Incyte Biosciences Research Articles

Combinatorial Treatment Options for Highly Resistant Compound Mutations in the Kinase Domain of the BCR::ABL1 Fusion Gene

The introduction of tyrosine kinase inhibitor (TKI)-based therapies has dramatically changed the outcome in patients with chronic myeloid leukemia (CML) and Ph-positive acute lymphoblastic leukemia (Ph+ALL). However, the occurrence of point mutations in the kinase domain (KD) of the BCR::ABL1 fusion gene can impair or inhibit the efficacy of individual TKIs. In advanced phases of CML and in Ph +ALL, patients frequently develop compound mutations (CMs), defined as the presence of more than one mutation on the same BCR::ABL1 molecule in a leukemic cell, which are often highly or even completely resistant to any individual TKI. Some CMs respond to high doses of the currently most potent available TKI, ponatinib, but the dose-related toxicity is an important impediment. The most frequently occurring CMs, which include the gatekeeper mutation T315I, are often resistant to any currently available TKI. We performed in vitro analyses using a common cell line model based on Ba/F3 cells expressing a panel of 12 different CMs (V299L/G250E, V299L/E255V, V299L/F359V, F317L/Y253H, F317L/E255V, F317L/F359V, F359V/Y253H, T315I/M244V, T315I/G250E, T315I/E255K, T315I/E255V, T315I/F359V) in BCR::ABL1 constructs introduced into the cells by a transposon-mediated approach. The presence of single insertion copies of the mutant constructs was verified by FACS analysis to preclude skewed test results potentially caused by multiple copies of the mutant construct. The cells pre-tested in this way were exposed in vitro to different concentrations of various drugs including ponatinib combined with a number of other agents such as asciminib, hydroxyurea, palbociclib, venetoclax, ibrutinib, vodobatinib, and crizotinib. The drug concentrations tested corresponded to the spectrum of the respective dosing regimens used in the clinical setting. The cell viability assays performed indicated that CMs responding only to elevated concentrations of ponatinib could be suppressed by combinatorial treatment with lower concentrations of ponatinib and different other agents tested. Moreover, CMs displaying high levels of resistance to TKIs applied as single agents mostly revealed adequate in vitro responses to individual drug combinations with ponatinib, most commonly including asciminib, hydroxyurea or crizotinib. Only the most resistant CM constellation tested, T315I/F359V, failed to respond to the compounds investigated and showed a limited response to the combination of high concentrations of ponatinib with hydroxyurea. A good response of this CM in vitro was only achieved by a combination of ponatinib with a very high concentration of crizotinib indicating the need for further testing of additional candidate drugs for this constellation. Overall, combinatorial treatment of BCR::ABL1 CMs indicated that relatively low concentrations of the drugs used are capable of effectively inhibiting in vitro survival of mutant cells in most instances, which is important with regard to the expected toxicity of combinatorial treatment approaches. Since our earlier data indicated a good correlation between in vitro test results and clinical responses, our observations may serve as a basis for novel treatment options in patients with Ph +leukemias displaying challenging BCR::ABL1 KD-mutations. [This project was supported by an educational grant from Incyte Biosciences International Sàrl]

Patient healthcare trajectories of intrahepatic cholangiocarcinoma in France: A nationwide retrospective analysis.

SummaryBackgroundLittle is known about the epidemiology and patterns of care of intrahepatic cholangiocarcinoma (iCCA) in daily clinical practice. The aims of this study were to estimate the number of declared cases during the study period 2014–2015 in France from a hospitalization database and to describe the healthcare trajectories of these patients.MethodsA retrospective analysis was carried out using the French nationwide prospective hospitalization database. All pts with a new diagnosis of "carcinoma of the intrahepatic bile duct" who had a first hospital stay in the Medicine, Surgery and Obstetrics departments (MSO) between 2014 and 2015 with a 2-year follow-up were included. Data related to the first identified stay (S1) in the MSO and on all subsequent stays in the MSO, aftercare and rehabilitation or home hospitalization were analysed.FindingsA total of 3650 new iCCA cases were identified. At S1 (admission via emergency room (ER) in 28%), the median age of the patients was 73 years, 57% were male and 35% had metastases. Jaundice/anaemia/ascites/cholangitis were reported in 17%/16%/12%/7% of patients, respectively. The care of patients at S1 was mainly provided in general hospitals (CHG, 60%). A total of 896 (24%) patients died during S1. They were more frequently hospitalized via the ER (48% vs 23%), metastatic (52% vs 35%) and symptomatic. Subsequent stays were identified for 2507 (69%) patients. Three healthcare pathways were defined: surgery (n = 519; 14%), chemotherapy (CT) without surgery (n = 812; 22%) and best supportive care (BSC) (n = 2319; 63%). CT, surgery and BSC were most frequently performed in the cancer centres, university hospitals and CHG, respectively.InterpretationThis medico administrative study reveals a higher number of iCCA cases than that previously reported by registries and highlights the severity of this disease.FundingThis study was sponsored by Incyte Biosciences International Sàrl., Geneva, Switzerland. INCYTE validated the design of the study, the analysis, the interpretation of data and the writing of the manuscript which was first written by the 2 experts and CEMKA.

