Enumerating bone marrow blasts from nonerythroid cellularity improves outcome prediction in myelodysplastic syndromes and permits a better definition of the intermediate risk category of the Revised International Prognostic Scoring System (IPSS-R).

The Revised International Prognostic Scoring System (IPSS-R) has been recognized as the score with the best outcome prediction capability in MDS, but this brought new concerns about the accurate prognostication of patients classified into the intermediate risk category. The correct enumeration of blasts is essential in prognostication of MDS. Recent data evidenced that considering blasts from nonerythroid cellularity (NECs) improves outcome prediction in the context of IPSS and WHO classification. We assessed the percentage of blasts from total nucleated cells (TNCs) and NECs in 3924 MDS patients from the GESMD, 498 of whom were MDS with erythroid predominance (MDS-E). We assessed if calculating IPSS-R by enumerating blasts from NECs improves prognostication of MDS. Twenty-four percent of patients classified into the intermediate category were reclassified into higher-risk categories and showed shorter overall survival (OS) and time to AML evolution than those who remained into the intermediate one. Likewise, a better distribution of patients was observed, since lower-risk patients showed longer survivals than previously whereas higher-risk ones maintained the outcome expected in this poor prognostic group (median OS < 20 months). Furthermore, our approach was particularly useful for detecting patients at risk of dying with AML. Regarding MDS-E, 51% patients classified into the intermediate category were reclassified into higher-risk ones and showed shorter OS and time to AML. In this subgroup of MDS, IPSS-R was capable of splitting our series in five groups with significant differences in OS only when blasts were assessed from NECs. In conclusion, our easy-applicable approach improves prognostic assessment of MDS patients.

Multidimensional assessment of patient condition and mutational analysis in peripheral blood, as tools to improve outcome prediction in myelodysplastic syndromes: A prospective study of the Spanish MDS group.

The International Prognostic Scoring System and its revised form (IPSS-R) are the most widely used indices for prognostic assessment of patients with myelodysplastic syndromes (MDS), but can only partially account for the observed variation in patient outcomes. This study aimed to evaluate the relative contribution of patient condition and mutational status in peripheral blood when added to the IPSS-R, for estimating overall survival and the risk of leukemic transformation in patients with MDS. A prospective cohort (2006-2015) of 200 consecutive patients with MDS were included in the study series and categorized according to the IPSS-R. Patients were further stratified according to patient condition (assessed using the multidimensional Lee index for older adults) and genetic mutations (peripheral blood samples screened using next-generation sequencing). The change in likelihood-ratio was tested in Cox models after adding individual covariates. The addition of the Lee index to the IPSS-R significantly improved prediction of overall survival [hazard ratio (HR) 3.02, 95% confidence interval (CI) 1.96-4.66, P < 0.001), and mutational analysis significantly improved prediction of leukemic evolution (HR 2.64, 1.56-4.46, P < 0.001). Non-leukemic death was strongly linked to patient condition (HR 2.71, 1.72-4.25, P < 0.001), but not to IPSS-R score (P = 0.35) or mutational status (P = 0.75). Adjustment for exposure to disease-modifying therapy, evaluated as a time-dependent covariate, had no effect on the proposed model's predictive ability. In conclusion, patient condition, assessed by the multidimensional Lee index and patient mutational status can improve the prediction of clinical outcomes of patients with MDS already stratified by IPSS-R.

Erythroleukemia shares biological features and outcome with myelodysplastic syndromes with excess blasts: a rationale for its inclusion into future classifications of myelodysplastic syndromes.

Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of ≥50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but ≥20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (≥50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with ≥50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having ≥20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data suggest that de novo erythroleukemia is in the spectrum of myelodysplastic syndromes with excess blasts and support its inclusion into future classifications of myelodysplastic syndromes.

Hematopoietic clonal dominance, stem cell mutations, and evolutionary pattern of JAK2V617F allele burden in polycythemia vera.

