Median OS Of Patients Research Articles

Correlation of Erythropoietin Stimulating Agents (ESAs) with the Post-Therapy Micro-Vessel Density (MVD) in Newly Diagnosed Myeloma Patients: a Possible Mechanism of ESAs Association with Reduced Survival Rates.

Abstract 4873Angiogenesis plays a significant role in the biology of multiple myeloma (MM). Erythropoiesis stimulating agents (ESAs) have been recently associated with reduced survival in a subset of cancer patients who receive ESAs, including MM but the etiology for this correlation has not been sufficiently explored. It is known that the endothelial cells produce angiogenic factors, promote the growth and survival of MM cells and carry erythropoietin receptors which in hypoxic conditions they transport the signal for their own proliferation and expansion under the influence of the endogenous erythropoietin. The aim of this study was to investigate the possible impact of ESAs administration on post-therapy angiogenesis. We studied 84 newly diagnosed MM patients (47M/37F; median age: 65 years, range: 39-82 years) who underwent conventional anti-myeloma therapy: 62 patients received VAD (53 of whom within the context of the randomized study VAD vs. TVAD, conducted by the Greek Myeloma Study Group) and 22 patients received MP. Fifty-two patients received ESAs for at least 8 weeks (ESA group), while 32 did not receive ESA (non-ESA group). MVD was assessed in bone marrow biopsies at baseline and at the time of best response by using monoclonal antibodies targeting CD34. The number of microvessels expressing the CD34 antibody was counted by two experienced pathologists through a grid at a magnification of 400x and was finally divided to the number of the high power fields used for screening the whole marrow surface. The counts were finally expressed as number of vessels per mm2 area of the involved marrow. Fifteen individuals with normal findings in the bone marrow were used as controls. Furthermore, the following cytokines that are involved in the angiogenesis process in MM were measured in the serum of both patients and controls on the day of the trephine biopsy performance: VEGF, bFGF, TGF-b, IL-6, soluble IL-6R (sIL-6R), IL-1b and TNF-α, using an ELISA methodology (R&D, Minneapolis, MN, USA). Patients characteristics between the ESA and non-ESA groups at baseline were well balanced except of Hb which was, as expected, significantly lower in the ESA-group (p<0.001). The median follow-up was 84 months (range 5-154). The median number of baseline MVD in the ESA group was 18.5/mm2 (range: 1-29.3) and in the non-ESA group 17.7/mm2 (range: 2-28.5; p=NS) and was higher compared to controls (median 1.2/mm2, range: 0-9; p<0.001 for both comparisons). The post-therapy MVD in the two groups were 16/mm2 (range: 1.8-26) for ESA and 12.8/mm2 (range: 2-29) for non-ESA group, respectively (p=0.03); the % reduction between baseline and post-therapy value was significantly greater in the non-ESA group (non-ESA group: 24.9%, range -36% to +76.6%, ESA group: 14.5%, range -410% to +85.6%, p=0.04). Myeloma patients before treatment had increased serum levels of VEGF (p=0.029), bFGF (p=0.012), IL-6 (p=0.007) and sIL-6R (p=0.047) compared to controls and showed no differences between ESA and non-ESA groups and no alterations post-therapy. Post-therapy, MVD positively correlated with the baseline MVD and baseline β2-microglobulin and negatively correlated with baseline Hb, response to treatment and PFS (p<0.05). In the ESA group but not in the non-ESA group, post-therapy MVD was negatively correlated with response to treatment (p<0.05). In the multivariate analysis, age and post-therapy MVD were the only independent predictors for OS (p=0.04 and p=0.005, respectively; Hz ratio for post-therapy MVD: 1.2, 95% CI: 1.04-1.28). In the ESA group, the multivariate analysis showed that post-therapy MVD >14/mm2 was the only independent predictor for survival (p=0.04; Hz ratio 0.136, 95% CI: 0.02-0.9) whereas in the non-ESA group, post-therapy MVD did not show any significant prognostic value, either used as a continuous or a dichotomous variable. The median PFS for patients with post-therapy MVD >14/mm2, was 13 months (95% CI: 8.5-17.5) and for patients with MVD <14/mm2 was 33 months (95% CI: 25-41; p=0.001). The median OS in patients with MVD >14/mm2 was 37 months (95% CI: 29-45) and for those with MVD <14/mm2 was 63 months (95% CI: 50-75; p=0.04). These results suggest that ESAs may negatively influence the post-therapy MVD. In the ESA group MVD negatively correlated with disease response and MVD >14/mm2 was the only independent predictor for OS. These findings could partially explain the possible association of ESAs with reduced survival rates in newly diagnosed MM patients. Prospective studies are required in order to fully investigate this current issue. DisclosuresNo relevant conflicts of interest to declare.

Features of Chromosomal Karyotype in 351 Chinese Adult Patients with Primary Myelodysplastic Syndromes: A Retrospective Analysis from a Single Institution

