scholarly journals Polycythemia Vera Patients Respond Better to Ropeginterferon Alfa-2b Than HU/BAT Irrespective of Pretreatment or Mutational Status; Results from 5 Years' Treatment in a Randomized, Controlled Setting in the PROUD-PV/Continuation-PV Trials

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3660-3660
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Chromosomal Aberrations ◽  
Research Funding ◽  
Response Rates ◽  
Driver Mutations ◽  
Molecular Response ◽  
Advisory Committees ◽  
Allele Burden ◽  
Mutational Status ◽  
Jak2v617f Allele Burden

Abstract Introduction: Ropeginterferon alfa-2b (BESREMi®), a novel pegylated interferon with an extended half-life, was approved in Europe for treatment of patients with PV based on results from the phase 3 PROUD-PV and CONTINUATION-PV trials. Ropeginterferon alfa-2b treatment is recommended in hydroxyurea (HU) naïve patients as well as in those who have previously received HU. Therefore, treatment response was analyzed by prior HU treatment status, and the influence of baseline JAK2V617F allele burden and additional mutations - which may increase over time during non-disease modifying treatment - was explored. Methods: In PROUD-PV, patients aged ≥18 years, diagnosed with PV according to WHO 2008 criteria, and either cytoreduction-naïve or HU-pre-treated (for <3 years, without intolerance or resistance) were randomized 1:1 to receive ropeg or HU at individualized doses. After 12 months' treatment, patients could roll over into CONTINUATION-PV and patients in the HU arm were permitted to switch to best available treatment (BAT). After 5 years' treatment, complete hematologic response (CHR) and molecular response defined by modified ELN criteria were assessed in patients enrolled in the extension study CONTINUATION-PV (N=171). Sub-group analyses were performed by prior HU treatment, JAK2V617F allele burden category (≤50% or>50%), and in patients with available data (N=159), by the presence of non-driver mutations (TruSight™ Myeloid Panel, Illumina) or chromosomal aberrations (Affymetrix SNP6.0 array) at baseline. Results: After 5 years of treatment with ropeginterferon alfa-2b, high rates of CHR were sustained in both HU-naïve and HU pre-treated patients (53.1% and 61.3%, respectively), whereas in the control arm, the CHR rate was lower among HU pre-treated patients (36.0% compared to 48.0% for HU-naïve patients). Molecular response rates at 5 years in HU naïve and pre-treated patients were 71.4% and 64.5% respectively in the ropeginterferon alfa-2b arm and 26.0% versus 12.5% respectively in the control arm. Rates of adverse events (AEs), treatment-related AEs, serious AEs, and AEs leading to discontinuation were similar between the subgroups regardless of HU pre-treatment. Similar CHR rates were observed at 5 years irrespective of baseline JAK2V617F allele burden category (ropeginterferon alfa-2b arm: 57.1% versus 53.1% for allele burden ≤50% or >50%, respectively; control: 46.9% versus 38.5%, respectively). The molecular response rate in the ropeginterferon alfa-2b arm was higher among patients with baseline allele burden >50% (84.4% versus 61.3% for allele burden ≤50%); in the control arm there was no difference in molecular response rates between the allele burden subgroups (23.1% versus 20.8%, respectively). Of interest, the presence of non-driver mutations or chromosomal aberrations at baseline had no apparent influence on molecular response rates to ropeginterferon alfa-2b (64.5% compared with 70.7% in patients without these genetic abnormalities). Conclusion: High hematologic and molecular response rates in both HU-pretreated and HU-naïve patients and in those with more advanced JAK2V617F burden suggest that ropeginterferon alfa-2b is also a suitable treatment option in patients switching from HU. Disclosures Gisslinger: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees, Research Funding; Novartis: Other: Personal fees, Research Funding; PharmaEssentia: Other: Personal fees; MyeloPro Diagnostics and Research: Other: Personal fees; Janssen-Cilag: Other: Personal fees; Roche: Other: Personal fees; Celgene: Other: Personal fees. Klade: AOP Orphan Pharmaceuticals GmbH: Current Employment. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. Mayer: AOP Orphan Pharmaceuticals GmbH: Research Funding. Krejcy: AOP Orphan Pharmaceuticals GmbH: Current Employment. Empson: AOP Orphan Pharmaceuticals GmbH: Current Employment. Hasselbalch: Novartis, AOP Orphan: Consultancy, Other: Advisory Board. Kralovics: AOP Orphan Pharmaceuticals GmbH: Other: Personal fees; PharmaEssentia: Other: Personal fees; Qiagen: Other: Personal fees; Novartis: Other: Personal fees; MyeloPro Diagnostics and Research: Current holder of individual stocks in a privately-held company. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: 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; PharmaEssentia: Other: Personal fees; Taiho Oncology, Inc.: Research Funding.

scholarly journals Treatment of Ropeginterferon Alpha-2b Achieves Hematologic Remission and Molecular Response in Patients with Hydroxyurea- and/or Anagrelide-Resistant/Intolerant Myeloproliferative Neoplasms

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4631-4631
Author(s):  
Chih-Cheng Chen ◽  
Ming-Chung Kuo ◽  
Yi-Jiun Su ◽  
Cih-En Huang ◽  
Chia-Chen Hsu ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Myeloproliferative Neoplasms ◽  
White Blood Cells ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Allele Burden ◽  
Jak2v617f Allele Burden

