Panagiotis Zikos

Markers of endothelial and in vivo platelet activation in patients with essential thrombocythemia and polycythemia vera

We investigated endothelial and in vivo platelet activation in a cohort of 52 patients with essential thrombocythemia (ET) and polycythemia vera (PV) before and after cytoreductive treatment, 22 healthy controls, and 17 patients with acute cerebrovascular ischemia (ACVI) and normal platelet counts.We measured platelet expression of CD62P and CD63 antigens and levels of soluble vascular cell adhesion molecule 1 (sVCAM-1).We found increased in vivo platelet activation in all patients with ET and PV, both before and after cytoreductive treatment, compared with controls. In patients with arterial thrombosis, platelet expression of CD62P, and in patients with erythromelalgia, expression of both markers was higher compared with expression in patients without thrombotic complications. In patients with ET and PV before and after treatment, sVCAM-1 expression was increased compared with expression in controls but also compared with expression in patients with ACVI and normal platelet counts. In patients with arterial thrombosis and erythromelalgia, in vivo platelet activation correlated with the level of sVCAM-1. Our findings indicated that in vivo platelet activation reflects intrinsic platelet defects in patients with ET and PV, persists after cytoreductive treatment, and results in endothelial damage, probably through release of angiogenic factors and/or activation of white blood cells.

Expression of Granzyme B and Perforin in Multiple Myeloma

Multiple myeloma (MM) remains an incurable disease by conventional therapy. MM tumor cells evade the immune system and can induce immunosuppression by producing immunomodifying agents such as TGF-β, FasL, vascular endothelial growth factor and Muc-1. In the present study, we show that bone marrow cells from a patient suffering from MM IgG/k type, stage IIIA, when cultured, expressed granzyme B and perforin, normally expressed exlusively by cytotoxic T cells (CTLs) and natural killer (NK) cells. In addition, phenotypic analysis revealed that the cultured cells were activated antigen-presenting cells with NK targeting capacity. We propose that expression of these cytolytic enzymes may constitute an additional adoptive mechanism by the tumor cells to actively destroy the host immune effector cells.

The outcome of patients with high-risk MDS achieving stable disease after treatment with 5-azacytidine: A retrospective analysis of the Hellenic (Greek) MDS Study Group

The demethylating factor 5‐azacytidine (5‐AZA) improves survival in intermediate‐2 and high‐risk myelodysplastic syndrome (MDS) patients [according to the International Prognostic Score System (IPSS)] responding to treatment. However, the outcome of patients achieving stable disease (SD) is unclear. This retrospective study of the Hellenic MDS Study Group included 353 intermediate‐2 or high IPSS risk patients treated with 5‐AZA. Forty‐four out of 86 (51.6%) patients achieving SD and continuing treatment with 5‐AZA showed a lower risk of transformation of MDS to acute myeloid leukemia (AML) and increased overall survival (OS), compared to SD patients who discontinued the treatment (estimated median AML‐free survival = 38 months, 95% CI = 10.7‐65.3 vs 15 months, 95% CI = 10.4‐19.6, P < .001; estimated median OS = 20 months, 95% CI = 5.5‐34.5 vs 11 months, 95% CI = 5.8‐16.2, P < .001). Moreover, SD patients continuing treatment with 5‐AZA had no differences in AML‐free survival compared to patients showing response to 5‐AZA (estimated median AML‐free survival = 38 months, 95% CI = 10.7‐65.3 vs 31 months, 95% CI = 23.6‐38.4, P = .45; estimated median OS 20 months, 95% CI = 5.5‐34.5 vs 25 months, 95% CI = 21.3‐28.7, P = .50). In conclusion, MDS patients achieving SD in the first 6 months of treatment with 5‐AZA as best response should continue receiving 5‐AZA as they may benefit from prolonged treatment.

Ectopic Lck expression in CLL demarcates intratumoral subpopulations with aberrant B-cell receptor signaling

Key Points Ectopic Lck expression signifies interpatient and intratumoral heterogeneity in CLL. Lck expression identifies CLL subpopulations with aberrant BCR signaling.

The prognostic value of monosomal karyotype (MK) in higher-risk patients with myelodysplastic syndromes treated with 5-Azacitidine: A retrospective analysis of the Hellenic (Greek) Myelodysplastic syndromes Study Group

In this study, we investigated the incidence and prognostic impact of monosomal karyotype (MK) in 405 higher‐risk Myelodysplastic Syndromes (MDS) patients treated with 5‐AZA. The MK was present in 66 out of 405 (16.3%) patients, most of whom had complex karyotype (CK). MK was strongly associated with CK and the cytogenetic risk defined according to IPSS‐R, as well as with high‐risk disease, according to IPSS (P = .029), IPSS‐R (P < .001), and WPSS (P < .001) classification systems. The overall response rate (ORR) was not different between MK+ and MK– patients (46.6% vs. 46.2%). At 28 months median follow‐up, the median duration of response was 11 months in the entire cohort, 9.5 months in MK+ patients and 11 months in MK‐patients (P = .024). The estimated median time to transformation to acute myeloid leukemia for MK+ patients was 17 months vs. 23 months for MK– patients (P = .025). The estimated median OS for MK+ patients was 12 months vs. 18 months for MK– patients (P < .001). Multivariate Cox regression analysis revealed that performance status (P < .001), IPSS‐R (P < .001), and MK (P = .002) were independently associated with overall survival (OS). In a subgroup consisting of high and very‐high risk patients according to IPSS‐R, MK– patients showed better OS rates compared to MK+ patients (estimated median OS: 17 months vs. 12 months, P = .002). In conclusion, we found that MK is associated with reduced OS in patients with higher‐risk MDS treated with 5‐AZA. Furthermore, we showed that in MDS with high or very‐high IPSS‐R risk score, MK can further distinguish patients with worse outcome.

Prognostic significance of deletion of the long arm of chromosome 20 in patients with myelodysplastic syndrome (MDS): a study of the Greek MDS Study Group

To the Editor: Deletion of the long arm of the chromosome 20 (del 20q) was observed in 10% of patients with polycythemia vera as well as in other myeloproliferative disorders (MPD) (1), in 4% of patients with myelodysplastic syndromes (MDS) (2) and in 1–2% of patients with acute myeloid leukemia (AML) (3). Del 20q is believed to arise in a pluripotent stem cell precursor of both myeloid and lymphoid cells (4) and to contribute to malignancy due to the loss of tumor suppressor genes. More than one gene on 20q is probably involved in leukemogenesis, which could account for the different clinical characteristics of myeloid disorders with del (20q) (5, 6). The 20q deletions are usually interstitial, involving bands q11.2– q13.1 and molecular studies have now identified two overlapping regions of deletion, one observed in patients with MDS/AML and one in patients with MPD (5). Translocations involving 20q are rare in myeloid malignancies with only occasional reports of unbalanced translocations involving chromosomes 1, 11, and 21 (7–9). According to the International Prognostic Scoring System (IPSS), MDS patients with del (20q) have good prognosis and a low transformation rate to acute leukemia (10, 11). The prognostic significance of del (20q) is not clear, because it has not been confirmed by other authors (12). Del (20q) as a sole aberration is associated with a favorable outcome while with additional aberrations in chromosomes 5 or 7, or both, predicts a relatively poor prognosis connected with shorter survival (13). MDS with hypereosinophilic syndrome and del (20q) has been reported with an indolent course (14). Duplication of del (20q) in a few MDS patients is of unknown prognostic significance while a t(17;20) in MDS and AML, involving genes on 17p and 20q seems to play a role in myeloid leukemogenesis (15). The aim of the study was to evaluate the clinical characteristics, risk of progression to acute leukemia, and survival in Greek MDS patients with del 20q. From 708 MDS patients, 28 patients with primary MDS and del 20q (23 patients with del 20q, as a sole and five patients, as a complex cytogenetic aberration), were identified. The study included 22 men and six women with a median age of 73.5 years (range: 37–87 years). Thirteen patients were diagnosed with refractrory anemia (RA), three with RA with ringed sideroblasts (RARS), six with RA with excess of blasts (RAEB-1), one with RAEB in transformation (RAEB-2), three with chronic myelomonocytic leukemia (CMML) and two patients were unclassified according to the last WHO classification. Nine patients were classified as low, 13 as intermediate-1, and six as intermediate-2 risk group according to IPSS. Fifty-six percent of this group presented with anemia, Hb £ 10 g/dL, and 88% with thrombocytopenia, platelet count 6 100 · 10/L. Peripheral blasts of 8% and 12% were identified in two patients with RAEB and RAEB-T, respectively. Levels of serum LDH were increased in two CMML and one RAEB-T patient. Six patients were red cell transfusion dependent (two packs of red cells per month). Three patients were platelet transfusion dependent every 2 weeks, and two patients were admitted to the hospital for neutropenic fever. No difference in the risk of leukemic evolution was observed in 28 patients with del 20q (25%) and the cohort of 680 patients without del 20q (30%). No significant difference in median or overall survival was observed between the two groups. The median survival, as shown in Figure 1, for 28 and 680