The presence of a chromosomal abnormality in cytopenia without dysplasia identifies a category of high-risk clonal cytopenia of unknown significance.

Myelodysplastic syndromes (MDS) are hematological malignancies classically defined by the presence of cytopenia(s) and dysmorphic myeloid cells. It is now known that MDS can be preceded by a pre-malignant condition called clonal cytopenia of unknown significance (CCUS), which associates a clonality marker with cytopenia in the absence of criteria of dysplasia. However, to date, it is not clear whether chromosomal abnormalities should be considered in the definition of CCUS or if they carry a prognostic impact in CCUS patients. In this study, we analyzed the clinico-biological features and outcomes of 34 patients who presented with one or more cytopenias, an absence of significant dysplasia, and a presence of a chromosomal abnormality (CA). We named this entity chromosomal abnormality with cytopenia of undetermined significance (CACtUS). We show that these patients are slightly older than MDS patients and that they more frequently presented with normocytic anemia. Most CACtUS patients exhibited only one unbalanced CA. The number and type of mutations were comparable between CACtUS patients and MDS patients. Regardless of the cytogenetic abnormality, the clinicobiological characteristics, overall survival, and risk of progression to high-risk (HR) MDS were similar between CACtUS patients and low-risk MDS patients. Thus, we suggest that CACtUS patients can be considered as HR-CCUS and should receive the follow-up regimen recommended for MDS patients.

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic, and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count, and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A, and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as Tumor Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid-to-myeloid ratio in bone marrow, although not altering their multilineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM, and CBL and mutations of ASXL1, SF3B1, and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.

Genetic characterization of B-cell prolymphocytic leukemia: a prognostic model involving MYC and TP53.

B-cell prolymphocytic leukemia (B-PLL) is a rare hematological disorder whose underlying oncogenic mechanisms are poorly understood. Our cytogenetic and molecular assessments of 34 patients with B-PLL revealed several disease-specific features and potential therapeutic targets. The karyotype was complex (≥3 abnormalities) in 73% of the patients and highly complex (≥5 abnormalities) in 45%. The most frequent chromosomal aberrations were translocations involving MYC [t(MYC)] (62%), deletion (del)17p (38%), trisomy (tri)18 (30%), del13q (29%), tri3 (24%), tri12 (24%), and del8p (23%). Twenty-six (76%) of the 34 patients exhibited an MYC aberration, resulting from mutually exclusive translocations or gains. Whole-exome sequencing revealed frequent mutations in TP53, MYD88, BCOR, MYC, SF3B1, SETD2, CHD2, CXCR4, and BCLAF1. The majority of B-PLL used the IGHV3 or IGHV4 subgroups (89%) and displayed significantly mutated IGHV genes (79%). We identified 3 distinct cytogenetic risk groups: low risk (no MYC aberration), intermediate risk (MYC aberration but no del17p), and high risk (MYC aberration and del17p) (P = .0006). In vitro drug response profiling revealed that the combination of a B-cell receptor or BCL2 inhibitor with OTX015 (a bromodomain and extra-terminal motif inhibitor targeting MYC) was associated with significantly lower viability of B-PLL cells harboring a t(MYC). We concluded that cytogenetic analysis is a useful diagnostic and prognostic tool in B-PLL. Targeting MYC may be a useful treatment option in this disease.

[A primitive plasma cell leukemia with immunoglobulin (Ig) E]. / À propos d'un cas de leucémie plasmocytaire primitive à IgE.

We report here a case of primitive plasma cell leukemia with immunoglobulin (Ig) E. IgE myeloma is an exceptional variant of multiple myeloma, with a very poor prognosis. Its biological diagnosis requires specific analyzes in order to detect IgE gammopathy. Plasma cell leukemia (PCL) is also a very rare and very severe form of multiple myeloma. There are two variants: primitive PCL (pPCL) occurring de novo and secondary PCL (sPCL), evolution of a preexisting myeloma. Its diagnosis is essentially biological since it is defined by a blood plasmocytosis greater than 2 G/L or 20% of the leucocytes.

Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact.

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.

Mutational and cytogenetic analyses of 188 CLL patients with trisomy 12: A retrospective study from the French Innovative Leukemia Organization (FILO) working group.

Trisomy 12 (tri12) is the second most frequent chromosomal aberration (15%-20%) in chronic lymphocytic leukemia (CLL). Tri12 confers an intermediate prognosis but is a heterogeneous entity. We examined whether additional mutational or chromosomal alterations might impact tri12 patient outcomes. This retrospective study, carried out by the French Innovative Leukemia Organization, included 188 tri12 patients with comprehensive information on immunoglobulin heavy chain (IGHV) gene status, karyotypic/FISH abnormalities, and NOTCH1, TP53, SF3B1, and MYD88 mutations. The main cytogenetic abnormalities associated with tri12 were del(13q) (25%), additional trisomies (14%) (including tri19 (10%) and tri18 (4%)), 14q32 translocations (10%), del(17p) (6.5%), del(14q) (4%), and del(11q) (4%). Unmutated (UM) IGHV, NOTCH1, and TP53, mutations were identified in respectively 66%, 25%, and 8.5% of cases. Multivariate analyses showed that additional trisomies (HR = 0.43, 95% CI = 0.23-0.78, P = .01) were associated with a significantly longer time to first treatment in Binet stage A patients and with a lower risk of relapse (HR = 0.37, 95% CI = 0.15-0.9, P = .03) in the overall tri12 population. Binet stage B/C, TP53 disruption, and UM IGHV status were associated with a shorter time to next treatment, while Binet stage B/C (HR = 4, 95% CI = 1.6-4.9, P = .002) and TP53 disruption (HR = 5, 95% CI = 1.94-12.66, P = .001) conferred shorter overall survival in multivariate comparisons. These data indicate that additional cytogenetic and mutational abnormalities, and particularly additional trisomies, IGHV status, and TP53 disruption, influence tri12 patient outcomes and could improve risk stratification in this population.