Abstract Background: Ropeginterferon alpha-2b (Ropeg) is a novel pegylated interferon-alpha approved for the treatment of polycythemia vera (PV) in Europe and Taiwan. Prior to its approval in Taiwan, the major options for patients with myeloproliferative neoplasms (MPNs) included hydroxyurea (HU) and/or anagrelide. Patients who are HU/anagrelide resistant/intolerant have limited options, as ruxolitinib is not subsidized by the national health insurance in Taiwan for PV. In 2017, the manufacturer provided a compassionate use program (CUP) for patients who were HU and/or anagrelide resistant/intolerant. Herein, we assessed the efficacy and safety of Ropeg in 20 MPN patients. Methods: To be eligible, patients must be resistant or intolerant to currently available therapies for MPN in Taiwan, mainly HU and anagrelide. Patients with autoimmune disorders, psychiatric illness, and acute/chronic infections were excluded. An accelerated dosing regimen was used, starting from 250 µg, and increased by 100 µg every two weeks until it reached the target dose of 500 µg, if no self-reported discomforts or abnormalities in biochemical or hematological profiles were observed. Efficacy assessments included hematologic parameters, phlebotomy need, and JAK2V617F allele burden. Hematologic remission was defined as platelets ≤400 x 10^9/L and white blood cells <9.5 x 10^9/L for essential thrombocythemia (ET), and platelets ≤400 x 10^9/L, white blood cells <10 x 10^9/L, and hematocrit <45% with no phlebotomy in the past 3 months for PV. Molecular response was defined as a reduction in JAK2V617F allele burden of at least 50% from baseline if baseline value was less than 50%, and a reduction of at least 25% from baseline if the baseline level was at least 50%. Each case was independently reviewed and approved for the use of Ropeg by both Institutional Review Board and the Ministry of Health and Welfare in Taiwan. Results: A total of 20 patients received treatment, which included 14 PV, 4 ET, 1 post-ET myelofibrosis (MF), and 1 pre-fibrotic primary MF (Table 1). There were 12 female and 8 male patients with a median age of 56.1 years old. Of these 20 patients, 18 had JAK2V617F mutation and 5 had a history of thrombosis. Of the 18 ET and PV patients, 13 achieved hematologic remission. The ET patients seemed to achieve hematologic remission faster than PV patients (19.3 vs. 33.2 weeks). Of the 18 patients with JAK2V617F mutation, 7 PV patients and 1 post-ET MF patient achieved molecular response, which took a median of 46 weeks after Ropeg treatment. Reduction in JAK2V617F allele burden was observed in 12 patients. One MF patient discontinued treatment due to disease progression. Another PV patient discontinued treatment due to acute myeloid leukemia transformation, although after treatment, the patient returned to PV state and continued Ropeg treatment. Overall, the drug was well tolerated, as most of the treatment-related adverse events (AEs) were mild to moderate. The AE profile was consistent with those from the phase 3 PROUD/CONTI-PV study. There were no unbearable side effects that led to treatment discontinuation. Conclusion: Our study provided evidence in the efficacy and safety of Ropeg for the treatment of HU-/anagrelide-resistant/intolerant MPNs. Hematologic remission was observed in ET and PV patients, whereas molecular response was observed in only PV patients, possibly due to the small sample size of ET patients. Our experience with Ropeg suggests it to be a promising option for the treatment of MPNs with drug-resistance/intolerance. Figure 1 Figure 1. Disclosures Chen: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen, Celgene, Novartis, and Panco Healthcare: Honoraria. Shih: PharmaEssentia Co: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Ltd: Research Funding; Ltd: Research Funding; Novartis: Research Funding. OffLabel Disclosure: Ropeginterferon alfa-2b is a novel interferon alpha indicated for the treatment of polycythemia vera in Europe and in Taiwan. This abstract describes the use of this agent for the treatment of myeloproliferative neoplasm patients with hydroxyurea/anagrelide resistance/intolerance.

scholarly journals Molecular Characterisation of Participants in the Phazar Trial Reveals Prognostic Impact of Mutations in Advanced-Phase-MPN

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Charlotte K Brierley ◽  
Alba Rodriguez-Meira ◽  
Matthew Bashton ◽  
Angela Hamblin ◽  
Rachel S Fletcher ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Chromosomal Aberrations ◽  
Research Funding ◽  
Poor Prognosis ◽  
Clonal Evolution ◽  
Molecular Profiling ◽  
Driver Mutation ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Advanced Phase