A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine Double Minute 2 Inhibitor, Combined with a BCR-ABL Tyrosine Kinase Inhibitor in Patients with Relapsed/Refractory, TP53WT, Ph+ Chronic Myeloid Leukemia

A Phase 1b/2 Study of Navtemadlin (KRT-232), a Murine Double Minute 2 Inhibitor, Combined with a BCR-ABL Tyrosine Kinase Inhibitor in Patients with Relapsed/Refractory, TP53WT, Ph+ Chronic Myeloid Leukemia

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study

COVID-19 in Patients with Chronic Myeloid Leukemia: Poor Outcomes for Patients with Comorbidities, Older Age, Advanced Phase Disease, and Those from Low-Income Countries: An Update of the Candid Study

Onset of Blast Crises in CML Patients in Treatment-Free Remission: Descriptive Analysis of 4 Cases

Aims: The onset of blast crisis (BC) in initially chronic phase (CP) CML patients that entered treatment-free remission (TFR) after TKI is an exceptional event, however, there is emerging evidence that this may occur in such patients (pts), although the pathogenesis remains unclear to date.Methods: Anonymous clinical case retrospective data collection from patients' datafiles, after written agreement of living patients, centralisation of available frozen nucleic acid collection from diagnosis and from blast crisis and reanalysis by Next-Generation Sequencing of samples (ASXL1, ASXL2, BCOR, CALR, CBL, CEBP alpha , CSF3R, DNMT3A, EP300, ETNK1, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2 JAK2, KIT, , KRAS,MPL, NPM1, NRAS, PHF6, PTPN11 , RAD2, RUNX1, SETBP1, SF3B1, SH2B3, SMC1A, SMC3, SRSF2, STAG1, STAG2, TET2, TP53, U2AF1, WT1 and ZRSR2 genes analysed) on Illumina platform. CNV analysis were performed using VisCAp or in-house pipelines and/or by Multiplex Ligation Dependant Probe Amplification (MLPA). ABL1 tyrosine kinase domain mutations were screened by NGS on cDNA or directly on DNA. BCR-ABL1 transcripts are expressed in % (IS) with at least 32,000 copies of ABL1 as control. All patients discontinued their TKI after 2 years of MR4.5 and a TKI was resumed in case of MMR loss.Results: Along 15-year experience of TFR in our country and ≥ ~800 patients experiencing a TKI cessation attempt, informations from 4 (~0.5%) TFR CML patients entering BC have been collected. All patients harboured Major BCR transcripts.The chronic phase characteristics are mentioned in Table 1.All these long-lasting CP CML pts were ELTS risk score low, and 1 was harbouring ACA at diagnosis. One pt was mutated for ASXL2 and 2 mutations for EP300, found again at BC. Three pts had IFN-a prior to imatinib for all. Three out of 4 lost their MMR after a first cessation attempt at 12, 10 and 3 months after cessation. Pt #1 experienced a 2 nd cessation attempt 52 months after re-initiation of TKIs and entered lymphoid BC 6 months after a second resumption of TKI for a 2 nd MMR loss.The BC characteristics are mentioned in Table 2.Three out of 4 BC were lymphoid, one had ACA different from those at CP diagnosis. Two pts explored had multiple mutations in Runx1, U2AF1, EP300 and ASXL2 genes, not present at CP diagnosis, in addition to multiple ABL1 mutations in 2 out of 4 pts (2 T315I, 3 P-Loop mutations). All pts underwent chemotherapy + various TKI leading to complete remission (CR) in all and 3 out of 4 pts could be allotransplanted in CR, one relapsed shortly after transplant, and a second one 34 months after transplant. Overall 3 pts are alive with 1 in controlled relapse.Conclusions: The onset of BC after TFR for sustained deep molecular response remains an exceptional event and is probably not induced by this therapeutic procedure. These 4 cases underline the need for a sustained long-lasting molecular follow-up of pts in TFR, although the majority of these BC seem sudden. [Display omitted] DisclosuresBauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

FINAL Analysis of a PAN European STOP Tyrosine Kinase Inhibitor Trial in Chronic Myeloid Leukemia : The EURO-SKI Study

