Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 789-789

Abstract: Next-Generation Sequencing (NGS)-based BCR-ABL1 kinase domain (KD) mutation screening has been shown to enable greater accuracy and sensitivity and straightforward identification of compound mutants (CM) as compared to Sanger sequencing (seq). However, the prevalence of CMs has never been assessed in prospective studies, and although in vitro data suggest that many of them may be challenging for all tyrosine kinase inhibitors (TKIs) including ponatinib, attempts to correlate such data with in vivo responses have never been made. To address these issues, we have reviewed the results of routine NGS-based BCR-ABL1 KD mutation screening performed over the past 3 years. Between 2015 and 2018, we have prospectively used NGS to analyze a consecutive series of 751 Ph+ leukemia patients (pts) on TKI therapy who were eligible for BCR-ABL1 KD mutation screening according to ELN/NCCN/ESMO recommendations. The study population included 664 chronic myeloid leukemia (CML) pts with failure or warning response (chronic phase [CP], n=593; accelerated or blastic phase [AP/BP] , n=71) and 87 Ph+ acute lymphoblastic leukemia (ALL) pts with relapsed/refractory disease. NGS of ≈400bp amplicons generated by nested RT-PCR was performed on a Roche GS Junior (until April 2017) or on an Illumina MiSeq (from May 2017 on) using custom protocols whose accuracy, sensitivity and reproducibility was checked by national and international (EUTOS) control rounds. Read alignment and variant calling was done using the AmpSuite software (SmartSeq srl), with a lower detection limit set to 3%. Cis or trans configuration of mutation pairs, indicating CMs or polyclonality, respectively, was determined correcting for the likelihood of PCR recombination. The 35INS insertion/truncation mutant was excluded from the analysis. NGS identified mutations in the BCR-ABL1 KD in a total of 313/664 (47%) CML pts (255/593 [43%] CP-CML and 58/71 [82%] AP/BP-CML) and 69/87 (79%) Ph+ ALL pts. Ninety-one percent of the mutations could be recognized as conferring resistance to at least one TKI on the basis of publicly available IC50 data or published reports. In 42/593 (7%) CP-CML, 6/71 (8.5%) AP/BP-CML and 12/87 (14%) Ph+ ALL pts, low burden mutations (i.e., mutations carried by a proportion of transcripts 〈 15% - hence invisible to Sanger seq) were the only detectable mutation(s). In 21/593 (3.5%) CP-CML, 26/71 (37%) AP/BP-CML and 40/87 (46%) Ph+ ALL pts low burden mutations co-existed together with at least one dominant mutation (i.e. a mutation carried by a proportion of transcripts 〉 15% - hence detectable by Sanger seq). Fifty-five (9.2%) CP-CML, 51 (72%) AP/BP-CML and 56 (49%) Ph+ ALL pts had ≥2 mutations (CP-CML: 1-5 mutations; AP/BP-CML: 1-6 mutations; Ph+ ALL: 1-13 mutations). Identification of CMs in pts with ≥2 mutations was fully possible (i.e., all the candidate pairs mapped within a distance of 400bp) in 71% of cases and partially possible (i.e., some, but not all the candidate pairs mapped within a distance of 400bp) in another 12% of cases. A total of 86 CMs (85 double and 1 triple) in 73 pts (21 [3.5%] CP-CML, 23 [32%] AP/BP-CML and 29 [37%] Ph+ ALL pts) could be catalogued (Figure 1A). All but two (T315I+D276G, M244V+E255K) were detected in pts who had received ≥2 TKIs and all included at least a 2nd-generation TKI-resistant mutation. The most frequent CMs were T315I+E255K, T315I+E255V, T315I+F359V, F317L+Y253H (Figure 1A). The triple CM, detected in a ponatinib-resistant pt, was F317I+Y253F+Q252H. Correlation of IC50 data with in vivo responses (the TKIs pts were clinically resistant to) confirmed only partially in vitro predictions (Figure 1B). In particular, although ponatinib was shown in vitro to be poorly effective against several CMs, only the T315I+E255V was consistently found to be associated with ponatinib failure. In conclusion, our results in a large unselected series of TKI-resistant pts analyzed by NGS show that:CMs are relatively infrequent in CP-CML, but may be a relevant issue in AP/BP-CML and Ph+ ALL;among pts with multiple mutations, those who have failed 1 line of therapy have most often polyclonality, whereas those who have failed ≥2 lines of therapy may have CMs or polyclonality;in vitro predictions of sensitivity and insensitivity based on IC50 data should be regarded with caution. In particular, the only compound mutant that we consistently found to be associated with ponatinib failure was the T315I+E255V. Supported by EUTOS 2016. Disclosures Soverini: Novartis: Consultancy; Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy. Pagano:Pfizer: Speakers Bureau; Gilead: Speakers Bureau; Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau. Gugliotta:Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Angelucci:Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC. Martinelli:Abbvie: Consultancy; Ariad/Incyte: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117166