Advanced phase myeloproliferative neoplasms (AP-MPN) are associated with a very poor prognosis. The Phase Ib PHAZAR study set out to assess the safety & tolerability of oral ruxolitinib (RUX) in combination with 5-azaciditine (AZA) in patients (pts) with advanced-phase-MPN, defined as blast count >10%. The study included an observational arm for pts not suitable for the trial intervention. The clinical results of this study are presented in a separate abstract. Here we evaluate the molecular characteristics of PHAZAR pts and correlate with clinical features, outcome and therapy response. Driver mutation (JAK2/CALR/MPL) allele burdens were quantified using targeted next-generation sequencing (NGS) and non-driver mutation analysis was performed using an ISO accredited Illumina TruSeq Custom Amplicon Panel, including 32 gene mutation hotspots & exons (~36,000 bp, 287 amplicons). SNP karyotyping was performed using the Illumina InfiniumOmniExpress-24v1-3 BeadChip assay. Data analysis was performed using R v4.0. Clinical data were censored in February 2020, and NGS sequencing data were available for 24 interventional trial and 13 observational cohort participants. 11/13 observational pts received best supportive care, while 2/13 were treated with high-dose chemotherapy. All pts had a mutation in ≥1 targeted gene. 16% of pts were 'triple-negative' for MPN driver mutations, while 59%, 16% & 8% carried canonical mutations in JAK2, CALR & MPL respectively. 89% carried additional non-driver mutations, with a median of 2 (range 0-4) detected per pt (Fig 1A). Mutations in epigenetic regulators were detected in 21/37 pts (57%) (TET2, 38%; EZH2, 19%; ASXL1, 14%; PHF6, 5%; SETBP1, 3%) while 8/37 (22%) carried mutually exclusive spliceosomal mutations (SRSF2, 8%; U2AF1, 8%; SF3B1, 5%). 10/37 (27%) were TP53 mutant. High molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2, TP53, U2AF1 Q157) were detected in 24/37 (65%), and >1 HMR mutation in 7/37 (19%). SNP karyotyping data were available for 42 pts (n=29 interventional, n=13 observational). 4/42 (10%) were wild-type, while 90% harboured >=1 chromosomal aberrations (median 4, range 0-16). Of these, 21 were recurrent in 3+ samples. 9 frequently recurrent events in >=5 samples included gains at 1q, 3q26, 17q21and losses of 5q, 6q12, 17p13, 19q13, 20q, and multiple losses and gains on chromosome 21q. 5 pts demonstrated evidence of chromothripsis. The presence of TP53 mutation was associated with a higher number of chromosomal aberrations (median of 3 vs 6.5, p=0.02). Concerning clinical correlation, baseline driver mutation status did not impact on OS nor likelihood of achieving a durable response (DR, defined as having achieved a minimum of 6 months of complete or partial remission or stable disease as per published criteria (Cheson Blood 2006, Mascarenhas Leuk Res 2012)). The presence of >=3 additional mutations significantly impaired OS regardless of trial arm (1 yr OS 12% vs 55%, p=0.02), as did the presence of HMR mutations (1 yr OS 22% vs 73%, p=0.008) and TP53 mutations in isolation (1 yr OS 13% vs 55%, p=0.05). The presence of HMR mutations reduced the likelihood of achieving a DR (p=0.02). Pts with losses of >=1 chromosomal arms (other than 5q-) had a poor prognosis (1yr OS 27% vs 58%, p=0.05), while no pt with chromothripsis (n=5) survived to a year (1yr OS 0% vs 53%, p=0.002). Mutational profiling of serial samples on therapy were available for 5 pts who achieved a remission during AZA and RUX therapy. One pt achieved a CMR but developed clonal evolution and emergence of a new ETV6 mutant clone at relapse. The other 4 cases demonstrated no change in clonal abundance during remission. This supports the hypothesis that response to AZA is mediated by alteration of subclonal contributions or prevention of further clonal evolution, rather than elimination of founder clones. AP-MPN continues to confer a very poor prognosis and more effective therapies are urgently required. Genetic and molecular profiling of this prospective trial cohort demonstrates the high mutational burden and structural variants seen in this disease. Initial serial sample profiling demonstrates that molecular responses to AZA and RUX are rare and, where they occur, are not sustained. Incorporation of molecular profiling into trial design may help inform which patients are more likely to benefit from the intervention - e.g. those without evidence of chromothripsis at trial entry. Disclosures Harrison: Gilead Sciences: Honoraria, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Incyte Corporation: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria. Drummond:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: 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, Speakers Bureau; Blueprint Medicine Corporation: Research Funding. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mead:Gilead: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Celgene/BMS: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau.

Clinical, Metabolic and Molecular Responses After 4 Courses of R-DHAP and After Autologous Stem Cell Transplantation for Untreated Mantle Cell Lymphoma Patients Included in the LyMa Trial, a Lysa Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 152-152 ◽  
Author(s):  
Steven Le Gouill ◽  
Mary Callanan ◽  
Elizabeth Macintyre ◽  
marie-Hélène delfau-Larue ◽  
Caroline bodet-Milin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Response Rates ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Abstract 152 Mantle cell lymphoma (MCL) is a rare B-cell malignancy characterized by the t(11;14) translocation. The European MCL network has demonstrated that a sequential R-CHOP/R-DHAP chemotherapy regimen prior to autologous stem cell transplantation (ASCT) provides better disease control than R-CHOP (Hermine et al, ASH 2010, abstract 110) and that molecular minimal residual disease (MRD) measured by IGH real-time quantitative polymerase chain reaction (PCR) before and after ASCT is an important prognostic factor to predict progression-free survival (PFS) (Pott et al. Blood. 2010;115(16):3215–23). Indeed, the use of high-dose aracytine upfront before ASCT is now recommended and molecular remission appears to be a major objective for future clinical trials in MCL. It therefore appeared interesting to appreciate response rates combining standard evaluation (Cheson 1999), FDG-PET imaging (Cheson 2007) and PCR techniques after rituximab plus upfront high-dose aracytine (R-DHAP) followed by ASCT. Response rates after 4 courses of R-DHAP were one of the objectives of the LyMa trial (NCT00921414). This trial is a randomized, open-label, phase III study that evaluates the efficacy of rituximab maintenance therapy in MCL patients aged between 18 and 66 years old, undergoing first-line treatment with 4xR-DHAP and exhibiting a response after ASCT (R-BEAM). Patients who do not reach a sufficient partial remission after R-DHAP are planned to receive 4 additional courses of R-CHOP before ASCT. The LyMa trial started in September 2008 and was designed to enroll 299 patients over a 4 years period. To date (August 2012), 295 patients have been included. Herein, we report response rates according to the combination of Cheson 1999 and 2007 criteria plus molecular response rates after 4xR-DHAP and after ASCT for the first 200 enrolled patients (last inclusion in August 2011). Results: One patient withdrew consent and the analysis is therefore on 199 patients. The cohort's median age is 57.2 years (range 29.7–65.7) and 41 patients are female (20%). At diagnosis, simplified MIPI was low in 104 cases (52%), intermediate in 55 (28%) and high in 40 (20%).Twenty-five patients (12.5%) presented with a blastoid variant. The panel of pathologist experts confirmed the diagnosis in all reviewed cases. Among the 199 evaluable patients, 182 (91%) received 4 courses of R-DHAP and 12 patients (all in PR according to Cheson 99 criteria) received 4 additional courses of R-CHOP because of insufficient clinical response after R-DHAP. Among these 12 patients, 5 reached CR/CRu after R-CHOP. Ultimately, 164 patients (82%) proceeded to ASCT (158 after R-DHAP and 6 after RDHAP/R-CHOP) and 154 (77.4%) have been randomized between rituximab maintenance or no maintenance. In an intention-to-treat (ITT) analysis and according to Cheson 1999 criteria, 152 patients (76.3%) reached CR (n=74) or CRu (n=78) after 4 courses of R-DHAP while 25 patients reached PR and 8 presented with SD/Prog. According to Cheson 2007 criteria (n= 170; PET not done in 17 cases and data missing in 12 cases), 129 patients reached CR while 41 patients remained FDG-TEP positive. Response rates according to Cheson 1999 and 2007 criteria for transplanted patients (n=164) were CR (n=109)/CRu (n=45) in 94% and CR in 84.5% (129 patients underwent FDG-PET after ASCT), respectively. Regarding MRD, diagnosis samples were available for 186/199 patients. Forty-one diagnosis samples have not yet been analyzed and 14 proved to be not informative. To date, the molecular response on peripheral blood (PB) after 4 courses of R-DHAP has been assessed in 103 cases and found negative in 80 cases and positive in 22 cases (not evaluable in one case). MRD on bone marrow (BM) after 4 courses of R-DHAP has been measured in 97 cases and found negative in 59 and positive in 36 (not evaluable in one case). After ASCT, PB and BM MRD were found negative in 91 patients (95 samples have been analyzed to date) and 67 (87 samples analyzed), respectively. Thus, in the LyMa trial,CR/CRu rates after only 4 courses of RDHAP, according to Cheson 1999 and 2007 criteria, are very high confirming the major anti-tumoral impact of high-dose aracytine upfront in MCL. In addition, these encouraging results seem to be confirmed at the molecular level strengthening the interest of an MRD-guided management of MCL patients. Results will be updated at the time of the meeting and patients' outcome according to disease status will be presented. Disclosures: Ribrag: Servier: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Sanofi-Aventis: Research Funding; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Long-Term Use of Ropeginterferon Alpha-2b in Polycythemia Vera: 5-Year Results from a Randomized Controlled Study and Its Extension