▪Background: With the dramatic success of tyrosine kinase inhibitors (TKI) to treat Chronic myeloid leukemia (CML), the life expectancy of CML patients is now close to that of the general population. In addition, treatment cessation is now a realistic goal for some CML patients. This was shown by several clinical trials such as the STIM study leading to the concept of TFR (treatment free remission). Around 40-60% of patients with stable DMR [deep molecular response, corresponding to <0.01% BCR-ABL (IS)] can stop the TKI successfully, e.g. in accordance with recommendations from the European LeukemiaNet. In the interim analysis of the first 200 patients of the EURO-SKI (European Stop TKI) trial, 62% were in major molecular response (MMR: <0.1% BCR-ABL1 IS) at 6 months. DMR duration before TKI stop was most predictive for maintenance of MMR. Here we present the final analysis of the EURO-SKI trial after 3 years of follow-up.Aims: The main objectives of The EURO-SKI trial were the evaluation of molecular recurrence-free survival (MRecFS) after Stopping TKI in a large Pan-european cohort of CML patients and definition of prognostic markers to increase the rate of patients in durable deep MR after stopping TKI. Further aims are the evaluation of harmonized methods of molecular monitoring.Methods: Adult CML patients in chronic phase CML on TKI treatment in confirmed DMR for at least one year (confirmed by three consecutive PCR tests) and under TKI treatment for at least 3 years were eligible. DMR confirmation was performed in standardized laboratories. Primary endpoint was maintenance of MMR after stopping TKI. According to protocol, a 36 months follow-up was planned. The null hypotheses were that MMR maintenance at 6 and 36 months was less or equal than 40% and less or equal than 35%, respectively.Results: Between May 2012 and December 2014, 868 patients were pre-registered by 61 centers from 11 countries. 140 pts were excluded (consent withdrawal n=1, protocol violation n=38, not eligible n=74, DMR not confirmed n=11, atypical/unknown transcript n=15, missing data n=1) resulting in 728 eligible patents. Of these, 46.8% were female. Median age at diagnosis was 52 years (range, 11 to 85 years). Median duration of TKI treatment was 7.5 years (range, 3.0-14.1 years) and median duration of MR4 before TKI cessation was 4.7 years (range, 1.0-13.3 years). Nine patients died without MMR loss (none CML related), 15 patients restarted TKI without MMR loss. At 6 months, 713 patients were available (without molecular test at 6 months: n=6, TKI restart without relapse: n=9). Since 434 patients (61%) [95% CI: 57-64] remained without relapse during the first 6 months, the null hypothesis was rejected (p<0.0001). At 36 months, 678 patients could be analyzed (TKI restart without relapse: n=17, no molecular test at 36 months: n=33). With 309 patients in MMR, corresponding to 46% [95% CI: 42-49], the null hypothesis of 35% or less was rejected (p<0.0001). MRecFS at 36 months resulted in 48% (CI: 44-52%) and molecular recurrence- and treatment-free survival (MRecTFS) in 46% (CI: 43-50%) (Fig 1). No blast crisis occurred.Regarding prognostic factors, we confirmed that TKI treatment duration and DMR duration were still the most important factors to predict MMR loss at 6 months. For the late recurrence, i.e., between 6 and 36 months (57 patients), TKI treatment duration before stop was the only relevant variable in a preliminary univariate logistic analysis.Summary/Conclusion: With this final analysis of the largest TFR trial, we confirm the MRecFS and MRecTFS rates at 6 months previously obtained from the interim analysis. However, late molecular recurrence (15% between 6 and 36 months) occurred and the underlying mechanisms need to be discussed. Nevertheless, 46% of the patients, were still in MRecTFS at 3 years. [Display omitted] DisclosuresHochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Hjorth-Hansen: AOP: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Mustjoki: Novartis: Research Funding; BMS: Research Funding; Janpix: Research Funding; Pfizer: Research Funding. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Saussele: Roche: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

An Update of Safety and Efficacy Results from Phase 1 Dose-Escalation and Expansion Study of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI), in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Failing Prior TKI Therapies

An Update of Safety and Efficacy Results from Phase 1 Dose-Escalation and Expansion Study of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI), in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Failing Prior TKI Therapies

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

The Outcome of Treatment-Free Remission after First-Line Nilotinib or Dasatinib in Chronic Phase Chronic Myeloid Leukemia Patients Is Different

Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Treatment-Free Remissions in Newly Diagnosed CP CML Patients Treated with the Combination of Nilotinib + Pegylated Interferon Alpha 2a Versus Nilotinib Alone in the National Phase III Petals Trial

Treatment Free Survival (TFS) in Patients (pts) with Chronic Myeloid Leukemia (CML) Carrying Atypical BCR-ABL1 Fusion Transcripts: The French CML Group (Fi-LMC) Experience

▪AimsLife expectancy of CML pts optimally responding to tyrosine kinase inhibitors (TKI) is close to that of the general population and recently, TFR has been acknowledged as a new goal of CML management. TKI discontinuation in the view of TFR requires the achievement of deep and long-lasting molecular responses (MR). The gold standard BCR-ABL mRNA quantification technology and MR definitions rely on internationally standardized (IS) RT-qPCR but atypical transcripts located outside the Major-BCR region, harbored by 1-2% of pts, cannot be expressed on the IS scale. Thus, most trials and clinical practice recommendations prevent such pts from attempting TFR. The Fi-LMC group retrospectively collected real-life observations to assess TFR likelihood in this rare population.MethodsData from CML pts with precise characterization of atypical transcripts in whom any line TKI was stopped for any reason but after at least 2 years of undetectable molecular residual disease (UMRD) by individualized non-standardized RT-qPCR were collected. RT-qPCR sensitivity varied depending on transcript type and local molecular biology laboratory. TFS was estimated by the Kaplan-Meier method. Relapse was analyzed using the cumulative incidence function, relapse being as UMRD loss at any time and any level during follow-up (FU).ResultsOur series comprised 16 adult CP CML pts with atypical BCR-ABL fusions including 12 males (75%). Median age at CML diagnosis was 56 years (range: 21-75) and that at TKI discontinuation was 67 years [range: 29-82]. Sokal score was low, intermediate and high in 7, 8 and 1 pts, respectively. ELTS score was low and intermediate in 10 and 4 pts, respectively and unknown in 2. Most pts expressed e19a2 (n=6) followed by e6a2 (n=4), b3a3 (n=3), b2a3 (n=2) and e8a2 (n=1). Seven pts discontinued imatinib, 4 stopped dasatinib, 4 nilotinib and 1 bosutinib. Number of lines of therapy was 2 in 8 pts, 1 in 5 pts and 3 in 3 pts. Median TKI treatment duration before discontinuation was 64 months (range: 31-218) and median duration of UMRD was 41 months (range: 21-168). The median FU after TKI discontinuation was 68 months (range: 3-149). Five pts experienced relapse leading to TKI resumption. Four relapses occurred within 3-6 months and included 2 loss of hematologic response in CP, 1 loss of hematologic response in accelerated phase CML and 1 molecular recurrence with BCR-ABL transcripts up to 1.5%. One relapse occurred at 49 months and consisted in loss of a complete cytogenetic response. These 5 pts resumed TKI and regained UMRD within 6 months, including 1 pt who died in UMRD from non-CML-related cause at the age of 82 years and 1 pt who rapidly failed a 2 nd TKI discontinuation attempt.In 1 additional pt, BCR-ABL transcripts became detectable intermittently with maximum transcript level of 0.15% and TKI was not resumed. The median FU of pts who remained treatment-free was 68 months (range: 8-149).Overall, the 5-year cumulative incidence of relapse regardless of whether TKI was resumed was 41.6% (95% confidence interval: 21.9%-78.7%) (Figure 1). The 5-year TFS rate was 65.2% (95% confidence interval: 40.3%-90.2%) (Figure 2).ConclusionsOur observational study of TKI discontinuation in CML pts with atypical BCR-ABL transcripts is the largest reported so far. While effort must be made for proper assessment of deep MR, preliminary results suggest that TFS pattern might favorably compare with that obtained in pts with Major-type BCR-ABL transcripts. However, relapses may be more aggressive and caution is required in order to avoid loss of hematologic responses and progression. Whether the type of atypical fusion gene influences TKI discontinuation outcome, as well as other potential prognostic factors, need to be determined in a larger series. [Display omitted] DisclosuresCharbonnier: Novartis: Speakers Bureau; Incyte: Speakers Bureau. Rea: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Etienne: Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Dose Modification Dynamics of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) from the PACE and Optic Trials

Dose Modification Dynamics of Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) from the PACE and Optic Trials

Therapy-Related Acute Myeloid Leukemia (t-AML) and the Advantage of Intensive Chemotherapy: Real-Life Analysis from Two Regional French Centers

Rational: Patients with t-AML are those previously treated for primary malignancy and are categorized with poor prognosis. t-AML treatment options include intensive chemotherapy (IC), hypomethylating agents (HMA) or low dose cytarabine (LDC). However, survival remains poor and allogeneic hematopoietic cell transplantation (Allo-HCT) could lead to better outcomes. The aim of this analysis is to assess the outcome of all consecutive t-AML pts from two regional centers in France, based on treatment intensity, and to identify prognostic factors.Patients and Methods: between January 2006 and December 2019, 112 adult pts diagnosed with t-AML occurring after treatment of solid tumors (ST; n=72), hematologic malignancies (HM; n=34) or autoimmune diseases (AID; n=6). Pts received chemotherapy and/or radiotherapy or high dose chemotherapy followed by autologous hematopoietic cell transplantation (Auto-HCT) in some. All eligible t-AML pts received intensive chemotherapy (IC, n=55) with the combination of anthracycline and cytarabine in 48 pts and CPX-351 in 7 pts. Unfit pts received non-IC (9 LDC, 24 HMA). The third study group (24 pts) received best supportive care (BSC). Fifteen pts underwent HSCT in first CR.Statistical analysis: We performed a descriptive analysis of the baseline characteristics and each treatment group was compared with a Kruskal-Wallis test and a Pearson's Chi-square test. Survival curves (Kaplan-Meier method) were compared with a log-rank test. Univariate and multivariate analyses on survival, relapse and NRM were done using Cox regression, Gray test, Fine & Gray regression. The bilateral level of significance was set at 5%. All analyses and graphics were made under the R program (v3.5.1). A pair-matched control analysis with de novo AML was performed only on pts who received IC matched for age, cytogenetics and ELN 2010 classification.Results: A total of 112 t-AML pts were identified, 56 were males (50%) with a median age of 68 yrs (19-87) at t-AML diagnosis. Before t-AML, 72 pts had ST (64.5%), 34 HM (30.5%) and 6 AID (5%). Forty-six pts (41%) received chemotherapy alone for their primary cancer, 17 (15%) radiotherapy alone, 49 (44%) radio chemotherapy, 17 (15%) auto-HCT and 6 (5%) long-term methotrexate for AID. Median interval from treatment of previous ST or HM to t-AML diagnosis was 4.7 years in ST, 6.6 years in HM and 21 years in AID (p=0.03). At t-AML diagnosis, 42% of pts presented an unfavorable karyotype and 44% an unfavorable ELN 2010 classification. Regarding molecular alterations, FLT3-ITD, FLT3-TKD, NPM1 and IDH1/2 mutations were observed in 6.9, 2.3, 11.5 and 2.3% of pts respectively. MECOM1 was overexpressed in 25.5% of cases. Among treated pts (n=88), 43 pts (49%) achieved CR: 4 from 33 (12%) in non-IC pts (3 in HMA and 1 in LDC) and 39 from 55 (71%) in IC pts. Fifteen pts (17%) underwent Allo-HCT with a median interval between AML diagnosis and Allo-HCT of 4.7 mo (2.6-17.5). The best response after transplantation was CR in 10 pts; at the last follow up, 4 pts are alive (3 in CR and 1 in relapse) and 11 died (5 from relapse, 5 from TRM causes and 1 from another subsequent malignancy). Overall, with a median follow up of 5.5 mo (0-144), the median OS and DFS were 9 mo (5.9-13.5) and 6.3 mo (5.3-10.3) respectively (Figure). There was a significant difference between the 3 treatment groups concerning OS (p<0.001) and DFS (p<0.001) with a significant difference in OS between IC and non-IC groups (p=0.02). In the 88 treated t-AML pts, with a median follow up of 8.2 mo (0.3-144), the median OS was 13.5 mo (10.3-19.6) and the median DFS was 8.2 mo (7-13.7). Multivariate analysis for total and treated populations showed no impact of all variables related to previous malignancies except for auto-HCT pre-t-AML (significant negative impact on OS, DFS, NRM), WBC at t-AML diagnosis (negative impact on OS, DFS) and chemotherapy (positive in total population on OS, DFS, NRM and negative impact of IC on OS and NRM in treated pts) . In IC treated pts, we showed, in a pair-matched analysis with de novo AML, no difference in term of OS and DFS due to a significant higher CI of NRM (p=0.045) at 24 mo (40% in t-AML versus 27.4% for de novo AML) and a lower CI of relapse (NS) at 24 mo (33% in t-AML versus 47.6% for de novo AML).Conclusion: The prognosis of t-AML remains poor and our study showed the advantage of using intensive chemotherapy whenever possible and, in comparison with de-novo AML, a higher NRM and a lower incidence relapse. [Display omitted] DisclosuresNicolini: Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria.

Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study

Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study

No Influence of BCR-ABL1 Transcript Types e13a2 and e14a2 on MR4.5 in Patients with Chronic Myeloid Leukemia Treated with Nilotinib Frontline