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Chemotherapy, S. Karger AG, Vol. 65, No. 3-4 ( 2020), p. 110-114

Abstract: 〈 b 〉 〈 i 〉 Introduction: 〈 /i 〉 〈 /b 〉 Adult patients with acute myeloid leukemia (AML) are usually treated with intensive chemotherapy, leading to prolonged bone marrow aplasia. It is usually assumed that a short duration of aplasia could be a surrogate marker of poor therapeutic efficacy in clearing bone marrow blasts, especially in older patients. No studies have evaluated the usefulness of such a surrogate marker in younger AML patients treated with intensive chemotherapy. 〈 b 〉 〈 i 〉 Materials and Methods: 〈 /i 〉 〈 /b 〉 In the present study, we retrospectively assessed the role of white blood cell (WBC) count nadir and duration of aplasia in 68 patients with AML treated with intensive chemotherapy and potentially candidate to stem cell transplantation. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 The median (interquartile range) bone marrow aplasia was 25 days, and the mean WBC count nadir from chemotherapy start was at day +12, whereas the median neutrophil recovery occurred at day +24. No significant differences were found between responders and nonresponders for mean aplasia duration (25 vs. 26 days, 〈 i 〉 p 〈 /i 〉 value = 0.76), mean WBC count nadir (12 vs. 12 days, 〈 i 〉 p 〈 /i 〉 value = 0.86), and median neutrophil recovery (24 vs. 24, 〈 i 〉 p 〈 /i 〉 value = 0.67). 〈 b 〉 〈 i 〉 Discussion: 〈 /i 〉 〈 /b 〉 The present study evaluated the potential prognostic role of WBC count nadir and duration of aplasia, demonstrating that they are not associated with treatment outcomes in adult patients with AML treated with intensive chemotherapy. Therefore, a short duration of aplasia seems not linked to poor therapeutic efficacy in clearing bone marrow blasts. Our findings, although needing validation in larger and more homogeneous cohorts, may offer helpful clues in the management of aplasia of AML patients.

Type of Medium: Online Resource

ISSN: 0009-3157 , 1421-9794

URL: Article

DOI: 10.1159/000509816

Language: English

Publisher: S. Karger AG

Publication Date: 2020

detail.hit.zdb_id: 1482111-4

SSG: 15,3

In: European Journal of Haematology, Wiley, Vol. 92, No. 6 ( 2014-06), p. 527-536

Abstract: In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion‐dependent patients with myelodysplastic syndromes ( MDS ), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. Methods The safety and efficacy of deferasirox was examined in a prospective, open‐label, single‐arm, multicenter trial of transfusion‐dependent patients with International Prognostic Scoring System low‐ or intermediate‐1‐risk MDS and evidence of transfusion‐related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. Results Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10–20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event ( AE ). Fourteen treatment‐related grade 3 AE s occurred in 11 patients, whereas no grade 4 or 5 drug‐related AE s were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS ‐Specific Comorbidity Index, and a shorter diagnosis–enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL ( P   〈  0.0001). The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6%, 12.3%, and 15.5% after 6, 9, and 12 months, respectively. Conclusions Deferasirox therapy in transfusion‐dependent patients with MDS was moderately well tolerated and effectively lowered serum ferritin levels. Positive hematological responses were observed, and a subset of patients achieved transfusion independence.

Type of Medium: Online Resource

ISSN: 0902-4441 , 1600-0609

URL: Issue

URL: Article

DOI: 10.1111/ejh.2014.92.issue-6

DOI: 10.1111/ejh.12300

Language: English

Publisher: Wiley

Publication Date: 2014

detail.hit.zdb_id: 2027114-1

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1570-1570

Abstract: Introduction Tyrosine Kinase Inhibitors (TKI) have completely changed the scenario of CML and dramatically improved the outcomes. Thus, early identification of patients expecting poor outcome is crucial to offer alternative TKI regimens or in some selected cases stem cell transplantation before disease progression may occur. The Evaluating Nilotinib Efficacy and Safety in Trial as First-Line Treatment (ENEST1st) is a phase 3b is an open-label study of nilotinib 300 mg twice daily (BID) in adults with newly diagnosed BCR-ABL positive CP-CML. Aim of the ENEST1st sub-study N10 was to investigate BM microenvironment markers that regulate leukemic stem cells in the bone marrow (BM) niche of Nilotinib-treated patients. Methods The study enrolled patients in 21 Italian ENEST1st participating centers. Response was based on ELN recommendations (Baccarani M, et al. Blood 2013 122:872-884). In an interim analysis, molecular and cytogenetic response by 24 months was assessed. Mononuclear cells were collected from BM and PB samples at the screening visit (V0) and after 3 months of treatment (V4). RT-qPCR for the expression of 10 genes (ARF, KIT, CXCR4, FLT3, LIF, NANOg, PML, PRAME, SET and TIE), involved in the stemness and hematopoietic stem cells survival signaling regulation was conducted. RT-qPCR data were normalized by the expression of GUS mRNA (normalized copy number, NCN). Plasma samples were collected at different time points from both BM or PB samples. Concentrations of 20 different analytes, including IL-1a, IL-3, M-CSF, SCF, SDF1-a, TRAIL, HGF, PDGF-bb, IL1b, IL-6, IL-7, IL-8, IL-10, IL-12, IL-15, G-CSF, GM-CSF, MIP-1a, TNF-a, and VEGF, were simultaneously evaluated using commercially available multiplex bead-based sandwich immunoassay kits. Results 33 out of 37 patients enrolled were available for an interim molecular analysis at 24 months: an optimal response was achieved in 25 patients, a warning response in 5 patients and a failure response in 3 patients. We observed a significant correlation between the expression of two genes involved in the regulation of stem cell pluripotency (NANOg) or cytokine signaling (SET) and patient outcome. Indeed, NANOg and SET mRNA were significantly down-regulated in PB samples at diagnosis of patients with optimal response compared to patients with warning/failure response (NANOg mRNA: 0.3±0.25 NCN vs 0.6±0.7 NCN, respectively; p=0.05; SET mRNA: 0.2±0.3 NCN vs 2.3±4.2 NCN, respectively; p=0.03). We also investigated the plasma level of several factors involved in the hematopoietic stem cells (HSCs). Some of these markers showed a significant correlation with patient's outcome when evaluated at diagnosis in either PB or BM samples. Indeed, high level of IL12 (in the BM samples), or HGF, mCSF and SCF (in the PB samples) were associated to a worst prognosis markers, since significantly correlating with no MMR@12months (IL12, p=0.03), intermediate/high Socal score (mCSF, p=0.03; SCF, p=0.03), no reduction of MMR below to 1 at 3 month (SCF, p=0.04) or warning/failure response to Nilotinib treatment (HGF, p=0.03; SCF, p=0.04). Indeed, we find a lower levels of PDGFb, SDF1, TNFa, TRAIL (in the BM samples), and HGF, SDF1, TRAIL (in the PB samples) in those patients with intermediate/high Hasford or Sokal score (PDGFb, p=0.0007; SDF1, p=0.02), warning/failure response to Nilotinib treatment (HGF, p=0.03) or lacking of MMR4.0 (SDF1, p=0.01; TNFa, p=0.02; TRAIL, p=0.05). Conclusion/Summary Taken together, our results suggest that the expression analysis of genes involved in cell pluripotency (NANOg) and/or cell signaling (SET) at baseline, may indicate early achievement of deep molecular response in shown CML-CP patients treated with nilotinib. In addition, in patients with optimal response to Nilotinib, high concentration of SDF-1, TRAIL (inversely correlated with BCR-ABL, and associated to an higher susceptibility to apoptosis in the leukemic blasts) were observed as well as BM TNF (cell-extrinsic and potent endogenous suppressor of HSC activity). A lower concentration of several factors associated to hematopoietic progenitor cell growth and survival (including HGF, SCF and IL12) were observed compared to patients failing to achieve response to Nilotinib. These data strongly suggest that stromal microenvironment supports the viability of BCR-ABL cells in BM niches through direct feeding, or environment releasing of survival factors. Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Martinelli:MSD: Consultancy; BMS: Speakers Bureau; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy. Saglio:Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis Pharmaceutical Corporation: Consultancy, Honoraria. Galimberti:Novartis: Employment. Giles:Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1570.1570

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 47-48

Abstract: Introduction Tyrosine kinase inhibitors (TKIs) have dramatically changed the outcome of chronic phase chronic myeloid leukemia patients (CP-CML),improving the long-term outcome; indeed, life expectancy is now very close to that of age matched individuals in the general population. Imatinib (IMA) the first generation TKI, increased the overall survival(OS)by more than 80%. Second-generation TKIs, (2gen TKIs) used in first line dasatinib and nilotinib, induced faster molecular responses, rapidly reducing the disease burden, but did not change the OS of CP-CML newly diagnosed patients. Most of the available data reported were extrapolated from sponsored clinical trials. The aim of this analysis is to detail and analyze the prognostic features influencing the OS in a large Italian CML cohort of patients prospectively enrolled in the GIMEMA CML Italian study. Methods Relevant clinical, demographic, biological and treatment-related information were web-based collected during a multicenter,observational Italian study that enrolled consecutive patients in each disease phase, at 68 Italian hematologic centers belonging to the GIMEMA network from January 2013 to June 2020. We analyzed prognostic factors influencing the OS by Kaplan Meier method and Cox multivariable models. Results A cohort of 1206 patients was prospectively analyzed, 608 of them received frontline IMA and 598 2genTKIs. Median age in the IMA cohort was 69 years (range 58-77) vs 52 years in the 2genTKIs cohort (range 41-63). The male/female ratio was 1.7 in the IMA group and 1.35 in the 2genTKIs cohort. Ninety-eight percent of patients were in CP. Results of molecular analysis of the BCR-ABL transcript at baseline showed: b2a2 in 33.1 % of patients and b3a2 in 59.9%, while an atypical transcript was found in 7%. The cytogenetic analysis at baseline showed major and minor additional aberrations in 5.7% and 1.6% of patients respectively. In the IMA cohort,according to the Sokal score, 27.7%, 57.3% and 15% of patients were stratified as low, intermediate and high risk, whereas according to the ELTS score 51.3%, 35.5% and 13.3%, of patients were classified as low, intermediate and high risk. In the 2genTKIs cohort, according to the Sokal score, 44.8%, 34.5% and 20.8%, were low, intermediate and high risk, respectively, whereas according to the ELTS score, 66.9%, 22% and 11% were assigned to the respective risk groups.The Charlson comorbidity index in the IMA cohort was 2-3 and 4-5 in 74% and 26% of patients respectively; in the 2genTKIs cohort the score was 2-3 in 89% and 4-5 only in 10% of patients. Overall, median follow-up of the whole population was 24.7 months (range 13.3-39.3).Seventy-three patients (6.1%) in the overall population died, the majority of them in the IMA cohort: 56 patients (9.2%), at median age of 80.5 years,11/608 (1.8%) due to CML-related causes. Conversely,in the 2genTKIs cohort only 17 patients (2.8%) died, at a median age of 62 years, 10/598 (1.7%) for CML-related causes. Estimated 60-months OS of the overall population was 86.4% (95% CI 81.3-90.2): 75.8% (95% CI 64.5-84) in the IMA cohort and 93.8% (95% CI 87.5-97) in the 2genTKIs group (p & lt;0.0001). The ELTS score provides a better stratification of 60 months OS both in the IMA (OS 60-months 91.4%, 65.2%, 48.7% in low, intermediate and high risk, p & lt;0.0001) (Fig.1a) and the 2genTKIs subgroups (OS 60-months OS 95.4%, 92%, 87.9% in low, intermediate and high risk, p=0.0013)(Fig.1b). An adjusted Cox model on the entire population showed that prognostic factors influencing OS are: ELTS score (high risk vs low HR= 5.2, 95%CI 2.7-10.03, p & lt;0.0001),the type of TKI (2genTKIs vs IMA HR= 0.46; 95% CI 0.24-0.87, p=0.018), age (HR=1.03 per year, 95%CI 1.00-1.05, p=0.025) and the Charlson index (4-5 vs 2-3, HR= 1.75, 95%CI 1.43-2.1, p & lt;0.0001). Conclusions In this first analysis of our study different clinical behaviors were observed among Italian hematologists, who prevalently prescribed IMA to older patients,with more comorbidities, as compared to 2genTKIs.These differences explain a better OS for patients treated with 2genTKIs vs IMA, however, the risk of death for CML related causes is quite similar between the two groups, all the differences being attributable to other causes of death.Prognostic baseline features associated to an increased OS confirmed that, in addition to age, the ELTS score and the comorbidities are the main clinical factors that independently influence the long-term OS Disclosures Pregno: Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Abruzzese:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levato:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Di Raimondo:GILEAD, Incyte: Research Funding; Amgen, Takeda, Novartis: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Pane:Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Foà:Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Roche: Research Funding; Novartis: Research Funding; Ariad: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-139307