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-33
Author(s):  
Heinz Gisslinger ◽  
Christoph Klade ◽  
Pencho Georgiev ◽  
Dorota Krochmalczyk ◽  
Liana Gercheva-Kyuchukova ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Extension Study ◽  
Molecular Response ◽  
Thromboembolic Events ◽  
Advisory Committees ◽  
Allele Burden ◽  
Long Term Treatment

Introduction: Patients with polycythemia vera (PV) require life-long treatment to prevent thromboembolic events and minimize the risk of progression. Ropeginterferon alpha-2b (BESREMi®; hereafter ropeg) may ultimately modify the natural history of PV by selectively targeting the malignant clone. In the PROUD-PV/CONTINUATION-PV studies, long-term treatment with ropeg was compared with standard cytoreductive therapy regarding thromboembolic and other adverse events as well as evolution of hematologic and molecular parameters over five years. Methods: Patients aged ≥18 years and diagnosed with PV according to WHO 2008 criteria who were either cytoreduction-naïve or hydroxyurea (HU)-pre-treated for < 3 years were enrolled. A total of 257 patients were randomized 1:1 (stratified by age > 60 years, prior thromboembolic events, and HU pre-treatment) to receive ropeg or HU at individualized doses for 12 months in the initial study (PROUD-PV). In the extension study (CONTINUATION-PV), patients in the HU arm were permitted to switch to best available treatment. Efficacy assessments included hematologic parameters, phlebotomy need, JAK2V617F allele burden, and molecular response defined by modified ELN criteria. An interim analysis was conducted once all patients reached 5 years of treatment; efficacy data for patients enrolled in the extension study and all available safety data were analyzed. Results: Ninety-five patients in the ropeg arm and 76 in the control arm entered the extension study. Most patients in the control arm continued to receive HU (88% at month 60). At the time of this 5-year analysis, 70 patients in the ropeg arm and 57 in the control arm remained on study; discontinuation rates were balanced between the treatment arms (ropeg: 26.3%; control: 25.0%). Hematocrit <45% was maintained without the need for phlebotomy in 81.8% patients in the ropeg arm in the fifth year of treatment, which was significantly higher than the rate of 63.2% observed in the control group (p=0.01). Very few patients experienced a major thromboembolic adverse event (4.2% [1.2%-patient year] of patients in the ropeg arm and 6.6% [1.2%-patient-year] of patients in the control arm during the entire treatment period). With respect to the causative JAK2V617F mutation, the median allele burden declined from 37.3% at baseline to 7.3% over 5 years of treatment in the ropeg arm, whereas in the control arm the median allele burden increased from 38.1% to 42.6% in the same period (p<0.0001). The rate of molecular response at 5 years was also significantly higher among ropeg-treated patients than in the control arm (69.1% versus 21.6%; RR: 3.2 [95% CI: 2.1 to 4.9; p<0.0001]). The sustained molecular response observed in ropeg-treated patients was accompanied by a low risk of disease progression; only 1 case of progression to myelofibrosis (0.20%-patient year) was reported during the entire study period and no leukemic transformation occurred. In contrast, 2 cases of progression to myelofibrosis and 2 cases of transformation to acute leukemia (1.0%-patient year in total) were reported in the control arm. A further analysis of combined hematologic and molecular parameters was performed, these being known to influence the risk of thrombosis and of progression in PV. At the 5 year visit, 58.5% of patients receiving ropeg had well-controlled hematocrit (<45%) without requiring phlebotomy, as well as achieving a molecular response, compared to 17.3% on standard treatment (RR: 3.52 [2.13 to 5.81]; p<0.0001). Regarding safety and tolerability, no new signals were detected in the fifth year. Treatment related adverse events were reported in 25.6% and 24.2% of patients in the ropeg and control arms, respectively, and one patient in each arm withdrew due to drug-related toxicity. Three patients (3.8%) in the ropeg arm reported grade ≥3 treatment-related adverse events in the fifth year; over the entire treatment period, the rate of grade ≥3 drug-related adverse events was the same in each study arm (16.5%). Conclusions: In a randomized controlled setting, ropeg treatment effectively controlled hematocrit and minimized the occurrence of thromboembolic events in patients with PV. Disease progression was very rare during long-term treatment with ropeg and this possible change in the disease natural history appears to be related to deep and durable molecular responses selectively achieved with ropeg. Disclosures Gisslinger: AOP Orphan Pharmaceuticals AG: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; PharmaEssentia: Honoraria; MyeloPro Diagnostics and Research: Honoraria; Janssen-Cilag: Honoraria; Roche: Honoraria; Celgene: Honoraria. Klade:AOP Orphan Pharmaceuticals AG: Current Employment. Illés:Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Celgene, Janssen, Novartis,Roche, Takeda: Consultancy. Mayer:Celgene: Research Funding. Krejcy:AOP Orphan Pharmaceuticals AG: Current Employment. Empson:AOP Orphan Pharmaceuticals AG: Current Employment. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals AG: Honoraria. Kralovics:AOP Orphan Pharmaceuticals AG: Honoraria; Qiagen: Honoraria; Novartis: Honoraria; MyeloPro Diagnostics and Research: Current equity holder in private company; PharmaEssentia: Honoraria. Kiladjian: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; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Impact of IgVH Gene Mutational Status and VH Family Usage on Chromosomal Aberrations Detected by High-Resolution Array-CGH in B-CLL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1246-1246
Author(s):  
Jose F Leis ◽  
Esteban Braggio ◽  
Scott Van Wier ◽  
Jonathan J Keats ◽  
Diane F. Jelinek ◽  
...  
Keyword(s):  
Standard Deviation ◽  
High Resolution ◽  
Board Of Directors ◽  
Chromosomal Aberrations ◽  
Copy Number ◽  
Research Funding ◽  
Median Number ◽  
Advisory Committees ◽  
Mutational Status ◽  
Genomic Aberrations

Abstract Abstract 1246 Poster Board I-268 B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a variable clinical course. Genomic aberrations as detected by FISH analysis and the mutational status of the IgVH genes have been found to have prognostic clinical significance with unmutated IgVH genes associated with clinically more aggressive disease. Previous studies have suggested that unmutated IgVH B-CLL is associated with increased chromosomal instability and increased chromosomal aberrations leading to accelerated disease progression. We recently performed a high-throughput, high-resolution array-based comparative genomic hybridization (aCGH) in a cohort of B-CLL patients. Fifty-eight patients have been analyzed by using the Sureprint G3 microarray (one million probes, Agilent). Our working hypothesis was that we would see increased genomic aberrations and instability in the unmutated IgVH group. The total number of copy number aberrations and total megabases (Mb) deleted or gained per genome were used as a surrogate marker for genomic instability. Variations in chromosomal aberrations in various VH families were also evaluated. B-CLL with unmutated IgVH genes utilized members of the VH1, VH3, VH4 and VH5 families with VH1-69 the most prevalent. B-CLL with mutated IgVH genes utilized VH families VH1, VH2, VH3, VH4, and VH6. Considerable variation was seen in the number of genomic abnormalities between cases. Overall, 315 abnormalities have been identified (236 deletions and 79 gains), with a median of 4 copy-number abnormalities per patient (range 0-32). In patients with IgVH mutational status available the median number of chromosomal aberrations in the mutated group was 5 (range 1-17) and unmutated group was 4 (range 0-20). Copy number deletions were significantly more common than chromosomal gains for the total group and in both the unmutated and mutated IgVH gene groups. Mean number of megabases (Mb) of DNA deleted in the unmutated IgVH group was 17.80Mb (standard deviation 24.17 Mb, median 6.63 Mb, range 0 - 90.55Mb) and 40.65 Mb in the mutated IgVH group (standard deviation 86.04 Mb, median 15.35Mb, range 0 – 307.57Mb). Mean number of Mb gained in the unmutated group was 37.74Mb (standard deviation 57.58Mb, median 0.44Mb, range 0 – 132.47Mb) and 32.99Mb (standard deviation 59.76Mb, median 0.14Mb, range 0 – 172.50Mb) in the mutated group. Nine patients had B-CLL with VH1-69 genes and 8 of them were unmutated. Median number of chromosomal deletions was 2 and gains also 2 (ranges 0 – 8 deletions and 0 – 4 gains) for this group. Similar findings were seen for the other VH families. These results initially suggest that total copy number variations do not account for the observed clinical differences between mutated and unmutated IgVH B-CLL. The catalogue of potentially clinically relevant chromosomal abnormalities found in this aCGH study is being currently evaluated. Disclosures Zent: Genentech, Bayer, Genzyme, Novartis: Research Funding. Shanafelt:Genentech: Research Funding; Hospira: Membership on an entity's Board of Directors or advisory committees, Research Funding; Polyphenon E International: Research Funding; Celgene: Research Funding; Cephalon: Research Funding; Bayer Health Care Pharmaceuticals: Research Funding. Kay:Genentech, Celgene, Hospira, Polyphenon Pharma, Sanofi-Aventis: Research Funding; Biogenc-Idec, Celgene, Genentech, genmab: Membership on an entity's Board of Directors or advisory committees. Fonseca:BMS: Consultancy; Amgen: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Medtronic: Consultancy; Genzyme: Consultancy.

scholarly journals Baseline Mutational Status of Patients with Myelofibrosis and Anemia in the Realise Trial and Impact on Outcome

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2952-2952
Author(s):  
Haifa Kathrin Al-Ali ◽  
Heinz Gisslinger ◽  
Francesco Passamonti ◽  
Lynda Foltz ◽  
David M Ross ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Functional Significance ◽  
Research Funding ◽  
Genetic Alterations ◽  
Advisory Board ◽  
Janus Kinase ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Mutational Status ◽  
Pharmaceutical Industries

Background: The Janus kinase (JAK) inhibitor ruxolitinib (RUX) is approved for the treatment of disease-related splenomegaly and symptoms in patients with myelofibrosis (MF). Treatment with RUX has been shown to significantly reduce splenomegaly and provide marked improvements in MF-related symptoms and quality-of-life. A number of mutations have been identified with known or likely functional significance in patients with MF (Vannucchi AM, et al. Leukemia. 2013), which may therefore have the potential to affect treatment response. This exploratory analysis aimed to investigate the mutational status of patients in the REALISE trial and to assess the relationship between baseline mutational status and outcome. Methods: REALISE was a multicenter, open label, single arm phase 2 study (NCT02966353). Eligible patients (N=51) had primary MF, post-essential thrombocythemia (ET) MF or post-polycythemia vera (PV) MF, with palpable (≥5 cm) spleen and hemoglobin level <10 g/dL. Patients started RUX at 10 mg bid with up titrations to 15 or 20 mg bid allowed after 12 weeks based on efficacy and platelet counts. The primary endpoint was achievement of ≥50% reduction in spleen length at Week 24. Secondary endpoints included transfusion requirements/dependence over time, adverse events, and patient-reported outcomes (PRO) (7-point MF score [MF-7], MF Symptom Assessment Form [MFSAF] version 2.0). Next generation sequencing (NGS) analysis using a 236 gene panel (Navigate BioPharma, Carlsbad, CA, USA) was performed on whole blood samples to identify genetic alterations. Results: NGS analysis data were available for 49/51 patients, median age was 67 years, 67.3% (33/49) had primary MF, 10.2% (5/49) had post-PV MF and 22.4% (11/49) had post-ET MF. DIPSS was available for 45 patients, 16.3% (8/49) were intermediate (Int)-1, 57.1% (28/49) were Int-2 and 18.4% (9/49) were high risk. The most frequent baseline mutations are shown in Figure 1. Classic driver mutations were found in JAK2 (n=33), CALR (n=11) and MPL (n=7), and did not affect response to RUX treatment. Two patients (4.1%) were triple negative for JAK2/CALR/MPL mutations, both responded to RUX treatment. The most commonly found non-driver mutations in patients with ≥50% reduction in spleen length at Week 24 (n=28) were TET2, ASXL1, U2AF1 and SRSF2; in non-responders, the most common non-driver mutations were TP53, FAT1 and ASXL1. The median number of mutations per patient was 2 (range 1-7); 35.7% (10/28) of patients with a response had ≥3 non-driver mutations vs 14.3% (3/21) of non-responders. Overall, no difference was seen in mutational distribution by change in spleen length at Week 24. In general, similar findings were seen for transfusion dependence status at baseline and improvements in symptom score with treatment (Table 1). However, there was a higher incidence of U2AF1 mutation in patients who were transfusion-dependent at baseline vs. non-transfusion dependent patients (4/8 [50%] vs 3/41 [7.3%], respectively). U2AF1 mutation is known to be associated with anemia and/or thrombocytopenia in myelodysplastic syndromes (Li B, et al. Genes Chromosomes Cancer. 2018). Mutations in TP53 were present in 6 patients. One patient showed a response to treatment at Week 24, and 5 were classified as non-responders. None of these 5 patients completed 24 weeks of treatment and 3 died during the study or safety follow-up period. Two progressed to acute myeloid leukemia prior to death. All patients were ≥60 years old, 4 were male and 4 were DIPSS Int-2 risk. Four patients had primary MF, 1 had post-ET MF and 1 had post-PV MF. Conclusions: Though these data should be interpreted with caution due to the small patient numbers, patients in the REALISE study showed variation in the type and number of genetic alterations with known/likely functional significance in MF. Compared with published mutational data on MF patients treated with RUX (Spiegel, et al. Blood Advances. 2017; Pacilli et al. Blood Cancer Journal. 2018) 12.2% of patients had a TP53 mutation compared to 4% and 4.2% respectively. This molecular difference may reflect the anemic study population. Despite the higher TP53 mutational burden, and alternative dosing strategy, 57.1% (28/49) patients had a response to RUX at Week 24. Although there was no strong association between mutation patterns and response, patients with TP53 mutations tended to have a poor outcome overall. Disclosures Al-Ali: Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Gisslinger:Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; Roche Austria GmbH: Consultancy; Myelopro GmbH: Consultancy; Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Janssen-Cilag: Honoraria; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding. Passamonti:Janssen: Honoraria, Other: Advisory board , Speakers Bureau; Novartis: Honoraria, Other: Advisory board , Speakers Bureau; Celgene: Honoraria, Other: Advisory board , Speakers Bureau. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Amgen: Other: Spouse Employment; Incyte: Research Funding; Constellation Pharma: Research Funding. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komatsu:Pharma Essentia: Research Funding, Speakers Bureau; Novartis K.K: Speakers Bureau; Wako Pure Chemical Industries, Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding, Speakers Bureau; Fuso Pharmaceutical Industries, Ltd.: Research Funding. Tiwari:Novartis: Employment. Zor:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Gilotti:Novartis Pharmaceuticals: Employment. Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

scholarly journals Second Imatinib Discontinuation Outcomes in Patients Regaining Durable Deep Molecular Response in the Korean Imatinib Discontinuation Study; KID Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 51-52
Author(s):  
Sung-Eun Lee ◽  
Joon Seong Park ◽  
Young Rok Do ◽  
Sung-Hyun Kim ◽  
Dae Young Zang ◽  
...  
Keyword(s):  
Prospective Study ◽  
Board Of Directors ◽  
Median Duration ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Close Monitoring ◽  
Advisory Committees ◽  
Deep Molecular Response ◽  
Multicenter Prospective Study

