Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosis

none36Ruxolitinib discontinuation syndrome: incidence, risk factors, and management in 251 patients with myelofibrosisopenPalandri F.; Palumbo G.A.; Elli E.M.; Polverelli N.; Benevolo G.; Martino B.; Abruzzese E.; Tiribelli M.; Tieghi A.; Latagliata R.; Cavazzini F.; Bergamaschi M.; Binotto G.; Crugnola M.; Isidori A.; Caocci G.; Heidel F.; Pugliese N.; Bosi C.; Bartoletti D.; Auteri G.; Cattaneo D.; Scaffidi L.; Trawinska M.M.; Stella R.; Ciantia F.; Pane F.; Cuneo A.; Krampera M.; Semenzato G.; Lemoli R.M.; Iurlo A.; Vianelli N.; Cavo M.; Breccia M.; Bonifacio M.Palandri, F.; Palumbo, G. A.; Elli, E. M.; Polverelli, N.; Benevolo, G.; Martino, B.; Abruzzese, E.; Tiribelli, M.; Tieghi, A.; Latagliata, R.; Cavazzini, F.; Bergamaschi, M.; Binotto, G.; Crugnola, M.; Isidori, A.; Caocci, G.; Heidel, F.; Pugliese, N.; Bosi, C.; Bartoletti, D.; Auteri, G.; Cattaneo, D.; Scaffidi, L.; Trawinska, M. M.; Stella, R.; Ciantia, F.; Pane, F.; Cuneo, A.; Krampera, M.; Semenzato, G.; Lemoli, R. M.; Iurlo, A.; Vianelli, N.; Cavo, M.; Breccia, M.; Bonifacio, M

Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy

open20siBackground Imatinib has so far been the first-choice treatment in chronic myeloid leukemia with excellent results. However, only a proportion of patients achieve major molecular response – hence the need to find biological predictors of outcome to select the optimal therapeutic strategy now that more potent inhibitors are available. Design and methods We investigated a panel of 20 polymorphisms in 7 genes, potentially associated with the pharmacogenetics of imatinib, in a subset of 189 newly diagnosed chronic myeloid leukemia patients enrolled in the TOPS trial. Included in this analysis were polymorphisms in the transporters hOCT1, MDR1, ABCG2, OCTN1, and OATP1A2, and in the metabolizing genes CYP3A4 and CYP3A5. Results In the overall population, the OCTN1 C allele (rs1050152), a simple combination of polymorphisms in the hOCT1 gene and in the genes involved in imatinib uptake were significantly associated with major molecular response. The combination of polymorphisms in imatinib uptake was also significantly associated with complete molecular response. Analyses restricted to Caucasians highlighted the significant association of MDR1 CC (rs60023214) genotype with complete molecular response. Conclusions We demonstrate the usefulness of a pharmacogenetic approach for stratification of chronic myeloid leukemia patients in terms of likelihood to achieve major or complete molecular response on imatinib. This represents an attractive opportunity for therapy optimization, worth testing in clinical trials.openAngelini S; Soverini S; Ravegnini G; Barnett M; Turrini E; Thornquist M; Pane F; Hughes TP; White DL; Radich J; Kim DW; Saglio G; Cilloni D; Iacobucci I; Perini G; Woodman R; Cantelli-Forti G; Baccarani M; Hrelia P; Martinelli GAngelini S; Soverini S; Ravegnini G; Barnett M; Turrini E; Thornquist M; Pane F; Hughes TP; White DL; Radich J; Kim DW; Saglio G; Cilloni D; Iacobucci I; Perini G; Woodman R; Cantelli-Forti G; Baccarani M; Hrelia P; Martinelli

A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol

none32Blood. 2005 May 1;105(9):3434-41. Epub 2005 Jan 13. A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol. Mancini M, Scappaticci D, Cimino G, Nanni M, Derme V, Elia L, Tafuri A, Vignetti M, Vitale A, Cuneo A, Castoldi G, Saglio G, Pane F, Mecucci C, Camera A, Specchia G, Tedeschi A, Di Raimondo F, Fioritoni G, Fabbiano F, Marmont F, Ferrara F, Cascavilla N, Todeschini G, Nobile F, Kropp MG, Leoni P, Tabilio A, Luppi M, Annino L, Mandelli F, Foà R. Department of Cellular Biotechnologies and Hematology, University "La Sapienza" Via Benevento 6 Rome, 00161 Italy. [email protected] The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorith for an optimal management of these patients.M. MANCINI; D. SCAPPATICCI; G. CIMINO; M. NANNI; V. DERME; L. ELIA; A. TAFURI; M. VIGNETTI; VITALE A; CUNEO A; CASTOLDI G; SAGLIO G; PANE F; MECUCCI C; CAMERA A; SPECCHIA G; TEDESCHI A; DI RAIMONDO F; FIORITONI G; FABBIANO F; MARMONT F; FERRARA F; CASCAVILLA N; TODESCHINI G; NOBILE F; KROPP MG; P. LEONI; TABILIO A; LUPPI M; ANNINO L; MANDELLI F; FOA RM., Mancini; D., Scappaticci; G., Cimino; M., Nanni; V., Derme; L., Elia; A., Tafuri; M., Vignetti; Vitale, A; Cuneo, A; Castoldi, G; Saglio, G; Pane, F; Mecucci, C; Camera, A; Specchia, G; Tedeschi, A; DI RAIMONDO, F; Fioritoni, G; Fabbiano, F; Marmont, F; Ferrara, F; Cascavilla, N; Todeschini, G; Nobile, F; Kropp, Mg; Leoni, Pietro; Tabilio, A; Luppi, M; Annino, L; Mandelli, F; Foa, R