The most common transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2). Previous studies suggest that e14a2 transcript predicts a faster and deeper response to imatinib compared to e13a2. However, the impact of the type of transcript on response after first-line therapy with a second generation tyrosine kinase inhibitor, nilotinib, is unknown.We retrospectively analyzed in this observational study 79 newly diagnosed patients with chronic phase (CP) CML, treated with nilotinib 600 mg BID frontline in 3 centers between 2007 and 2017 inside or outside clinical trials.Thirty-eight patients (48.1 %) expressed e14a2, 35 (44.3 %) e13a2 and 6 patients (7.6 %) both transcripts. Characteristics at diagnosis did not differ between patients expressing e14a2 or both transcripts and e13a2 with respectively a median age of 49 (range, 23-85) and 55 years (range, 19-78) (p=.13), a white blood cell count of 132.4 and 173.6 G/L (p=.15) and a platelet count of 529 and 404 G/L (p=.15). Relative risks of CP-CML at diagnosis were similar according to the Sokal score (p=.37), the Eutos Score (p=.98) or ELTS score (p=.39). Nilotinib was discontinued in 15 patients (18.9%) mostly for failure or progression (n=5) and intolerance (n=9) after a median time of 14.7 months (4.5-55.2). The proportion of patients e14a2 (or expressing both transcripts) and e13a2 achieving complete cytogenetic response at 6 months was respectively 95% and 85.2% (p=.155) whereas the rate of major molecular response at 1 year was 59% and 50% (p=.414). The probability to attain MR4.5 did not differ from the 2 groups (p=.264) with a median follow-up of 44.7 months (2.9-110.8).This retrospective analysis confirms the excellent efficacy and tolerance of nilotinib frontline in CP CML, with similar results in terms of limitation of progression and deep molecular responses for both transcripts. [Display omitted] DisclosuresNicolini:ARIAD: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Guyotat:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau.

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - Results from the EURO-SKI Trial

“Duration of Deep Molecular Response” Has Most Impact on the Success of Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia - Results from the EURO-SKI Trial

What's Next in CML - a Prospective Study Evaluating Sanger Sequencing and Next Generation Sequencing (NGS) for BCR-ABL1 Kinase Domain (KD) Mutation Screening

What's Next in CML - a Prospective Study Evaluating Sanger Sequencing and Next Generation Sequencing (NGS) for BCR-ABL1 Kinase Domain (KD) Mutation Screening

Long-Term Survival of Patients with Chronic Phase Chronic Myeloid Leukemia Who Received Autologous Stem Cell Transplantation and Further Exposed to Tyrosine Kinase Inhibitors. a Study on Behalf of the French Society of Blood and Marrow Transplantation and the French Group of CML

Background: Prior to the introduction of tyrosine kinase inhibitors (TKI), the median survival of chronic phase chronic myeloid leukemia (CP-CML) patients was approximately 60 months [Roy L et al, Blood 2006] and the standard treatment with interferon-alpha resulted in complete cytogenetic responses in about 30% of the patients [Bonifazi F. et al, Blood 2001]. Peripheral blood autologous stem cell transplantation (Auto-SCT) was first attempted for patients in transformation in order to restore a second CP and was introduced secondarily in CP to try to prolong the response. The principal rationale for autografting in CP resides on the reduction of the tumor burden and the number of leukemic cells at risk of developing blastic transformation, and the possibility of eradicating already mutated cells. In addition, it takes advantage as well of the endogenous mobilization in the circulation of Ph- HSCs. Nevertheless, Auto-SCT alone was not able to maintain a long-term cytogenetic and/or molecular remission. Nowadays, TKIs represent the state-of-the-art therapy for CML and the concept of Auto-SCT has only little interest while long-term follow-up and outcome in this setting are currently unknown.Aims: The aim of our study is to evaluate the long-term outcome of CP-CML patients who received Auto-SCT and who have received TKIs later during their treatment course.Patients: A total of 182 patients were included in this study, 114 (63%) were males and 68 (37%) females. The median age at diagnosis was 45 years (range: 20-66), interferon-alpha was initiated and then all patients received Auto-SCT between years 1989 and 2004 while they remained in CP, 30% of these patients were included in the auto-CML trials and the rest were treated accordingly. The median time between diagnosis and Auto-SCT was 24 months (range: 1-113). Stem cells source was peripheral blood in 172 (95%) of patients, mostly collected at diagnosis, and bone marrow in 10 (5%) patients. Patients were conditioned by Busulfan 4mg/Kg/day 4 days + Melphalan 140 mg/m2 1 day prior to the cells reinfusion. TKIs were introduced later on in these patients, information concerning the context of their use as well as response after treatment is currently under collection from centers and will be reported later during the meeting.Results: After a median follow-up of 14.5 years (range: 2-30), the probability of overall survival (OS) for the whole population from diagnosis at 10, 15 and 20 years is 97% (95% CI: 92-99), 82% (95% CI: 74-88) and 68% (95% CI: 56-77). OS from date of Auto-SCT at 10, 15 and 20 years was 90% (95%CI: 83-94), 78% (95% CI: 69-85) and 63% (95%CI: 51-74) respectively. When we stratify the population according to age at Auto-SCT, patients younger than 45 years had an OS from diagnosis at 10, 15 and 20 years of 100%, 96% and 86% respectively compared to 94%, 72% and 54% respectively for those with 45 years and older, p=0.0015. A total of 33 (18%) patients died, 15 (8%) of them because of disease progression, 2 secondary malignancies, and the rest because of other causes including pneumonia, hemorrhage, renal failure and cirrhosis.Additional data requests have been sent to centers querying about prognosis, molecular responses, treatment and disease details. An extensive analysis will be performed and the study will be updated with more results.Conclusion: We demonstrate here with the preliminary results that Auto-SCT followed by TKIs has induced remarkable rates of long-term survival and raise the question about the place of intensification in the therapeutic strategy in CML. [Display omitted] DisclosuresCharbonnier:Incyte: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Coiteux:BMS: Speakers Bureau; Incyte: Speakers Bureau. Rea:Novartis: Consultancy, Honoraria; Incyte: Honoraria; BMS: Consultancy, Honoraria; Pfizer: Honoraria. Delmer:Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Honoraria. Mahon:PFIZER: Consultancy, Honoraria; BMS: Consultancy, Honoraria; NOVARTIS PHARMA: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; INCYTE: Honoraria. Nicolini:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Etienne:BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Research Funding.

Efficacy and Safety of Ponatinib in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) According to the Extent of Treatment with Prior Tyrosine Kinase Inhibitors (TKIs): Final (5-Year) Results of the PACE Study

Efficacy and Safety of Ponatinib in Chronic Phase-Chronic Myeloid Leukemia (CP-CML) According to the Extent of Treatment with Prior Tyrosine Kinase Inhibitors (TKIs): Final (5-Year) Results of the PACE Study

SETD2 Loss of Function Is a Recurrent Event in Advanced-Phase Chronic Myeloid Leukemia

Abstract In recent years, deregulation of epigenetic modifiers has turned out to be a recurrent event in cancer evolution. The SETD2 tumor suppressor gene encodes a histone methyltransferase that catalyzes the trimethylation of lysine 36 on histone H3 (H3K36Me3), the major chromatin mark associated with active transcription and alternative splicing. Recent studies have also implicated SETD2 in homologous recombination repair, mismatch repair, mitosis and cytokinesis. SETD2 loss of function was initially uncovered in clear cell renal cell carcinomas and was subsequently found in many other solid tumors. More recently, it has also been reported in a variety of hematologic myeloid and lymphoid malignancies, including acute lymphoblastic leukemia,acute myeloid leukemia, chronic lymphocytic leukemia, T-cell lymphoma, systemic mastocytosis and myeloproliferative neoplasms. We thus wondered whether advanced-phase chronic myeloid leukemia (CML), that shareS similarities with acute leukemias including a high level of genetic instability, may also exhibit SETD2 loss of function. To this purpose, we studied a relatively large cohort of 69 advanced phase CML patients (pts), including pts with accelerated phase (AP; n=15), myeloid blast crisis (my-BC; n=30), and lymphoid blast crisis (ly-BC; n=15) and pts with tyrosine kinase inhibitor (TKI)-resistant chronic phase harboring 2 or more BCR-ABL kinase domain mutations (mut-CP; n=9). Samples collected at diagnosis from CP pts (n=8) who achieved optimal response to therapy were also studied for comparison. A recent study in advanced systemic mastocytosis has demonstrated that SETD2 loss of function may result not only from genomic disruption but also from post-translational events, suggesting that the frequency of SETD2 involvement in solid tumors or hematologic malignancies might be higher than sequencing and copy number data alone would suggest. We thus decided to use a Western Blotting (WB) approach to assess H3K36Me3 levels as a surrogate marker of SETD2 loss of function and to screen for the expression of SETD2 full-length vs truncated protein isoforms, that are the most frequent result of inactivating nonsense or frameshift mutations. Reduced or null H3K36Me3 (as compared to a pool of healthy donors) was detected in the great majority of pts with advanced-phase CML (58/69, 84.1%; 12/15 AP, 24/30 my-BC, 12/15 ly-BC, 8/9 mut-CP). In contrast, CP pts at diagnosis showed H3K36Me3 levels superimposable to those of healthy donors. In some of them, however, the CD34+ cell fraction was available and reduced H3K36Me3 levels were detected in all cases. No evidence of abnormal SETD2 protein isoforms was detected, but pts with no H3K36Me3 also had no detectable SETD2 protein and pts with reduced H3K36Me3 had similarly reduced levels of full-length SETD2 protein as assessed by densitometric analysis of WB (Spearman R=0.95, p To rule out the possibility that SETD2 loss of function might be another age-associated alteration in an epigenetic regulator, we collected a series of 80 healthy individuals with an age ranging from 65 to 95 years. In this cohort, we checked for SETD2 mutations by sequencing and for SETD2 and H3K36 trimethylation levels by WB. No mutations were detected and protein levels were not significantly lower in older adults than in a pool of younger adults. Advanced-phase CML is characterized by a profound genetic heterogeneity. We here show the first evidence for a novel, nearly unifying alteration. However, SETD2 downmodulation and, consequently, H3K36Me3 deficiency seem to be most frequently accomplished at the post-translational level rather than being the results of genetic/genomic hits or transcriptional repression. Further studies aimed to assess whether H3K36Me3 loss might contribute to the genetic instability that is the hallmark of advanced-phase CML are warranted. Restoring physiological H3K36Me3 levels may help improve the outcome of this critical subset of pts. Supported by AIL and AIRC (project code 16996) Disclosures Castagnetti: Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Gugliotta: Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rosti: Incyte: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Iurlo: Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Abruzzese: Novartis: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy. Crugnola: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Bonifacio: Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tiribelli: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Galimberti: Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Baccarani: Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Martinelli: Celgene: Consultancy; Amgen: Consultancy; JohnsonJ Pfizer: Consultancy; Ariad/Incyte: Consultancy; Roche: Consultancy. Soverini: Bristol-Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy.

Long-Term Outcome of Patients Receiving Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies: Results from an Observational Study on 106 Patients

Graft-versus-host disease (GVHD), and complications of its treatment are the major causes of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Even with the use of standard GVHD prophylaxis with classical administration of Anti-thymocyte globulin (ATG), calcineurin inhibitors (CNIs) and methotrexate, the incidence of acute and chronic forms of GVHD remains not negligible. Extracorporeal photopheresis (ECP) has shown very promising results as curative strategy for GVHD but also when used prophylactically.The primary objective of this observational study was to perform an exhaustive description concerning patients receiving ECP after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes.We included 106 patients who underwent allo-HCT between years 2001 and 2016, 65 (61%) were males, median age at allo-HCT was 52 years (20-67). Major diagnoses were acute leukemias (N=48, 45%), myelodysplastic syndromes (N=18, 17%) and multiple myeloma (N=12, 11%). Before transplantation, 56 (53%) patients were in complete remission or in chronic phase. Donors were identical siblings in 51% of patients, matched unrelated in 24%, mismatched unrelated in 24% and haploidentical in 1%. Cells source was peripheral blood in 65%, bone marrow in 27% and cord blood in 8%. Conditioning regimens were of reduced intensity in 62% and myeloablative in 38%. ATG was used during conditioning in 67% of patients. GVHD prophylaxis consisted on cyclosporine A (CsA) alone in 22 (21%) patients, CsA + mycophenolate mofetil in 29 (27%), CsA + methotrexate in 28 (26%), the rest received other combinations.In acute GVHD, first treatment consisted in methyl-prednisolone 2mg/Kg/day in combination with CNIs; and in chronic GVHD, it was methyl-prednisolone 0.5 - 1 mg/Kg/day + CNIs. ECP was performed using peripheral venous access. The ECP used the CELLEX system from Therakos®. ECP was initiated after transplantation either for acute GVHD [N=25 (24%), 12 grade III and 13 grade IV] affecting skin alone (N=5), gut alone (N=12), gut + liver (N=8); or for chronic GVHD [N=81 (76%), 15 (14%) limited and 66 (62%) extensive]. A total of 3300 ECP sessions were performed, majority (N=91, 85%) were twice a week; the median number of sessions/patient was 22 (min: 2, max: 132) for a median duration of 2.5 months (range: 0.5-48). ECP response evaluation was assessed after 4 weeks of treatment, patients were considered responding to ECP if more than 50% resolution of clinical GVHD manifestation of the organ involved was registered.Among the 25 patients treated for acute GHVD, one was not evaluable because of disease progression and early death, 16/24 (67%) were responders to ECP and 8/24 (33%) were not responders and died later from GVHD associated to other complications. Among the 81 patients with chronic GVHD, 63/81 (78%) were responders and had tapering of ECP, the remaining 18 patients had limited response were associated to infection, had other complications and died later. Of note, in both forms of acute and chronic GVHD, responding patients had more skin or mucosa forms whereas non-responding patients has more organ-involved forms especially liver and gut.After a median follow-up of 21 months, 52 (49%) patients are alive and 54 (51%) died with 39 (24%) from TRM causes (26 of them from GVHD) and 13 (26%) from relapse. Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 35% [95%CI: 14-56], those with chronic GVHD had a median OS of 72 months with a survival probability at 2 years of 68% [95%CI: 56-78]. The cumulative incidence of relapse for the whole population at 2 years was 16.7% (95% CI: 10-24), when stratifying according to the GVHD group, patients with chronic GVHD had lower relapse rate at 2 years with 12.6% (95% CI: 6-21) versus 31% (95% CI: 13-52) for those with acute GVHD, p=0.05.In conclusion, we confirm that ECP is an effective treatment for GVHD with overall response rate of more than 74%. Interestingly, we observed a low relapse incidence in patients receiving ECP for longer time as in the case of chronic GVHD, which could be related to the GVL effect itself but also a possible involvement of the ECP. As patients with advanced phase of GVHD were poor responders, we suggest that an early use of ECP in the acute phase of the inflammation before organ damage, could lead to optimal results. [Display omitted] DisclosuresNicolini:Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau.