consultancy. Sweet:Stemline: Consultancy; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz:Novartis: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Janssen: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Sanofi: Speakers Bureau.

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First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Blood ◽

10.1182/blood-2021-145411 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1474-1474

Author(s):

Massimo Breccia ◽

Elisabetta Abruzzese ◽

Fabio Stagno ◽

Alessandra Iurlo ◽

Fabrozio Pene ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Time ◽

Interim Analysis ◽

Myeloid Leukemia ◽

Molecular Response ◽

First Line ◽

Full Dose ◽

Consolidation Phase ◽

Treatment Free Remission

Abstract Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL; indeed, pts with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48; TFR rate at wk 96 and 144; BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Interim results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau; Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

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Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: An International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped) Study

Blood ◽

10.1182/blood-2020-135844 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 53-54

Author(s):

Frédéric Millot ◽

Meinolf Suttorp ◽

Stéphanie Ragot ◽

Guy Leverger ◽

Jean-Hugues Dalle ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Age At Diagnosis ◽

Molecular Response ◽

Imatinib Treatment ◽

Advisory Committees ◽

Treatment Free Remission ◽

Tki Discontinuation

Background: Imatinib, a tyrosine kinase inhibitor (TKI) is currently proposed as first line therapy in children with chronic myeloid leukemia (CML) in chronic phase (CP). Studies in adults with CML demonstrated that 40 to 50% of patients with prolonged deep molecular response under TKI could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. Methods: Using the ELN criteria we identified in the International Registry of Childhood Chronic Myeloid Leukemia 18 patients less than 18 years of age at diagnosis with CML in CP exhibiting under imatinib treatment sustained deep molecular response >MR4.0 (DMR) for ≥ 2 years and then discontinued the TKI. We retrospectively analyzed outcome of these patients and treatment-free remission rate (TFR) at various time points. Treatment with imatinib was resumed in case of molecular relapse defined as loss of major molecular response (MMR). Results: There were 11 boys and 7 girls. From diagnosis in CP until TKI discontinuation the 18 children showed no progression, resistance, warning or suboptimal response or switch to another TKI before discontinuation. Median age at diagnosis of CML was 11.9 years (range, 2.3 to 15.8 years) and median age at discontinuation of TKI was 16 years (range, 9 to 24 years). Median overall follow-up from diagnosis of CML was 107 months (range, 67-209 months). DMR was achieved after a median time of 12 months (range, 3 - 50 months) on imatinib. Before discontinuation median treatment duration of imatinib was 73.25 months (range, 32 to 109 months) and median duration of MR4.0 was 46.2 months (range, 23.9 to 98.6 months). Seven patients experienced molecular relapse 4.1 months (range, 1.9-6.4 months) after stopping and restarted imatinib. Two patient resumed imatinib 3.6 and 3.4 months after discontinuation because of increased in transcript level (from 0.001% to 0.01 and 0.012, respectively) but without loss of MMR. The median molecular follow up after discontinuation was 116 months (range, 71 to 209 months) for the patients without molecular relapse. The proportion of patients maintaining molecular free remission was 61% (95% CI, 38%-83%), 56% (95% CI, 33%-79%) and 56% (95% CI, 33%-79%) at 6, 12, and 36 months, respectively (Figure 1). Six of the 7 children who experienced molecular relapse after discontinuation again achieved MR4.0 at median of 4.7 months (range, 2.5-18 months) after restart of imatinib; the remaining patient achieved MMR but not DMR and was switched to Dasatinib. No withdrawal syndrome was observed in this cohort of 18 patients. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment duration before discontinuation and duration of DMR until imatinib discontinuation had no influence on treatment free remission. Conclusion: These data indicate that imatinib could be safely discontinued in children younger than 18 years of age at diagnosis of CML with sustained MR4.0 for at least 2 years under imatinib. Larger studies of TKI discontinuation in children with CML are needed in order to identify factors predicting treatment free remission. Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

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A Phase I Trial of Incorporating Natural Killer (K-NK) Cells for Patients with Chronic Myeloid Leukemia (CML) and Molecular Residual Disease after Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽

10.1182/blood-2020-142062 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 5-5

Author(s):

Lindsay A.M. Rein ◽

David A Rizzieri

Keyword(s):

Chronic Myeloid Leukemia ◽

Tyrosine Kinase ◽

Phase I ◽

Nk Cells ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Residual Disease ◽

Clinical Care ◽

Molecular Response ◽

Advisory Committees

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of patients with chronic myeloid leukemia (CML) ushering in an era where, in select patient populations, treatment planning goals have shifted towards the achievement of treatment free remission (TFR) after TKI cessation. Both duration and depth of response to TKI therapy are predictors of future success in achieving a lasting TFR and with improved outcomes independent of TKI cessation. Unfortunately, molecular residual disease (MRD) persists in many patients despite optimal therapy and predicts for worse outcomes over time and decreased ability to maintain a TFR after TKI cessation. Achievement of a major molecular response (MMR) and probability of TFR have been associated with increased numbers of NK cells, particularly mature cytolytic NK cells. Kiadis K-NK003 cells are off-the-shelf NK cells from a universal donor expanded using PM21, proprietary membrane particles modified to express membrane bound IL-21 and 4-1bb ligand. The resulting expanded K-NK003 cells have a hyperfunctional phenotype that are simultaneously highly cytotoxic with high release of perforin and Granzyme B, and potent producers of the cytokines IFN-γ, TNF-α and IL-2. This is an open label, non-randomized, prospective phase I pilot study designed to evaluate safety and to examine whether the addition of K-NK003 to ongoing TKI therapy for CML patients with persistent MRD will allow patients to achieve MRD negative status. Patients will be treated with K-NK003 on day 1 of each 14 day cycle, for a total of 6 cycles, in conjunction with their ongoing TKI therapy. The primary endpoint is safety. The efficacy objective is to estimate the rate of optimal molecular responses (negative to at least MR4.5). Secondary and exploratory endpoints include the proportion of patients with a reduction in BCR-ABL transcripts and NK cell number and function. Adult patients with chronic phase CML who have been on TKI therapy for at least 1 year prior to enrollment in the study will be eligible. Patients must have been on their most recent TKI consistently for at least 6 months prior to enrollment on study and must be expected to remain on current TKI for the duration of the study. Patients with current accelerated or blast crisis phase disease will be excluded. Disclosures Rein: Celgene: Consultancy; Blueprint Medicine: Consultancy; Novartis: Consultancy; Clinical Care Options: Consultancy, Other: Speaker. Rizzieri:Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; abbvie: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Interim Analysis of a Pan European Stop Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI study

Blood ◽

10.1182/blood.v124.21.151.151 ◽

2014 ◽

Vol 124 (21) ◽

pp. 151-151 ◽

Cited By ~ 16

Author(s):

Francois-Xavier Mahon ◽

Johan Richter ◽

Joelle Guilhot ◽

Martin C Muller ◽

Christian Dietz ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Interim Analysis ◽

Null Hypothesis ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Molecular Response ◽

Advisory Committees ◽

Tki Treatment

Abstract Background: The tyrosine kinase inhibitors (TKIs) have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. The option of treatment cessation has recently become of utmost importance. Indeed, prospective trials suggest that imatinib therapy may be safely and successfully discontinued in CML pts with deep and sustained molecular responses (Mahon Lancet Oncol 2010, Ross Blood 2013). The major aim of the EURO-SKI study (European Leukemia Net Stop TKI study) was to define prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims were the evaluation of harmonized methods of molecular monitoring, assessment of quality of life, and calculation of saved treatment costs per country. Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed deep molecular response (MR4, BCR-ABL <0.01%) for at least one year (>4 log reduction on TKI therapy for >12 months confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. MR4confirmation was performed in a standardized laboratory (n=6). Primary endpoint was the assessment of the duration of MR (defined by continuous MMR) after stopping TKI. Patients (pts) after a prior TKI failure were excluded. According to protocol, an interim analysis was planned after 200 patients with eligible molecular results at month (mo) 6 were available to test the null hypothesis that relapse-free survival at 6 mo is less or equal 40%. Results: From June 2012 to June 2014, 498 CML pts in chronic phase from 10 countries were enrolled and included in the trial. From June 2012 to July 2013, 254 pts from 8 countries were registered; 54 were excluded (consent withdrawal n=1, protocol violation n=1, not eligible n=34, restart of TKI without relapse n=4, atypical or unknown transcript n=6, missing data n=8). Of the eligible 200 pts, 41.5% were female. Median age at diagnosis was 53.3 years (range, 13.8 to 85.5). In assessable pts 8.7% and 18.2 % were high-risk according to EUTOS and Sokal Scores. 103 pts were treated prior to the start TKI therapy, mostly with hydroxyurea or interferon. 1st-line TKI was imatinib in 97%, dasatinib in 1.5%, and nilotinib in 1.5% of pts. Twenty-four pts switched to second-line TKI therapy due to intolerance, 16 to dasatinib, 2 to imatinib, and 6 to nilotinib. The median time from diagnosis of CML to TKI cessation was 8 years (range, 3-19 years). TKI treatment duration was less than 5 years in 16%, 5-8 years in 36% and > 8 years in 48% of pts. Median duration of TKI treatment was 8 years (range, 3-12.6 years) and median duration of MR4 before TKI cessation was 5.4 years (range, 1-11.7 years). MR4duration was less than 2 years in 8%, 2-5 years in 37%, 5-8 years in 39% and >8 years in 16% of pts. For all eligible pts, a standardized European laboratory confirmed MR4 assessment. Since 123 of the 200 pts (61.5%, 95% CI: [54.4%; 68.3%]) remained without relapse the first 6 mo, the null hypothesis could be discarded (p<0.0001). Recurrence of CML, defined as loss of MMR, was observed in 43/92 pts (47%) treated <8 years, as compared to 23/87 pts (26%) treated for >8 years (p= 0.005). So far, there was a trend for prognostic significance of MR4 duration: 33/71 pts with MR4 <5 years (46%) lost MMR within 6 mo as compared to 28/87 pts (32%) with MR4duration >5 years (p=0.07). No significant difference was observed for relapse within 6 mo according to depth of molecular response at discontinuation (MR4 vs MR4.5 vs MR5). TKI cessation was a safe procedure but a substantial proportion of pts reported transitory musculoskeletal pain starting within weeks after imatinib discontinuation. The phenomenon was described in 30% of Swedish patients as a “TKI withdrawal syndrome” (Richter JCO 2014). Taking into account the cost of imatinib in Europe and time without treatment in the total study population at the most recent analysis, total savings for the community within the EURO-SKI trial were estimated at 7 million Euros. Conclusion: Employing a standardized molecular testing for patient selection within a TKI cessation trial in CML the chance to stay in treatment-free remission could be higher than previously reported. The EURO-SKI trial will further elucidate the prognostic factors but the preliminary results confirm (as reported in the STIM Study) the prognostic impact of the duration of TKI therapy before stopping. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BRISTOL MYERS SQUIBB: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria; PFIZER: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Hjorth-Hansen:Novartis: Honoraria; Bristol-myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Almeida:Celgene: Consultancy; Novartis: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyer Squibb: Membership on an entity's Board of Directors or advisory committees. Berger:Genzyme/Sanofi and Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other.

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Factors Predicting Intentional Non-Adherence In Chronic Myeloid Leukemia: A Multivariate Analysis On 2546 Patients By The CML Advocates Network

Blood ◽

10.1182/blood.v122.21.4023.4023 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4023-4023 ◽

Cited By ~ 1

Author(s):

Jan Geissler ◽

Fabio Efficace ◽

Felice Bombaci ◽

Jan de Jong ◽

Anthony Michael Gavin ◽

...

Keyword(s):

Multivariate Analysis ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Univariate Analysis ◽

Significant Proportion ◽

First Line ◽

Advisory Committees ◽

Significant Difference ◽

The Impact

Abstract Background Adherence to the prescribed dose of tyrosine kinase inhibitors (TKIs) is critical to maximize treatment effectiveness in chronic myeloid leukemia (CML). While patient-centered outcome studies are lacking in this area, literature has shown that a significant proportion of patients report both intentional and unintentional non-adherence. Objective The main objective of this multivariate analysis was to identify risk factors that might predict intentional non-adherence to TKIs in CML. Methods The CML Advocates Network, connecting 79 CML patient groups from 63 countries, conducted an international project investigating patterns of medication-taking behaviors of CML patients, supported by CML investigator groups in Germany, Italy and France. We sought to demonstrate the relationship between 16 factors and adherence in this multinational cohort. A web-based survey was launched in 12 languages, enrolling CML patients from Sept 2012 to Jan 2013. The identical questionnaire was provided to a cohort of patients recruited in clinics in France, Germany and Italy, returned by patients in a pre-stamped envelope to an independent data center. Questions included potential factors associated with non-adherence as well as on patients' perception of disease and treatment burden. Based on previous literature and on clinical relevance, a pool of 16 candidate factors, potentially predicting intentional non-adherence, was selected for analysis. These included: frequency of CML medication, co-payment for CML treatment, and current TKI therapy. Patients who reported having skipped intentionally one or more doses over the last year were considered as “intentional non-adherers”. Univariate logistic regression analysis was performed to examine the impact of pre-selected candidate factors on the probability of intentional non-adherence. Two multivariate models were fitted based on line of therapy received by patients (i.e. first line and second or greater lines of therapy). Results This patient-led study is the largest study conducted to date on the influencers of non-adherence in CML. Overall, 2546 adult CML patients (47.6% female) under TKI treatment from 79 countries responded to the survey. 2151 patients responded online, 395 questionnaires were returned on paper. No significant difference on intentional non-adherence was observed between paper or online responses. Median age of patients was 51 years (range 18-96) and median time from diagnosis was 4 years (0-27). Overall, 51.6% of all respondents reported having missed at least one dose unintentionally over the last year, and 19.5% did so intentionally. This analysis regards the intentional non-adherent population (n=490). Of those, 60% were on imatinib, 20% on nilotinib, 14% on dasatinib, 6% on other TKIs. Several factors predicted intentional non-adherence in univariate analysis, including education level (P=0.016) and co-payment for TKIs (P=0.005). For patients on first line TKI (n=1551), the following factors independently predicted a higher likelihood of being intentional non-adherers: younger age (P=0.015), longer time since diagnosis (P<0.001), lower satisfaction with information received from healthcare providers (P=0.002), higher burden on social life (P<0.001) and not being fully informed on the importance of adherence (P=0.042). Non-adherence was lower when patients were told every dose was important to make the treatment work (P=0.042). Overall, intentional non-adherers intended to avoid fatigue (13%), diarrhea and GI issues (11%), nausea (10%) and muscle pain (9%). For patients in second or greater lines of therapy (n=985) all of the above factors were still statistically significant except for satisfaction with information received. Being female (P<0.001) also increased the likelihood of intentional non-adherence in this group. Discussion Despite there is clear evidence that survival is close to that of the general population when CML is treated effectively in chronic phase with current therapies, every fifth CML patient deliberately skips doses. Key factors predicting intentional non-adherence can potentially help physicians and patient organisations to identify patients early who should be monitored more closely and informed about the importance of adherence. Managing side effects proactively also reduces reasons for intentional non-adherence. Disclosures: Geissler: Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Efficace:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Bombaci:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. de Jong:Novartis: Membership on an entity’s Board of Directors or advisory committees. Gavin:Celgene: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Daban:Ariad: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Pelouchová:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Sharf:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees.

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The Genomic and Epigenomic Landscapes of Blast Crisis Transformation in Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.3737.3737 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3737-3737 ◽

Cited By ~ 3

Author(s):

S. Tiong Ong ◽

Thushangi Pathiraja ◽

Asif Javed ◽

Xin Xuan Sheila Soh ◽

Simeen Malik ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Candidate Genes ◽

Myeloid Leukemia ◽

Research Funding ◽

Blast Crisis ◽

Advisory Committees ◽

Cpg Sites

Abstract The transition from chronic phase (CP) to blast crisis (BC) chronic myeloid leukemia (CML) is characterized by reprogramming of the CML transcriptome (Radich et al. PNAS 2006), and shortened survival. Current models propose genomic instability as causal in BC transformation with enhanced DNA damage and impaired DNA repair inducing genetic mutations (ranging from large chromosomal aberrations to point mutations), altered gene function, and eventually BC transformation (Perrotti et al. JCI 2010). Consistent with this model are the phenomena of BC clonal evolution, and the increased frequency of ABL kinase domain mutations found in BC. Because different mutational processes are associated with distinct cancer-specific mutation signatures (Alexandrov et al. Nature 2013), this model also predicts the existence of a CML-specific mutation signature. In addition, recent work has highlighted the importance of epigenetic alterations in hematologic malignancies (Shih et al., Nat. Rev. Cancer, 2012). However, we lack a complete understanding of the type or frequency of genetic alterations in BC, and the relative contribution of genetic vs. epigenetic events in reprogramming the BC transcriptome. To address these knowledge gaps, we analyzed the CML progression genome, epigenome, and transcriptome in 12 CP/BC sample pairs. Whole-genome sequencing revealed the CML genome to be relatively stable with respect to structural variations, indels, and somatic single nucleotide variants. The average number of nonsynonymous coding mutations per BC genome was 5, placing the BC coding genome in the same mutation frequency range as AML and ALL genomes (Alexandrov et al. Nature 2013). In addition, we identified a novel mutation signature in all CML samples suggesting a CML-specific mutational process. 1175 genes were 'hit' by genomic, mostly copy number, alterations in >1 sample, and included TCR genes and Ikaros (IKZF1) among lymphoid BC pairs. Only 21 recurrently altered genes were affected by somatic SNVs or indels, with resistance-associated ABL1 mutations being commonest. We next used DNA methylation arrays to assess the BC epigenome, and found 20,651 CpG sites (out of 455,187) to be hyper-methylated, and 3225 to be hypo-methylated in BC compared to CP. Combined methylome and transcriptome analysis demonstrated an inverse relationship between methylation and expression changes at a subset of CpG sites enriched at promoters. Genes with increased methylation/decreased expression or decreased methylation/increased expression included those involved in cell cycle control/heme biosynthesis, and molecular mechanisms of cancer/G-protein coupled receptor signaling/MAPK signaling respectively. Unsupervised methylation-based clustering segregated samples into CP, lymphoid BC and myeloid BC groups, recapitulating expression-based clustering, and further supporting a functional role for DNA methylation in BC transcriptional reprogramming. We next performed an integrative analysis by combining the genome, methylome, and transcriptome datasets, and included data from 34 additional CML samples. Top ranking candidate genes included epigenetic modifiers, and hematopoetic differentiation- and stem cell-related genes. Functional analysis of candidate genes and epigenetic processes using genetic and epigenetic drug-based approaches are ongoing. In summary, we conclude that: 1. The genomic and epigenomic landscapes in BC are characterized by a modest number of recurring events in the former, but consistent and striking differences in the latter, 2. The BC methylome is functionally associated with the robust gene expression changes found in BC, and 3. Epigenetic modifier drugs may be of use in reversing the gene expression changes characteristic of BC. Disclosures Chuah: Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Takahashi:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Masis: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau.

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Generic Versus Branded Imatinib As Frontline Therapy in Chronic-Phase Chronic Myeloid Leukemia Patients in Italy: A Case-Control Study

Blood ◽

10.1182/blood-2019-131272 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5909-5909

Author(s):

Massimiliano Bonifacio ◽

Mario Tiribelli ◽

Gianni Binotto ◽

Maria Cristina Miggiano ◽

Marco Basso ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Historical Cohort ◽

Molecular Responses ◽

Sokal Score

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis. Aims. To analyze the rates of molecular responses at 3, 6 and 12 months and of treatment discontinuation in CML patients treated frontline with generic imatinib, compared to a case-matched historical cohort of CML patients who received frontline branded imatinib at our institutions. Methods. We analyzed 31 newly diagnosed CP-CML patients consecutively enrolled in a prospective observational registry between January 2017 and July 2018, treated frontline with generic imatinib 400 mg/day (diverse manufacturers) and evaluable for all the ELN2013 molecular milestones (if not discontinued earlier). They were compared to a retrospective cohort of 31 patients, matched for age, gender, and Sokal risk, diagnosed between 2007 and 2014 and treated with branded imatinib 400 mg/day for at least 24 months before eventual switching to a generic formulation. Definitions of molecular responses were made according to the ELN2013 recommendations. Results. A total of 62 patients were included in the analysis: 31 patients (21 males and 10 females) treated with generic imatinib ("cases") and 31 treated with branded imatinib ("controls"). Median age at diagnosis of the cases was 68 years (range 33-89), Sokal score was low/intermediate/high in 8 (26%), 19 (61%) and 4 (13%) patients, respectively. The controls were matched for gender, age (+/- 4 years, median age 68, range 35-85) and Sokal score. As median follow-up time for the cases was 18.6 months (range 2.2-28.5), controls were censored at 24 months after imatinib start. Optimal molecular response at 3 months was attained in 23/30 (76.7%) cases and in 18/29 (62%) controls (p=0.35); one case died after 2 months of imatinib therapy for a CML-unrelated cause, while 2 controls were molecularly not evaluable. At 6 months, 17/29 (58.6%) cases and 17/30 (56.7%) controls achieved BCR/ABL transcript <1%, respectively (p=1). At 12 months, MMR was attained by 14/30 (46.7%) cases and by 13/29 (44.8%) controls (p=1). Twelve out of 31 patients (38.7%) permanently discontinued generic imatinib due to warning/failure response (n=6), intolerance (n=4) or death while on treatment at 2 and 13 months (meningoencephalitis of unknown origin and cardiovascular event, respectively). Among patients treated with branded imatinib, 12/31 (38.7%) stopped within the 24th month of therapy for resistance (n=8), intolerance (n=3) or death at 16 months (acute renal failure). No patient receiving generic imatinib progressed to advanced phase, while one control developed a blast crisis at 6 months of branded imatinib and deceased shortly after. Estimated overall survival at 24 months in cases and controls was 92.5% and 93.1%, respectively. Conclusions. Our preliminary data suggest an equivalent efficacy of generic imatinib compared to a matched population of historical patients treated with the originator drug in Italy. A continue pharmacovigilance by reporting efficacy and safety outcomes of generic drugs is needed to ensure an optimal management of CML patients. Disclosures Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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