CDKN2A/B alterations impair prognosis in adult BCR-ABL1-positive acute lymphoblastic leukemia patients.

none21PURPOSE: The 9p21 locus, encoding three important tumor suppressors (p16/CDKN2A, p14/ARF, and p15/CDKN2B), is a major target of inactivation in the pathogenesis of many human tumors. PATIENTS AND METHODS: To explore, at high resolution, the frequency and size of alterations affecting this locus in adult BCR-ABL1-positive acute lymphoblastic leukemia (ALL) and to investigate their prognostic value, 112 patients (101 de novo and 11 relapsed cases) were analyzed by genome-wide single-nucleotide polymorphism arrays and gene candidate deep exon sequencing. Paired diagnosis-relapse samples were further available and analyzed for 19 (19%) cases. RESULTS: CDKN2A/ARF and CDKN2B genomic alterations were identified in 29% and 25% of newly diagnosed patients, respectively. Deletions were monoallelic in 72% of cases, and in 43% of them, the minimal overlapping region of the lost area spanned only the CDKN2A/B gene locus. An analysis conducted at relapse showed an increase in the detection rate of CDKN2A/ARF loss (47%) compared with the time of diagnosis (P = 0.06). Point mutations within the 9p21 locus were found at very low levels, with only a nonsynonymous substitution in the exon 2 of CDKN2A. Of note, deletions of CDKN2A/B were significantly associated with poor outcomes in terms of overall survival (P = 0.0206), disease free-survival (P = 0.0010), and cumulative incidence of relapse (P = 0.0014). CONCLUSIONS: Inactivation of the 9p21 locus by genomic deletion is a frequent event in BCR-ABL1-positive ALL. Deletions are frequently acquired during leukemia progression and are a poor prognostic marker of long-term outcomes.openIacobucci I; Ferrari A; Lonetti A; Papayannidis C; Paoloni F; Trino S; Storlazzi CT; Ottaviani E; Cattina F; Impera L; Abbenante MC; Vignetti M; Vitale A; Potenza L; Paolini S; Soverini S; Pane F; Luppi M; Foà R; Baccarani M; Martinelli G.Iacobucci I; Ferrari A; Lonetti A; Papayannidis C; Paoloni F; Trino S; Storlazzi CT; Ottaviani E; Cattina F; Impera L; Abbenante MC; Vignetti M; Vitale A; Potenza L; Paolini S; Soverini S; Pane F; Luppi M; Foà R; Baccarani M; Martinelli G

Divergent behavior of hydrogen sulfide pools and of the sulfur metabolite lanthionine, a novel uremic toxin, in dialysis patients.

Dialysis patients display a high cardiovascular mortality, the causes of which are still not completely explained, but are related to uremic toxicity. Among uremic toxins, homocysteine and cysteine are both substrates of cystathionine β-synthase and cystathionine γ-lyase in hydrogen sulfide biosynthesis, leading to the formation of two sulfur metabolites, lanthionine and homolanthionine, considered stable indirect biomarkers of its production. Hydrogen sulfide is involved in the modulation of multiple pathophysiological responses. In uremia, we have demonstrated low plasma total hydrogen sulfide levels, due to reduced cystathionine γ-lyase expression. Plasma hydrogen sulfide levels were measured in hemodialysis patients and healthy controls with three different techniques in comparison, allowing to discern the different pools of this gas. The protein-bound (the one thought to be the most active) and acid-labile forms are significantly decreased, while homolanthionine, but especially lanthionine, accumulate in the blood of uremic patients. The hemodialysis regimen plays a role in determining sulfur compounds levels, and lanthionine is partially removed by a single dialysis session. Lanthionine inhibits hydrogen sulfide production in cell cultures under conditions comparable to in vivo ones. We therefore propose that lanthionine is a novel uremic toxin. The possible role of high lanthionine as a contributor to the genesis of hyperhomocysteinemia in uremia is discusse

Safe discontinuation of nilotinib in a patient with chronic myeloid leukemia: a case report

Case presentation. We report the case of a 64-year-old Caucasian man diagnosed with chronic-phase chronic myeloid leukemia in April 2005. After 4 years of treatment with imatinib, he became intolerant to the drug and was switched to nilotinib. Two years later, he decided to stop nilotinib. Undetectable molecular response persisted for 30 months after discontinuation of the drug. Introduction. Although there is a considerable amount of data in the literature on safe discontinuation of first-generation tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia, little is known about discontinuation of second-generation tyrosine kinase inhibitor therapy. Most previous studies have been focused on dasatinib, and the few cases of nilotinib withdrawal that have been reported had a median follow-up of 12 months. To the best of our knowledge, the present report is the first to describe nilotinib withdrawal with 30 months of follow-up. Conclusion: Our present case suggests that nilotinib withdrawal is safe for patients with chronic myeloid leukemia who achieve a stable undetectable molecular response. Our patient was homozygous for killer immunoglobulin-like receptor haplotype A, previously reported to be a promising immunogenetic marker for undetectable molecular response. We recommend additional studies to investigate patient immunogenetic profiles and their potential role in complete response to therap

European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR