Monosomal karyotype in chronic lymphocytic leukemia: Association with clinical and biological features and potential prognostic significance
Authors: Maria Joao Baptista, Isabel Granada, Mireia Morgades, María‐José Calasanz, Jordi Canals, Diego Robles De Castro, Elisa Luño, Neus Ruiz‐Xivillé, Inés Rodríguez‐Hernández, Teresa González, María‐José Terol, Alberto Valiente, Francisco Ortuño, María‐Dolores Garcia‐Malo, María‐Ángeles Piñan, Ana Carla Oliveira, Maria Talavera, Ismael Buño, Ana Batlle‐López, Carol Moreno, Christelle Ferra, Francesc Solé
Journal: American Journal of Hematology (2017)

Cytogenetic abnormalities play an important role in the management of patients with chronic lymphocytic leukemia (CLL). For many years the del(17p) and del(11q) have been identified as poor prognostic factors and together with +12 and del(13q) are the most recurrent de novo genetic abnormalities. The modern practice is to study CLL cytogenetics by FISH, nevertheless the importance of metaphase analysis is reemerging due to recent studies showing the impact of complex karyotype (CK) on CLL prognosis.1-3 In other hematological malignancies, not only the number of cytogenetic abnormalities given by CK (depending on the pathology ≥3 or ≥5 abnormalities, in CLL ≥3) but also the type of abnormalities, given for instance by monosomal karyotype (MK: defined by the presence of ≥2 autosomal monosomies or 1 monosomy with ≥1 structural abnormality), were shown to be of prognostic importance.4 The aim of this study was to analyze the prognostic significance of MK in a large series of patients with CLL registered in the database of the Spanish Cooperative Group for Hematological Cytogenetics (GCECGH; “Grupo Cooperativo Español de Citogenética Hematológica”) and the Spanish Group of CLL (GELLC; “Grupo Español de Leucemia Linfática Crónica”). The study was approved by the local ethic committee “Comité de Ética de la Investigación del Hospital Universitari Germans Trias i Pujol” (Reference: PI-17-033). From the 2772 patients registered in the database, 1013 patients with CLL had karyotype data at diagnosis or before treatment initiation and from those, 881 patients were included in the study since follow-up data was also available. Further details on patients and methods are disclosed in Supporting Information Methods. The median age of the evaluable patients was 67 years (range, 27-95) and 63% were male. The median follow-up of survivors was 4.32 years (95%CI [0.02-22.87]) and 39.4% of the patients required treatment during the course of the disease. Please consult Supporting Information Table I for patient characteristics. Among 881 patients, 351 (39.8%) presented a clonal abnormal karyotype. Monosomies were observed in 52 out of 881 patients (5.9%) and they were detected in all chromosomes except in chromosomes 1, 2, 4, and 7. MK was identified in 37 patients (4.2%), 18 had two or more monosomies and the remaining 19 had one monosomy associated with a structural chromosomal abnormality. The frequency of MK in CLL was lower than that observed in other leukemia types (eg, acute myeloid leukemia: 9%).4 Patients with MK had worse prognostic baseline characteristics than those without MK (Supporting Information Table I). They were older at diagnosis (median age: 71 vs. 67 years, P = .019), presented higher levels of lactate dehydrogenase (median levels: 354 vs. 302 IU/L, P = .037) and beta 2-microglobulin (B2M) (median levels: 2.5 vs. 2.1 mg/L, P < .001), had more adverse cytogenetic features (del(11q): 26.7% vs. 8.7%, P = .005; del(17p): 56.7% vs. 4.8, P < .001; CK: 86.5% vs. 2.7%, P < .001), and more cases expressed ZAP-70 (64.3% vs. 32.6%, P = .017) and had unmutated IGHV genes (83.3% vs. 29.4%, P = .013). When compared with patients with other abnormal karyotypes (Supporting Information Table I), patients with MK showed higher B2M levels (median levels: 2.5 vs. 2.2 mg/L, P = .006). Also, more patients with MK had unmutated IGHV genes (83.3% vs. 33.3%, P = .032), del(17p) (56.7% vs. 7.2%, P < .001), and CK (86.5% vs. 7.3%, P < .001) but less patients with MK had trisomy 12 (16.7% vs. 39.7%, P = .014). The median overall survival (OS) of patients with MK (6.44 years) was approximately half of those without MK (12.40 years, P < .001; Figure 1A) or with other abnormal karyotypes (12.40 years, P = .006, Figure 1B). More patients with MK required treatment (70.3%) than patients without MK (38.0%, P < .001) or with other abnormal karyotypes (45.5%, P = .004) and in a shorter period of time (median time to first treatment (TTFT) in years; 1.77 vs. 6.99, P < .001 or vs. 4.42, P < 0.001, respectively; Figure 1C,D). Despite the impact of MK on OS, MK was not an independent prognostic factor. In line with the recent published CLL-IPI, in this CLL series the independent predictors of OS were age, ECOG status, B2M, and del(17p) (Supporting Information Table II).5 Likewise, MK was not an independent predictor of shorter TTFT, but according to previous data, Binet stages B-C, presence of B-symptoms and of adenopathies, hemoglobin ≤10 g/L, hypogammaglobulinemia, del(11q) and CK retained their deleterious impact on TTFT in the multivariate analysis (Supporting Information Table III).1, 5 Kaplan–Meier plots comparing overall survival (OS) and time to first treatment (TTFT) of patients with monosomal karyotype (MK) versus patients with non-monosomal karyotype (non-MK) or versus patients with other abnormal karyotypes in the whole series and in the subsets of patients with deletion 17p or with complex karyotype (CK). A, OS of patients with MK versus patients with non-MK in the whole series. B, OS of patients with MK versus patients with other abnormal karyotypes in the whole series. C, TTFT of patients with MK versus patients with non-MK in the whole series. D, TTFT of patients with MK versus patients with other abnormal karyotypes in the whole series. E, OS of patients with deletion 17p and MK versus patients with deletion 17p without MK. F, TTFT of patients with deletion 17p and MK versus patients with deletion 17p without MK. G, OS of patients with complex and monosomal karyotype versus patients with complex but not monosomal karyotype. H, TTFT of patients with complex and monosomal karyotype versus patients with complex but not monosomal karyotype Since MK was strongly associated with CK and del(17p), MK was studied independently in each of those CLL subsets. Within the group of patients with del(17p), the absence of MK allowed the identification of a subset with an extremely good prognosis. Patients with del(17p) and MK showed worse median OS than patients with del(17p) and non-MK (3.26 vs. 10.39 years, P = .012; Figure 1E) and tended to present shorter median TTFT (1.64 vs. 2.56 years; P = .095; Figure 1F). Although it could be surprising to disclose patients with del(17p) and such good survivals, these were previously reported in the literature.6 In our subset of patients with del(17p), MK was associated with CK but surprisingly with lower Binet stages (Supporting Information Table IV). It is worth to mention that in the study by Strati et al., in the subset of patients with del(17p), CK was not associated with OS, and in the study by Le Bris et al., CK did not predict shorter OS in high risk patients.2, 3 Moreover, most of the patients with del(17p) and long survivals reported by Best et al., also had CK.6 Although more studies are needed, findings suggest that the type of chromosomal abnormalities could be more important than their number, and that MK could be a valuable prognostic marker of OS in the subgroup of patients with del(17p) CLL. In the subset of patients with CK, a concomitant MK was associated with the presence of del(17p) and absence of +12 (Supporting Information Table V). However, there were no statistically significant differences on OS or TTFT for patients with CK depending on the presence of MK (Figure 1G,H, respectively). To the best of our knowledge the present study is the first study assessing the impact of MK on CLL. It showed that patients with MK had poorer outcomes than patients without MK or with other abnormal karyotypes, although MK was not an independent prognostic marker for OS or for TTFT. In patients with del(17p), the presence of MK could help identify those with the poorest prognosis. These observations argue in favor of reassessing conventional karyotype analysis on CLL. The authors thank the contributing efforts of the members of the “Grupo Cooperativo Español de Citogenética Hematológica” (GCECGH) and of the “Grupo Español de Leucemia Linfática Crónica” (GELLC). This work was supported in part by grants 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds given to Josep Carreras Leukaemia Research Institute from Josep Carreras International Foundation, “la Caixa” Foundation and Celgene Spain. The authors declare no competing financial interests. Additional Supporting Information may be found online in the supporting information tab for this article. 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