Backgroud: Although multiple trials have shown that stopping tyrosine kinase inhibitor (TKI) treatment can be employed in CP CML patients with sustained deep molecular response (DMR) after enough TKI therapy, they emphasized the need for close monitoring because about 50-70% of patients experienced molecular relapse. However, most patients with molecular recurrence regain their initial molecular level after restarting TKI therapy. Aims: In this study, we analyzed second imatinib (IM) discontinuation outcomes in patients regaining durable DMR in the Korean multicenter prospective study (Korean Imatinib Discontinuation Study; KID Study) Methods: CP CML patients who were treated with IM for more than 3 years and maintained DMR for at least 2 years were eligible for the Korean multicenter prospective study and in cases of MMR loss on 2 consecutive assessments, IM treatment was re-introduced. After IM resumption, the molecular response was evaluated every month until re-achievement of MMR and every 3 months thereafter. The second stop was permitted in the patients who were in second DMR for at least 2 years. Results: Among the patients who maintained a second DMR for at least 2 years after IM resumption, 23 patients entered into a second IM stop. Prior to first discontinuation, the median duration of IM therapy was 73.2 months (range, 38.4-133.2 months) and the duration of sustained UMRD was 38.4 months (range, 24-102 months). After first attempt of IM discontinuation, they relapsed after a median duration of 3.7 months (range, 1.8-20.8 months) and re-achieved UMRD at a median of 5.8 months (range, 1.7-12.1 months) after IM resumption. After sustaining a second DMR for a median of 26.3 months, IM therapy discontinued for a second time. With a median follow-up of 29.5 months (range, 9-63 months) since second IM stop, 15/23 patients (65%) lost MMR after a median 2.9 months (range, 1.8-30.7 months), which was similar to those of the first IM discontinuation [median 3.7 (range, 1.8-20.8 months)]. The patients who lost MMR were retreated with IM for a median of 24.5 months (range, 1.2-49.7 months); 14 patients re-achieved MMR and one patient was in therapy for 1.2 months. Conclusion: Our data demonstrated that a second attempt might be possible and the median time to MMR loss after second discontinuation was similar to those of the first discontinuation. Further studies on the predictors to select patients for a trial of second TFR and novel strategies will be warranted. Disclosures Kim: Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.

scholarly journals Patterns of Clonal Evolution Assessed By Whole Exome Sequencing during Progression from MDS to AML Are Related to Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4309-4309
Author(s):  
María Abáigar ◽  
Jesús M Hernández-Sánchez ◽  
David Tamborero ◽  
Marta Martín-Izquierdo ◽  
María Díez-Campelo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Clonal Evolution ◽  
Clonal Expansion ◽  
Driver Mutations ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Mutational Burden ◽  
Whole Exome ◽  
Leukemic Phase

Abstract Introduction: Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to acute myeloid leukemia (AML). Although, next-generation sequencing has increased our understanding of the pathogenesis of these disorders, the dynamics of these changes and clonal evolution during progression have just begun to be understood. This study aimed to identify the genetic abnormalities and study the clonal evolution during the progression from MDS to AML. Methods: A combination of whole exome (WES) and targeted-deep sequencing was performed on 40 serial samples (20 MDS/CMML patients evolving to AML) collected at two time-points: at diagnosis (disease presentation) and at AML transformation (disease evolution). Patients were divided in two different groups: those who received no disease modifying treatment before they transformed into AML (n=13), and those treated with lenalidomide (Lena, n=2) and azacytidine (AZA, n=5) and then progressed. Initially, WES was performed on the whole cohort at the MDS stage and at the leukemic phase (after AML progression). Driver mutations were identified, after variant calling by a standardized bioinformatics pipeline, by using the novel tool "Cancer Genome Interpreter" (https://www.cancergenomeinterpreter.org). Secondly, to validate WES results, 30 paired samples of the initial cohort were analyzed with a custom capture enrichment panel of 117 genes, previously related to myeloid neoplasms. Results: A total of 121 mutations in 70 different genes were identified at the AML stage, with mostly all of them (120 mutations) already present at the MDS stage. Only 5 mutations were only detected at the MDS phase and disappeared during progression (JAK2, KRAS, RUNX1, WT1, PARN). These results suggested that the majority of the molecular lesions occurring in MDS were already present at initial presentation of the disease, at clonal or subclonal levels, and were retained during AML evolution. To study the dynamics of these mutations during the evolution from MDS/CMML to AML, we compared the variant allele frequencies (VAFs) detected at the AML stage to that at the MDS stage in each patient. We identified different dynamics: mutations that were initially present but increased (clonal expansion; STAG2) or decreased (clonal reduction; TP53) during clinical course; mutations that were newly acquired (BCOR) or disappearing (JAK2, KRAS) over time; and mutations that remained stable (SRSF2, SF3B1) during the evolution of the disease. It should be noted that mutational burden of STAG2 were found frequently increased (3/4 patients), with clonal sizes increasing more than three times at the AML transformation (26>80%, 12>93%, 23>86%). Similarly, in 4/8 patients with TET2 mutations, their VAFs were double increased (22>42%, 15>61%, 50>96%, 17>100%), in 2/8 were decreased (60>37%, 51>31%), while in the remaining 2 stayed stable (53>48%, 47>48%) at the AML stage. On the other hand, mutations in SRSF2 (n=3/4), IDH2 (n=2/3), ASXL1 (n=2/3), and SF3B1 (n=3/3) showed no changes during progression to AML. This could be explained somehow because, in leukemic phase, disappearing clones could be suppressed by the clonal expansion of other clones with other mutations. Furthermore we analyzed clonal dynamics in patients who received treatment with Lena or AZA and after that evolved to AML, and compared to non-treated patients. We observed that disappearing clones, initially present at diagnosis, were more frequent in the "evolved after AZA" group vs. non-treated (80% vs. 38%). By contrast, increasing mutations were similar between "evolved after AZA" and non-treated patients (60% vs. 61%). These mutations involved KRAS, DNMT1, SMC3, TP53 and TET2among others. Therefore AZA treatment could remove some mutated clones. However, eventual transformation to AML would occur through persistent clones that acquire a growth advantage and expand during the course of the disease. By contrast, lenalidomide did not reduce the mutational burden in the two patients studied. Conclusions: Our study showed that the progression to AML could be explained by different mutational processes, as well as by the occurrence of unique and complex changes in the clonal architecture of the disease during the evolution. Mutations in STAG2, a gene of the cohesin complex, could play an important role in the progression of the disease. [FP7/2007-2013] nº306242-NGS-PTL; BIO/SA52/14; FEHH 2015-16 (MA) Disclosures Del Cañizo: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding; Arry: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Impact of DNMT3a Status on Post Induction NPM1 MRD Predictive Value on Survival in Elderly AML Patients Treated Intensively

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-8
Author(s):  
Maël Heiblig ◽  
Hélène Labussière ◽  
Marie Virginie Larcher ◽  
Gaelle Fossard ◽  
Marie Balsat ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Predictive Value ◽  
Scoring System ◽  
Research Funding ◽  
Risk Group ◽  
Advisory Committees ◽  
Post Induction ◽  
Mutational Status ◽  
Elderly Aml

Minimal residual disease is now a powerfull surrogate marker to assess response to chemotherapy in acute myeloid leukemia (AML). In younger adults, NPM1 MRD has recently demonstrated to be a favorable predictive marker for EFS and OS independently of fms-like tyrosine kinase-3 internal tandem duplications (FLT3-ITD) status. However, there is very few datas regarding predictive value of NPM1 MRD in elderly patients treated with intensive chemotherapy. Moreover, numerous studies have suggested the negative impact of DNMT3a mutation in NPM1 AML patients, especially in those with concurrent FLT3-ITD mutation. In this study, we aimed to investigate the impact of DNMT3a status on post induction NPM1 MRD1 predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1 mutated AML in two French institutions (Lyon, Lille) were analyzed retrospectively. Median age of the entire cohort was 66.1 years old (range 60-78.2). An FLT3-ITD mutation was evidenced in 52 of 138 patients (37.6%) with a median FLT3-ITD AR of 0.53 (range, 0.05-3). With a median follow-up of 19.61 months (0.07-128.4), the overall CR rate was 89.9% with no influence of DNMT3a or FLT3 mutational status on the probability of CR. In this elderly cohort of NPM1mut patients, a 4log reduction of NPM1 bone marrow (BM) MRD1 was associated with better outcome (median OS: NR vs 13.4 months, HR=0.35, p&lt;0.01)(Figure A). Overall, DNMT3 status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. However, only 9/44 (20.4%) FLT3-ITD patients reached ≥ 4log MRD1 reduction whereas 38/80 FLT3wt (47.5%) were good molecular responders (p&lt;0.001). FLT3-ITD mutated patients who achieved a 4log reduction had a superior outcome compared to those who did not (HR=0.34; 95% CI, 0.16 to 0.70; P &lt;0.001). Similarly, NPM1mut FLT3wt patients with a 4log reduction in NPM1 BM-MRD1 had a longer OS (3-year OS, 68.1%; 95% CI, 48.8 to 82.9) than those without good molecular response (3-year OS, 46.5%; 95% CI, 30.2 to 61.7)(Figure B). DNMT3a negative patients who achieved a 4log reduction had a superior outcome to those who did not reached at least a 4log reduction (HR=0.23; 95% CI, 0.07 to 0.72; P &lt;0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and leukemia free survival (LFS) in DNMT3amut patients. DNMT3amut patients has a very poor LFS which was even worst in poor NPM1 MRD1 responders compared to those who reached at least 4log reduction (median LFS: 8.3 months vs 17.4 months, HR = 0.48, 95% CI, 0.25-0.91, p=0.023)(Figure C). In multivariate analysis, only DNMT3a mutational status and a 4-log reduction in NPM1 BM-MRD were significantly associated with survival. Based on these results, we identified among NPM1 positive patients 3 groups with distinct prognosis, based on FLT3-ITD, DNMT3a status and NPM1 BM-MRD post induction response (NPM1 scoring system)(Figure D). When compared to ELN 2017 intermediate risk group (AUC=0.695), NPM1 scoring system (NPM1 SS) was more accurate for OS prediction in patients within intermediate (AUC=0.833) and unfavorable (AUC=0.863) NPM1 SS risk group. However, there was no significant difference in AUC between NPM1 SS favorable and ELN 2017 favorable risk group. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3a also identify a subgroup of patients at very high risk of relapase, despite good molecular responses. As hematopoietic stem cell transplantation (HSCT) might improve OS in elderly patients, DNMT3a positive AML elderly patients should be considered for HSCT or post induction maintenance strategies, even within the favorable ELN risk group. Figure Disclosures Sujobert: Gilead/Kyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding.

scholarly journals EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Sebastian Stasik ◽  
Jan Moritz Middeke ◽  
Michael Kramer ◽  
Christoph Rollig ◽  
Alwin Krämer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutational Status ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

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