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 5472-5472

Abstract: Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative neoplasm (MPN) observed in the adhering centers. Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades. Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005. Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II). The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p 〈 0.001; clonality tests (JAK2 and/or others): 80% vs 9%, p 〈 0.001; cytogenetic evaluation: 55% vs 57%, p 0.58; abdominal echography: 46% vs 41%, p 0.016. The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p 〈 0.001; age 〉 60 years in 50% vs 45% of cases, p 〈 0.01); a similar rate of prior thrombosis (19% vs 19%), prior hemorrhage (3% vs 4%), CVRFs 69% vs 66%), splenomegaly (25% vs 25%), and hepatomegaly (22% vs 24%); a lower rate of disease-related symptoms (36% vs 40%, p 0.04); a higher rate of comorbidities (55% vs 51%, p 0.03). Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p 〈 0.001; 〈 600 x 109/L in 22% vs 14% of cases, p 〈 0.001); a similar white blood cell (WBC) count (median 8.6 vs 8.5 x 109/L; 〉 10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004. In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p 〈 0.001): AntiPLT 29% vs 24%, CYT 13% vs 16%, CYT+AntiPLT 49% vs 46%, CYT ± AntiPLT 62% vs 62%, AntiPLT ± CYT 78% vs 69%. The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively. The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age ( 〉 60 and 40-60 vs 〈 40 years, p 〈 0.001), higher PLT count ( 〉 1000 and 700-1000 vs 〈 700 x 109/L, p 〈 0.001), prior thrombosis (p 〈 0.001), symptoms (p 〈 0.001). Noteworthy, no relationship was found with JAK2 mutation, and WHO diagnosis. Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%). The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count 〉 700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs. Table Table. Disclosures Gugliotta: SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.5472.5472

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2023-05-03)

Type of Medium: Online Resource

ISSN: 2044-5385

URL: Article

DOI: 10.1038/s41408-023-00834-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2023

detail.hit.zdb_id: 2600560-8

In: American Journal of Hematology, Wiley

Abstract: Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP‐CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD‐eligible patients, we conducted TFR‐PRO, a cohort retro‐prospective study: 870 CP‐CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person‐years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person‐years (95% CI [0.003–0.138]) in the overall group; 0.0 (95% CI [0–0.163] ) in the discontinuation cohort; and 0.030 (95% CI [0.004–0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p   〈  .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.

Type of Medium: Online Resource

ISSN: 0361-8609 , 1096-8652

URL: Article

DOI: 10.1002/ajh.27073

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 1492749-4

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 458-458

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

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119182

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Experimental Hematology, Elsevier BV, Vol. 55 ( 2017-11), p. 71-75

Type of Medium: Online Resource

ISSN: 0301-472X

URL: Article

DOI: 10.1016/j.exphem.2017.07.007

Language: English

Publisher: Elsevier BV

Publication Date: 2017

detail.hit.zdb_id: 2005403-8