OBJECTIVES: Clonal dominance is characteristic of patients with post-polycythemia vera myelofibrosis (post-PV MF), whereas patients in chronic phase usually display polyclonal hematopoiesis. The aim of this work was to study the mutational burden of JAK2V617F at the progenitor level in patients with PV and correlate it with the evolutive phase of the disease and the presence of mutations in genes different to JAK2V617F. METHODS: JAK2V617F was measured in stem cells, progenitor cells, and granulocytes of 45 patients with PV (early chronic phase n = 26, late chronic phase n = 10, post-PV MF n = 9). In addition, screening of TET2, DNMT3A, ASXL1, SF3B1, SRSF2, U2AF1, and TP53 was performed with quantification of the mutation in CD34+ cells in positive cases. Moreover, we assessed whether JAK2V617F allele burden in granulocytes (at a single time point or monitoring) could be used as a surrogate of clonal dominance. RESULTS: Ten patients presented clonal dominance at progenitor level (PV at diagnosis n = 2, late chronic phase n = 1, post-PV MF n = 7). Additional mutations were identified in four patients at diagnosis, three in TET2, and one in DNMT3A gene, with clonal dominance present in three of them. At PV diagnosis, clonal dominance was demonstrated only in patients with additional mutations. JAK2V617F monitoring showed better diagnostic accuracy than single time point measurement as a marker of clonal dominance. CONCLUSIONS: Clonal dominance may be present at diagnosis, especially in those cases carrying other mutations. JAK2V617F monitoring during follow-up could help in the identification of patients with clonal dominance.

Multilineage dysplasia is associated with a poorer prognosis in patients with de novo acute myeloid leukemia with intermediate-risk cytogenetics and wild-type NPM1.

Acute myeloid leukemia (AML) with myelodysplasia-related changes is characterized by the presence of multilineage dysplasia (MLD), frequently related to high-risk cytogenetics and poor outcome. However, the presence of MLD does not modify the favorable prognostic impact of NPM1 mutation. The prognosis of patients with AML presenting marked dysplasia lacking high-risk cytogenetics and NPM1 mutation is uncertain. We evaluated the prognostic impact of MLD in 177 patients with intermediate-risk cytogenetics AML (IR-AML) and wild-type NPM1. Patients were categorized as MLD-WHO (WHO myelodysplasia criteria; n = 43, 24 %), MLD-NRW (significant MLD non-reaching WHO criteria; n = 16, 9 %), absent MLD (n = 80, 45 %), or non-evaluable MLD (n = 38, 22 %). No differences concerning the main characteristics were observed between patients with or without MLD. Outcome of patients with MLD-WHO and MLD-NRW was similar, and significantly worse than patients lacking MLD. The presence of MLD (66 vs. 80 %, p = 0.03; HR, 95 % CI = 2.3, 1.08-4.08) and higher leukocyte count at diagnosis was the only variable associated with lower probability of complete remission after frontline therapy. Concerning survival, age and leukocytes showed an independent prognostic value, whereas MLD showed a trend to a negative impact (p = 0.087, HR, 95 % CI = 1.426, 0.95-2.142). Moreover, after excluding patients receiving an allogeneic stem cell transplantation in first CR, MLD was associated with a shorter survival (HR, 95 % CI = 1.599, 1.026-2.492; p = 0.038). In conclusion, MLD identifies a subgroup of patients with poorer outcome among patients with IR-AML and wild-type NPM1.

Single nucleotide polymorphism array karyotyping: a diagnostic and prognostic tool in myelodysplastic syndromes with unsuccessful conventional cytogenetic testing.

Cytogenetic aberrations identified by metaphase cytogenetics (MC) have diagnostic, prognostic, and therapeutic implications in myelodysplastic syndromes (MDS). However, in some MDS patients MC study is unsuccesful. Single nucleotide polymorphism array (SNP-A) based karyotyping could be helpful in these cases. We performed SNP-A in 62 samples from bone marrow or peripheral blood of primary MDS with an unsuccessful MC study. SNP-A analysis enabled the detection of aberrations in 31 (50%) patients. We used the copy number alteration information to apply the International Prognostic Scoring System (IPSS) and we observed differences in survival between the low/intermediate-1 and intermediate-2/high risk patients. We also saw differences in survival between very low/low/intermediate and the high/very high patients when we applied the revised IPSS (IPSS-R). In conclusion, SNP-A can be used successfully in PB samples and the identification of CNA by SNP-A improve the diagnostic and prognostic evaluation of this group of MDS patients.

Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations.

Lenalidomide is an effective drug in low-risk myelodysplastic syndromes (MDS) with isolated del(5q), although not all patients respond. Studies have suggested a role for TP53 mutations and karyotype complexity in disease progression and outcome. In order to assess the impact of complex karyotypes on treatment response and disease progression in 52 lenalidomide-treated patients with del(5q) MDS, conventional G-banding cytogenetics (CC), single nucleotide polymorphism array (SNP-A), and genomic sequencing methods were used. SNP-A analysis (with control sample, lymphocytes CD3+, in 30 cases) revealed 5q losses in all cases. Other recurrent abnormalities were infrequent and were not associated with lenalidomide responsiveness. Low karyotype complexity (by CC) and a high baseline platelet count (>280 × 10(9) /l) were associated with the achievement of haematological response (P = 0·020, P = 0·013 respectively). Unmutated TP53 status showed a tendency for haematological response (P = 0·061). Complete cytogenetic response was not observed in any of the mutated TP53 cases. By multivariate analysis, the most important predictor for lenalidomide treatment failure was a platelet count <280 × 10(9) /l (Odds Ratio = 6·17, P = 0·040). This study reveals the importance of a low baseline platelet count, karyotypic complexity and TP53 mutational status for response to lenalidomide treatment. It supports the molecular study of TP53 in MDS patients treated with lenalidomide.

Reproducibility of the World Health Organization 2008 criteria for myelodysplastic syndromes.

The reproducibility of the World Health Organization 2008 classification for myelodysplastic syndromes is uncertain and its assessment was the major aim of this study. The different peripheral blood and bone marrow variables required for an adequate morphological classification were blindly evaluated by four cytomorphologists in samples from 50 patients with myelodysplastic syndromes. The degree of agreement among observers was calculated using intraclass correlation coefficient and the generalized kappa statistic for multiple raters. The degree of agreement for the percentages of blasts in bone marrow and peripheral blood, ring sideroblasts in bone marrow, and erythroid, granulocytic and megakaryocytic dysplastic cells was strong (P<0.001 in all instances). After stratifying the percentages according to the categories required for the assignment of World Health Organization subtypes, the degree of agreement was not statistically significant for cases with 5-9% blasts in bone marrow (P=0.07), 0.1-1% blasts in peripheral blood (P=0.47), or percentage of erythroid dysplastic cells (P=0.49). Finally, the interobserver concordance for World Health Organization-defined subtypes showed a moderate overall agreement (P<0.001), the reproducibility being lower for cases with refractory anemia with excess of blasts type 1 (P=0.05) and refractory anemia with ring sideroblasts (P=0.09). In conclusion, the reproducibility of the World Health Organization 2008 classification for myelodysplastic syndromes is acceptable but the defining criteria for blast cells and features of erythroid dysplasia need to be refined.

Leukemic Involvement Is a Common Feature in Waldenström Macroglobulinemia at Diagnosis.

Waldenström Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with bone marrow (BM) involvement and IgM monoclonal gammopathy. To date, no studies have focused specifically on peripheral blood (PB) involvement. In this study, 100 patients diagnosed with WM according to the World Health Organization (WHO) criteria were included based on the demonstration of MYD88mut in BM and the availability of PB multiparametric flow cytometry (MFC) analysis. Leukemic involvement by MFC was detected in 50/100 patients. A low percentage of mature small lymphocytes in PB smears was observed in only 15 cases. MYD88mut by AS-qPCR was detected in PB in 65/100 cases. In cases with leukemic expression by MFC, MYD88mut was detected in all cases, and IGH was rearranged in 44/49 cases. In 21/50 patients without PB involvement by MFC, molecular data were consistent with circulating disease (MYD88mut by AS-qPCR 3/50, IGH rearranged 6/50, both 12/50). Therefore, PB involvement by standard techniques was detected in 71/100 patients. MYD88mut was detected in PB by dPCR in 9/29 triple negative cases. Overall, 80% of the patients presented PB involvement by any technique. Our findings support the role of PB MFC in the evaluation of patients with IgM monoclonal gammopathy and provide reliable information on correlation with molecular features. The development of a feasible MFC assay may stand as an objective tool in the classification of mature B cell neoplasms presenting with IgM monoclonal gammopathy.

Prognostic value of trisomy 8 as a single anomaly and the influence of additional cytogenetic aberrations in primary myelodysplastic syndromes.

Trisomy 8 is the most common chromosomal gain in myelodysplastic syndromes (MDS), however, little is known about the features of MDS with isolated trisomy 8 and the influence of additional cytogenetic aberrations. We determined the characteristics and prognostic factors of 72 patients with trisomy 8 as a single anomaly and analysed also the impact of other aberrations added to trisomy 8 in another 62 patients. According to our study, MDS with isolated trisomy 8 was more frequent in men, with more than one cytopenia in most patients (62%) and having about 4% bone marrow blasts. The multivariate analysis demonstrated that platelet count and percentage bone marrow blasts had the strongest impact on overall survival (OS). The median OS for isolated trisomy 8, trisomy 8 plus one aberration (tr8 + 1), plus two (tr8 + 2) and plus three or more aberrations (tr8 + ≥3) was 34·3, 40, 23·4 and 5·8 months, respectively (P < 0·001). Trisomy 8 confers a poorer prognosis than a normal karyotype in MDS patients with ≥5% bone marrow blasts. This study supports the view that MDS with isolated trisomy 8 should be included in the intermediate cytogenetic risk group.

Cytogenetic aberrations and their prognostic value in a series of 330 splenic marginal zone B-cell lymphomas: a multicenter study of the Splenic B-Cell Lymphoma Group.

We conducted a retrospective collaborative study to cytogenetically characterize splenic marginal zone lymphoma (SMZL) and ascertain the prognostic value of chromosomal aberrations. Of 330 cases, 72% displayed an aberrant karyotype, 53% were complex, and 29% had a single aberration. The predominant aberrations were gains of 3/3q and 12q, deletions of 7q and 6q and translocations involving 8q/1q/14q. CD5 expression was detected in 39 of 158 cases (25%). The cytogenetic makeup of the CD5(+) group differed significantly from that of the CD5(-) group. Cases with unmutated IGHV were significantly associated with deletions of 7q and TP53. A strong association was noted between usage of the IGVH1-2 and deletion 7q, 14q alterations, and abnormal karyotype. On univariate analysis, patients with more than or equal to 2 aberrations, 14q alterations, and TP53 deletions had the shortest survival; 7q deletion did not affect survival. On multivariate analysis, cytogenetic aberrations did not retain prognostic significance; the parameters negatively affecting survival were hemoglobin and age. In conclusion, the cytogenetic profile of SMZL is distinct from other B-cell lymphomas. Complexity of the karyotype, 14q aberrations, and TP53 deletions are poor prognostic indicators and may be considered together with other clinicobiologic parameters to ascertain the prognosis of SMZL.

Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis.

BACKGROUND: Refractory anemia with ring sideroblasts associated with marked thrombocytosis was proposed as a provisional entity in the 2001 World Health Organization classification of myeloid neoplasms and also in the 2008 version, but its existence as a single entity is contested. We wish to define the clinical features of this rare myelodysplastic/myeloproliferative neoplasm and to compare its clinical outcome with that of refractory anemia with ring sideroblasts and essential thrombocythemia. DESIGN AND METHODS: We conducted a collaborative retrospective study across Europe. Our database included 200 patients diagnosed with refractory anemia with ring sideroblasts and marked thrombocytosis. For each of these patients, each patient diagnosed with refractory anemia with ring sideroblasts was matched for age and sex. At the same time, a cohort of 454 patients with essential thrombocythemia was used to compare outcomes of the two diseases. RESULTS: In patients with refractory anemia with ring sideroblasts and marked thrombocytosis, depending on the Janus Kinase 2 V617F mutational status (positive or negative) or platelet threshold (over or below 600 × 10(9)/L), no difference in survival was noted. However, these patients had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia (P<0.001) but better survival (P<0.001) and a higher risk of thrombosis (P=0.039) than patients with refractory anemia with ring sideroblasts. CONCLUSIONS: The clinical course of refractory anemia with ring sideroblasts and marked thrombocytosis is better than that of refractory anemia with ring sideroblasts and worse than that of essential thrombocythemia. The higher risk of thrombotic events in this disorder suggests that anti-platelet therapy might be considered in this subset of patients. From a clinical point of view, it appears to be important to consider refractory anemia with ring sideroblasts and marked thrombocytosis as a distinct entity.

Clinical significance of clonality assessment in JAK2V617F-negative essential thrombocythemia.

JAK2V617F-negative essential thrombocythemia (ET) is a heterogeneous disease including clonal cases and others without evidence of clonality. However, it is unknown if the detection of myeloid clonality in JAK2V617F-negative ET patients confers a different clinical outcome than those in whom clonal hematopoiesis cannot be demonstrated. The objective of the present study was to evaluate the clinical significance of clonality assessment in patients with JAK2V617F-negative ET. Clonality investigation including mutational status of MPL, TET2, and ASXL1 genes and human androgen receptor (HUMARA) assay was performed in 73 JAK2V617F-negative cases out of 186 subjects consecutively diagnosed with ET in a single institution, at diagnosis or during follow-up. Mutations in MPL, TET2, and ASXL1 were observed in 7, 4, and 2 cases, respectively, whereas clonality by HUMARA assay was demonstrated in 21 out of 46 (46 %) female patients. With a median follow-up of 8 years, death, thrombosis, bleeding, and disease transformation were registered in 7, 10, 8, and 6 patients, respectively. No differences in thrombosis, bleeding or survival were observed according to clonality assessment. The probability of disease transformation at 10 years was higher in patients showing clonal hematopoiesis by presenting mutations in either MPL, TET2, or ASXL1 (64 versus 2 % in patients without mutations, p < 0.001) and in those with HUMARA clonality (35 versus 0 % in patients with polyclonal hematopoiesis, p < 0.004). In conclusion, disease transformation is associated with evidence of clonality in JAK2V617F-negative ET.

Outcomes and molecular profile of oligomonocytic CMML support its consideration as the first stage in the CMML continuum.

Patients with oligomonocytic chronic myelomonocytic leukemia (OM-CMML) are currently classified according to the 2017 World Health Organization myelodysplastic syndromes classification. However, recent data support considering OM-CMML as a specific subtype of chronic myelomonocytic leukemia (CMML), given their similar clinical, genomic, and immunophenotypic profiles. The main purpose of our study was to provide survival outcome data of a well-annotated series of 42 patients with OM-CMML and to compare them to 162 patients with CMML, 120 with dysplastic type (D-CMML), and 42 with proliferative type (P-CMML). OM-CMML had significantly longer overall survival (OS) and acute myeloid leukemia-free survival than did patients with CMML, considered as a whole group, and when compared with D-CMML and P-CMML. Moreover, gene mutations associated with increased proliferation (ie, ASXL1 and RAS-pathway mutations) were identified as independent adverse prognostic factors for OS in our series. We found that at a median follow-up of 53.47 months, 29.3% of our patients with OM-CMML progressed to D-CMML, and at a median follow-up of 46.03 months, 28.6% of our D-CMML group progressed to P-CMML. These data support the existence of an evolutionary continuum of OM-CMML, D-CMML, and P-CMML. In this context, we observed that harboring more than 3 mutated genes, carrying ASXL1 mutations, and a peripheral blood monocyte percentage >20% significantly predicted a shorter time of progression of OM-CMML into overt CMML. These variables were also detected as independent adverse prognostic factors for OS in OM-CMML. These data support the consideration of OM-CMML as the first evolutionary stage within the proliferative continuum of CMML.

Identification of Two Novel EPOR Gene Variants in Primary Familial Polycythemia: Case Report and Literature Review.

Primary familial and congenital polycythemia is a rare disease characterized by an increase in red cell mass that may be due to pathogenic variants in the EPO receptor (EPOR) gene. To date, 33 genetic variants have been reported to be associated. We analyzed the presence of EPOR variants in two patients with polycythemia in whom JAK2 pathogenic variants had been previously discarded. Molecular analysis of the EPOR gene was performed by Sanger sequencing of the coding regions and exon/intron boundaries of exon 8. We performed in vitro culture of erythroid progenitor cells. Segregation studies were done whenever possible. The two patients studied showed hypersensitivity to EPO in in vitro cultures. Analysis of the EPOR gene unveiled two novel pathogenic variants. Genetic testing of asymptomatic relatives could guarantee surveillance and proper management.

Modulation of JAK2 V617F allele burden dynamics by hydroxycarbamide in polycythaemia vera and essential thrombocythaemia patients.

The modulation of JAK2 V617F allele burden dynamics was prospectively analysed in 47 patients (26 polycythaemia vera [PV] and 21 essential thrombocythaemia [ET]) treated with first-line hydroxyurea (HU) and compared with the JAK2 V617F dynamics of a control group of 45 PV and ET patients. A partial molecular response (PMR), according to European Leukaemia Net criteria, was observed in 27/47 (57%) patients. Median time to PMR was 14 months (3-66) with a probability of PMR at 3 years of 57%. A significant decrease in JAK2 V617F allele load was observed at 36 months both in PV and ET patients, being the reduction in PV higher than in ET patients (P = 0·01). A haematocrit ≥0·45 L/L was associated with a higher probability of attaining a PMR (HR:3·4; 95%CI:1·02-11·6, P = 0·04). Control group showed a slight increase of JAK2 V617F allele burden over time. The reduction in the mutated allele load comparing treated patients versus controls was highly significant both in PV and ET, demonstrating a clear effect of HU on the JAK2 V617F allele burden. In conclusion, first-line HU can attain PMR in more than 50% of newly diagnosed PV and ET patients, with a continuous decrease of the JAK2 V617F allele burden in PV patients during treatment.

Differential expression of JAK2 and Src kinase genes in response to hydroxyurea treatment in polycythemia vera and essential thrombocythemia.

This study investigates the differential gene expression profile of JAK2(V617F)-positive myeloproliferative neoplasm (MPN) patients, with and without response to hydroxyurea (HU) treatment. Twenty-one polycythemia vera, 28 essential thrombocythemia, eight secondary erythrocytosis, and 30 controls were studied. Thirty-four genes were overexpressed in patients who did not respond to HU. Of these, some participate in proliferative pathways: MAPK, AKT, Src kinase (SFK), and JAK2 pathway. JAK2 allele burden was similar between groups of responders and nonresponder. A molecular fingerprint distinguishes JAK2(V617F)-positive MPN patients without response to HU treatment, with overexpression of JAK2, MAPK14, PIK3CA, and SFK genes.

Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31-32, 1p21-22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation-independent prognostic markers indicating poor outcome.

Oligomonocytic and overt chronic myelomonocytic leukemia show similar clinical, genomic, and immunophenotypic features.

Oligomonocytic chronic myelomonocytic leukemia (OM-CMML) is defined as those myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms, unclassifiable with relative monocytosis (≥10% monocytes) and a monocyte count of 0.5 to <1 × 109/L. These patients show clinical and genomic features similar to those of overt chronic myelomonocytic leukemia (CMML), although most of them are currently categorized as MDS, according to the World Health Organization 2017 classification. We analyzed the clinicopathologic features of 40 patients with OM-CMML with well-annotated immunophenotypic and molecular data and compared them to those of 56 patients with overt CMML. We found similar clinical, morphological, and cytogenetic features. In addition, OM-CMML mirrored the well-known complex molecular profile of CMML, except for the presence of a lower percentage of RAS pathway mutations. In this regard, of the different genes assessed, only CBL was found to be mutated at a significantly lower frequency. Likewise, the OM-CMML immunophenotypic profile, assessed by the presence of >94% classical monocytes (MO1s) and CD56 and/or CD2 positivity in peripheral blood monocytes, was similar to overt CMML. The MO1 percentage >94% method showed high accuracy for predicting CMML diagnosis (sensitivity, 90.7%; specificity, 92.2%), even when considering OM-CMML as a subtype of CMML (sensitivity, 84.9%; specificity, 92.1%) in our series of 233 patients (39 OM-CMML, 54 CMML, 23 MDS, and 15 myeloproliferative neoplasms with monocytosis and 102 reactive monocytosis). These results support the consideration of OM-CMML as a distinctive subtype of CMML.