Myelodysplastic syndrome (MDS) with isolated trisomy 8: a type of MDS frequently associated with myeloproliferative features? A report by the Groupe Francophone des Myélodysplasies.

Isolated trisomy 8 (+8) is a frequent cytogenetic abnormality in the myelodysplastic syndromes (MDS), but its characteristics are poorly reported. We performed a retrospective study of 138 MDS patients with isolated +8, classified or reclassified as MDS (excluding MDS/myeloproliferative neoplasm). Myeloproliferative (MP) features were defined by the repeated presence of one of the following: white blood cell count >10 × 109 /l, myelemia (presence of circulating immature granulocytes with a predominance of more mature forms) >2%, palpable splenomegaly. Fifty-four patients (39·1%) had MP features: 28 at diagnosis, 26 were acquired during evolution. MP forms had more EZH2 (33·3% vs. 12·0% in non-MP, P = 0·047), ASXL1 (66·7% vs. 42·3%, P = 0·048) and STAG2 mutations (77·8% vs. 21·7%, P = 0·006). Median event-free survival (EFS) and overall survival (OS) were 25 and 27 months for patients with MP features at diagnosis, versus 28 (P = 0·15) and 39 months (P = 0·085) for those without MP features, respectively. Among the 57 patients who received hypomethylating agent (HMA), OS was lower in MP cases (13 months vs. 23 months in non-MP cases, P = 0.02). In conclusion, MP features are frequent in MDS with isolated +8. MP forms had more EZH2, ASXL1 and STAG2 mutations, responded poorly to HMA, and tended to have poorer survival than non-MP forms.

"Double-hit" chronic lymphocytic leukemia: An aggressive subgroup with 17p deletion and 8q24 gain.

Chronic lymphocytic leukemia (CLL) with 17p deletion (17p-) is associated with a lack of response to standard treatment and thus the worst possible clinical outcome. Various chromosomal abnormalities (including unbalanced translocations, deletions, ring chromosomes and isochromosomes) result in the loss of 17p and one copy of the TP53 gene. The objective of the present study was to determine whether the type of chromosomal abnormality leading to 17p- and the additional aberrations influenced the prognosis in a series of 195 patients with 17p-CLL. Loss of 17p resulted primarily from an unbalanced translocation (70%) with several chromosome partners (the most frequent being chromosome 18q), followed by deletion 17p (23%), monosomy 17 (8%), isochromosome 17q [i(17q)] (5%) and a ring chromosome 17 (2%). In a univariate analysis, monosomy 17, a highly complex karyotype (≥5 abnormalities), and 8q24 gain were associated with poor treatment-free survival, and i(17q) (P = .04), unbalanced translocations (P = .03) and 8q24 gain (P = .001) were significantly associated with poor overall survival. In a multivariate analysis, 8q24 gain remained a significant predictor of poor overall survival. We conclude that 17p deletion and 8q24 gain have a synergistic impact on outcome, and so patients with this "double-hit" CLL have a particularly poor prognosis. Systematic, targeting screening for 8q24 gain should therefore be considered in cases of 17p- CLL.

Impact of baseline cytogenetic findings and cytogenetic response on outcome of high-risk myelodysplastic syndromes and low blast count AML treated with azacitidine.

Karyotype according to the revised IPSS is a strong independent prognostic factor for overall survival (OS) in myelodysplastic syndromes (MDS), however established in untreated patients. The prognostic impact of cytogenetics and cytogenetic response (CyR) in MDS patients receiving azacitidine (AZA) remains uncertain. We examined the prognostic value of baseline cytogenetics and CyR for overall response rate (ORR) and OS in 702 AZA-treated higher risk MDS and low blast count acute myeloid leukemia (AML), including 493 (70%) with abnormal karyotype. None of the cytogenetic abnormalities had significant impact on ORR (43.9%) or complete response (15.35%), except 3q abnormalities and complex karyotypes, which were associated with a lower ORR. OS differed significantly across all R-IPSS cytogenetic subgroups (p<10-4) but patients with non complex del(7q) had similar survival as patients with normal cytogenetics. CyR was achieved in 32% of the 281 evaluable patients with abnormal cytogenetics, was complete (CCyR) in 71 (25.3%) patients. We found no correlation between hematological response and cytogenetic response and 21% of the patients with CCyR did not achieve morphological response. In the 281 patients, we found no impact of CyR on survival, but when restricting to MDS (ie: <20% marrow blasts) achievement of CCyR was associated with better OS.

Impact of cytogenetic abnormalities in adults with Ph-negative B-cell precursor acute lymphoblastic leukemia.

Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/KMT2A-AFF1 and 14q32/IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.

Cytogenetics in the management of chronic lymphocytic leukemia: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

Acquired recurrent cytogenetic abnormalities are frequent in chronic lymphocytic leukaemia (CLL). They can be associated with good or poor prognostic factors, and also with gene mutations. Chromosomal abnormalities could be clonal or sub-clonal. Assessing the TP53 status (deletion/mutation) is currently mandatory before treating patients. The search for 11q deletion (ATM gene) is also recommended. Finally, the prognostic value of other chromosomal abnormalities including complex karyotype is still debated.