Myelodysplastic syndromes(MDS) are a heterogeneous group of myeloid neoplasms characterized by bone marrow failure with peripheral cytopenia and morphologic dysplasia in one or more of hematopoietic cell lineages. Chromosomal abnormalities, detected in 40–70% patients with primary MDS, are presented heterogeneous due to the disparities in race and environment. In the current study, 351 adult patients in our institution were retrospectively analyzed to clarify features of karyotype in Chinese primary MDS. There were 237 cases (67.5%) demonstrated karyotypic abnormalities including numeral changes alone(99 cases, 41.7%), structural changes alone(70 cases,29.5%) and both changes(68 cases,28.8%). Single, double and complex (more than two independent aberrations) anormaly were 130 cases(54.8%),54 cases(22.8%), 53 cases(22.4%), respectively. There were 3 cases(1.3%) with tetraploid, 1 case(0.4%)with multiploid,1 case(0.4%) with hyperdiploid and 3 cases(1.3%) with hypodiploid. Changes of aneuploid or anomaly of chromosomal arm could be detected in all of the 24 chromosomes and the aberrations frequently seen were +8, −20/20q-/del(20)(q11–13), −7/7q-/del(7)(q21–32), −5/5q-/del(5)(q13–33), −18, −11/11q-/del(11) (q23–25), +21, −Y, −21, −10, −16, −22, +9, del(12) (p12) in order. The incidence of −5/5q-/del(5)(q13–33)(5.1%)was lower than western countries(8.7–23.4%)and 5q-syndrome was even less (0.3%). The incidences of +8(19.1%) and −20/20q-/del(20)(q11–13) (9.4%) were higher than western countries(1.2–7.0%, 2.0– 3.5%, respectively). Chromosome translocations could be detected in 31 cases(13.1%) and among them 12 translocations have not been reported in MDS. In addition, i(17)(q10) could be detected in 9 cases(3.8%)in which 6 cases were single anormaly. Chromosomal duplication presented in 7 cases(3.0%) in which 4 cases involved chromosome 1. According to IPSS chromosomal prognositic classification, the incidence of poor-risk karyotypes was increasing as following orders: RA, RARS and 5q-syndrome;RCMD and RCMDRS;RAEB-I;RAEB-II and the difference was statistically significant(χ2 = 59.169, P < 0. 001). Among the 178 patients with follow-up data, the median follow-up time was 14.5(1–131)months and the median OS was 36 (95% confident interval(CI) 25–46) months with 2 and 5 year of OS 58.7% and 38.0%, respectively. According to IPSS chromosomal prognositic classification, the median OS of patients with good, intermediate and poor-risk cytogenetic subgroups were 51(95%CI 25–77),35(95%CI 5–65),13(95%CI 9–17)months respectively and the difference of OS was statistically significant by log rank test(P=0. 004). According to NN-AN-AA classification, the median OS of patients with NN, AN, AA were 51(95%CI 24–78),36(95%CI 0.3–71), 23(95%CI 10–35)month respectively and the difference of OS was statistically significant by log rank test(P =0. 039). In summary, features of chromosomal abnormalities in Chinese patients with primary MDS were not the same with that in western countries. Cytogenetical abnormalities validate vigorously malignant texture of MDS and are considered to be of great importance in revealing pathogenesis, determinating diagnosis and evaluating prognosis in MDS.

Impact of Chromosome 13 Deletion and Plasma Cell Load on Long-Term Survival of Patients with Multiple Myeloma Undergoing Autologous Transplantation

High-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) is the most common treatment for patients under 60–65 years of age with multiple myeloma (MM). In this study, we present a retrospective analysis of the prognostic impact of different factors in patients who have received this treatment as first line therapy in our centre. Abnormalities in chromosome 13 were identified by fluorescence in situ hybridization at the time of diagnosis. The median OS and PFS from transplantation time in the whole group of 193 patients were 90 and 48 months respectively. The median follow-up was 65 months (range: 6–186 months). The complete remission (CR) rate in patients with and without del(13) was 31% and 40% respectively whereas the median OS in patients with del(13) was 58 months but not reached in patients without del(13) (p=0.006). The PFS was 26 months in patients with del(13) and 84 months in those without del(13) (p=0.001). The transplantation related mortality was 2.5% both in the absence and presence of del(13). Patients who achieved CR following ASCT had longer OS and PFS when compared to those who only achieved partial remission. Thus, this study confirms the role of del(13) as a marker of poor prognosis. Multivariate analysis showed that the existence of del(13) was the only single independent factor effecting survival (p=0.001). In patients without del(13), the prognostic impact was even stronger when combined with the plasma cell load in the bone marrow (p=0.020), whereas the plasma cell load had no effect on survival of patients with del(13). Overall, the absence of del(13) in combination with low plasma cell infiltration at diagnosis predicts the best survival.

HER-2 expression is a prognostic factor in patients with metastatic breast cancer treated with a combination of high-dose cyclophosphamide, mitoxantrone, paclitaxel and autologous blood stem cell support.

The expression levels of a circulating extracellular domain of HER-2 can be detected in the plasma and serum of patients with metastatic breast cancer using an enzyme immunoassay (ELISA) method. In this study, we evaluated the clinical significance of high and low levels of HER-2 in the plasma of 46 patients with metastatic breast cancer enrolled in a clinical trial of high-dose chemotherapy (HDCT) using cyclophosphamide, mitoxantrone, and paclitaxel with autologous stem cell transplantation (ASCT). Using 2500 U/ml as the cut-point, 20 patients (46%) had elevated HER-2 levels (HER-2 positive). Our results suggest that patients with metastatic breast cancer and high soluble plasma HER-2 have a significantly poorer overall (OS) and progression-free survival (PFS) following high-dose chemotherapy with paclitaxel and ASCT. The median OS of patients with low levels of HER-2 was significantly longer (P < 0.01) than the median OS of patients with high levels of HER-2 (29.8 months vs 15.9 months). PFS was also significantly longer (P < 0.01) for patients who were HER-2-negative, than for patients who were HER-2-positive (13.0 vs 8.6 months). Univariate analysis showed that patients with liver or lung metastases had significantly reduced OS and PFS. Patients with metastases to two or more sites also had a significantly reduced time to disease progression, but not OS. In multivariable analysis, lung metastases contributed along with HER-2-positive status to determine a group of patients with significantly poorer OS. However, HER-2-positive status remained the only independent predictor of PFS.