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The online version of this article has a Supplementary Appendix. BackgroundThe prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes. Design and MethodsWe studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia. ResultsPatients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMMLspecific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis. ConclusionsCytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.Key words: chronic myelomonocytic leukemia, CMML, cytogenetic. leukemia. Haematologica 2011;96(3):375-383. doi:10.3324/haematol.2010 This is an open-access paper. Citation: Such E, Cervera J, Costa D, Solé F, Vallespí T, Luño E, Collado R, Calasanz MJ, Hernández-Rivas JM, Cigudosa JC, Nomdedeu B, Mallo M, Carbonell F, Bueno J, Ardanaz MT, Ramos F, Tormo M, Sancho-Tello R, del Cañizo C, Gómez V, Marco V, Xicoy B, Bonanad S, Pedro C, Bernal T, and Sanz GF. Cytogenetic risk stratification in chronic myelomonocytic Cytogenetic risk stratification in chronic myelomonocytic leukemia

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• In intermediate-risk AML,effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio.• Combined evaluation of NPM1 mutation and FLT3-ITD burden might contribute to identify patients who benefit from early allogeneic HSCT.Risk associated to FLT3 internal tandem duplication (FLT3-ITD) in patients with acute myeloid leukemia (AML) may depend on mutational burden and its interaction with other mutations. We analyzed the effect of FLT3-ITD/FLT3 wild-type (FLT3wt) ratio depending on NPM1 mutation (NPM1mut) in 303 patients with intermediate-risk cytogenetics AML treated with intensive chemotherapy. Among NPM1mut patients, FLT3wt and low ratio (<0.5) subgroups showed similar overall survival, relapse risk, and leukemia-free survival, whereas high ratio ( ‡0.5) patients had a worse outcome. In NPM1wt AML, FLT3-ITD subgroups showed a comparable outcome, with higher risk of relapse and shortened overall survival than FLT3wt patients. Allogeneic stem cell transplantation in CR1 was associated with a reduced relapse risk in all molecular subgroups with the exception of NPM1mut AML with absent or low ratio FLT3-ITD. In conclusion, effect of FLT3 burden is modulated by NPM1 mutation, especially in patients with a low ratio. (Blood. 2013;121(14): 2734-2738) IntroductionThe presence of FLT3 internal tandem duplication (FLT3-ITD) is associated with an increased risk of relapse (RR) and inferior overall survival (OS) in patients with normal karyotype acute myeloid leukemia (AML), arising as one of the main prognostic factors in this group of patients. 1-4 However, the risk conferred by this mutation has been related to specific characteristics, such as the allelic burden, length of the mutation, or specific sequence. [4][5][6][7] Thus, the proportion of the mutant allele among leukemic population is considered one of the most important features modulating the prognostic impact of the mutation.6,7 Nonetheless, the resulting effect of the FLT3-ITD is not only a consequence of intrinsic characteristics of the mutation but can also depend on the interaction with other mutations, such as WT1 or DNMT3A, which seem to add an adverse effect in patients with FLT3-ITD AML. [8][9][10] Moreover, FLT3-ITD, considered as a secondary mutation involving signaling cell pathways that confer a proliferation advantage to the leukemic clone (type I mutation), is frequently observed in patients harboring NPM1 mutations, associated to a favorable prognosis.11-14 Therefore, the effect of FLT3-ITD burden might depend on the presence or absence of an underlying NPM1 mutation, as recently suggested. [15][16][17] To test this hypothesis we analyzed a large series of patients with a long follow-up from the Spanish cooperative group CETLAM (Grupo cooperativo para el estudio y tratamiento de las leucemias agudas mieloblásticas). Study designPatients and treatment The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solel...

The online version of this article has a supplementary appendix.Background Imatinib, given concurrently or alternating with chemotherapy, has improved the response and survival of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) but relapses are still frequent. The aim of this study was to evaluate the feasibility and results of giving imatinib concurrently with intensive chemotherapy, stem cell transplantation and post-transplant imatinib maintenance therapy in patients with newly diagnosed Ph + ALL. Design and MethodsThis was a phase II study of patients with newly diagnosed Ph + ALL given standard chemotherapy, together with imatinib (400 mg/day) until stem cell transplantation, followed by imatinib maintenance therapy for all patients regardless of the molecular status of the disease. ResultsOf the 30 patients included, 27 (90%) achieved complete remission, one was resistant to treatment and two died during induction therapy. The percentages of major and complete molecular responses were 86% and 21% after induction, and 81% and 65% after consolidation, respectively. Similar results were observed assessing minimal residual disease by flow cytometry. Of the 27 patients who achieved complete remission, 21 underwent stem cell transplantation (16 allogeneic, 5 autologous). Imatinib (400 mg/day) could be administered after transplantation for a median of 3.9 months in 12 patients, although it was interrupted in 10 patients (in 2 cases because of side effects of the drug). Nine patients relapsed, four before and five after stem cell transplantation and eight patients died of transplantrelated causes. With a median follow-up of 4.1 years, the probabilities (95% CI) of diseasefree and overall survival were 30% (15% to 45%) and 30% (16% to 45%), respectively. ConclusionsThese results confirm that imatinib is an effective first-line treatment for adult Ph + ALL when given concurrently with chemotherapy, making stem cell transplantation feasible in a high proportion of patients. However, post-transplantation imatinib administration was limited, mainly because of transplantation-derived complications rather than drug-specific toxicity.Key words: acute lymphoblastic leukemia, Philadelphia chromosome, BCR-ABL, imatinib, intensive chemotherapy, stem cell transplantation, imatinib maintenance. CSTIBES02 trial. Haematologica. 2010; 95:87-95. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Ribera J-M, Oriol A, González M, Vidriales B, Brunet S, Esteve J, del Potro E, Rivas C, Moreno M-J, Tormo M, Martín-Reina V, Sarrá J, Parody R, Pérez de Oteyza J, Bureo E, and Bernal M-T on behalf of the Programa Español de Tratamiento en Hematología (PETHEMA) and Grupo Español de Trasplante Hemopoyético (GETH) Groups. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the Concurrent intensive chemotherapy and imatinib before and after stem cell tran...