Allogeneic blood transfusion in patients in Dukes B stage of colorectal cancer

The aim of this study is to evaluate influence of allogeneic blood transfusion on prognosis in patients in Dukes B stage of colorectal cancer. All patients with colorectal cancer who were admitted at our Department of Surgery between January 2000 and December 2004 were analyzed. One hundred fifty-one patients who fulfilled inclusion criteria were enrolled in further evaluation. B stage according to Dukes classification and curative resection were inclusion criteria. Exclusion criteria were polyposis syndromes, nonpolyposis syndromes, inflammatory bowel disease, autoimmune disease and previous blood transfusion. Patients were divided into two groups: Group 1 received ≤3 units of allogeneic blood transfusion and group 2 received >3 units of allogeneic blood transfusion. “Cutoff” value of 3 units of blood was defined according to our results and literature data. Follow-up was 5 year. There was no statistical difference between these groups in local recurrence (χ² = 0.009, P > 0.05) and distant metastasis (χ²  = 0.44, P > 0.05). Also, the Kaplan–Meier survival curves were calculated, and long-rank test did not show a survival difference between these two groups (log rank = 0.075, P > 0.05). Postoperative complications are significantly more frequent in Group 2 (χ² = 4.67, P < 0.05). Multivariate logistic regression analysis confirmed that intraoperative blood transfusion more than three units had independent influence on local recurrence. Postoperative transfusion more than 3 units was statistically independent prognostic factor for metastasis and mortality. Overall transfusion less than 3 units of allogeneic blood does not influence the outcome of patients in Dukes B stage of colorectal cancer.     

Excellent Prognosis of Low-Risk Myelodysplastic Syndromes (MDS) Without Detectable Myeloid-Related Mutations

BackgroundUnexplained cytopenia (UC) and low-risk myelodysplastic syndrome (MDS) are distinguished mainly by morphologic dysplasia, which sometimes shows inter-observer discrepancy. We hypothesized that gene mutations are strong prognostic factors for these low-risk patients.Materials and methodsWe enrolled patients from 4 medical centers with unexplained cytopenia of at least 1 lineage. Diagnosis of low-risk MDS was made according to WHO 2016 classification and a revised international prognostic scoring system (R-IPSS) score of ≤ 3.5. DNA was extracted from bone marrow or blood and sequenced by targeted next generation sequencing (NGS).ResultsOne hundred twenty-one patients were recruited: 25% with UC and 75% with low-risk MDS. Complete blood counts were similar, but low-risk MDS patients carried higher numbers of mutations (1 vs. 0; P = .04) than UC patients. Overall, the most frequent mutated genes were TET2 (14.6%), SF3B1 (12.2%), and ASXL1 (9.7%). Survival rates of low-risk MDS patients versus UC patients were not significantly different. UC patients and low-risk MDS patients without genetic abnormalities showed superior 5-year progression free survival compared to MDS patients with mutations (100% vs. 76.0%; P = .005). Overall, ASXL1 mutations were associated with decreased 4-year overall survival compared to wild-type (59% vs. 31%; P = .01). In a multivariate analysis, ASXL1 and DNMT3A mutations in low-risk MDS patients were associated with a higher risk of disease progression with hazard ratios of 7.88 (95% CI 1.76-35.32, P = .01) and 7.45 (95% CI 1.61-34.46, P = .01), respectively.ConclusionMutation detection is important for proper risk stratification of patients presenting with idiopathic cytopenia.     

Outcome of children with neuroblastoma after progression or relapse. A retrospective study of the Italian neuroblastoma registry

The Italian Neuroblastoma Registry was investigated to describe 781 children with neuroblastoma experiencing tumour recurrence (424 progressions and 357 relapses). Ten-year overall survival (OS) was 6.8% (95% confidence interval (CI) 4.3–10.0) after progression and 14.4% (95% CI 10.5–18.9) after relapse. For both circumstances, OS was better for age at diagnosis <18 months, less advanced International Neuroblastoma Staging System (INSS) stage, normal lactate dehydrogenase (LDH) serum level, normal MYCN gene status (P < 0.001) and a non-abdominal primary site (P = 0.034 for progression, and P = 0.004 for relapses). A local type of recurrence had a significantly better outcome only in case of relapse (P < 0.001). Probability of survival increased by era of diagnosis.Survival of children with recurrent neuroblastoma is very poor. A small cohort of patients, mainly represented by children with stages 1 and 2 who underwent local recurrence or developed late relapse may still benefit from further conventional treatment. For the remaining larger proportion of patients, experimental therapies should be proposed.     

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

Patients with lower‐risk myelodysplastic syndromes (LR‐MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter‐individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS‐relevant genes in 159 patients with LR‐MDS using next‐generation sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129‐4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144‐8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662‐14.230) and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848‐16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273‐4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR‐MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher‐risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of the IPSS with mutation status/burden of certain MDS‐relevant genes may improve the prognostication of patients with LR‐MDS and could help identify those with worse‐than‐expected prognosis for more aggressive treatment.     

Clinical Prognostic Factors for Survival and Risk of Progression to Acute Myeloid Leukemia in Patients With Myelodysplastic Syndromes With < 10% Marrow Blasts and Non-Unfavorable Cytogenetic Categories

BackgroundPrognosis of MDS and particularly in patients categorized as lower risk (< 10% blasts or low and intermediate-1 International Prognostic Scoring System [IPSS]) is very heterogeneous and includes patients with very different outcomes with current scoring systems. Recently, a new cytogenetic classification has been proposed for the revised IPSS in predicting the outcome for MDS.Patients and MethodsTo evaluate the prognostic significance of multiple variables for survival and risk of progression to acute myeloid leukemia, we analyzed baseline characteristics of 332 lower risk MDS patients within the lower risk cytogenetic categories by IPSS and the recent proposal for the new cytogenetic classification.ResultsIn multivariate analysis, severity of cytopenias, age > 60 years, bone marrow blasts (5%-9%) and transfusion dependency significantly influenced outcome. The combination of these variables allowed development of a model which categorizes patients in 3 different groups with median survival of 95, 44, and 13 months for groups 1, 2, and 3, respectively (P < .001). In addition, this score also stratified patients for their risk for leukemic progression, estimated at 2 years in 3.1%, 7.6%, and 21.3% for each group (P = .024).ConclusionAlthough karyotype remains the main prognostic factor in MDS, the current study identifies clinical parameters predicting outcome among patients with the better cytogenetic profile. Degree of cytopenias, blasts 5%-9% and transfusion dependence might identify a subset of patients within the nonadverse karyotype, in which early or more aggressive approaches could possibly be required to improve survival or prevent disease progression.     

Impact of Lenalidomide Treatment on Overall Survival in Patients With Lower-Risk,Transfusion-Dependent Myelodysplastic Syndromes

BackgroundFor patients with lower-risk (LR) myelodysplastic syndromes (MDS), overall survival (OS) is rarely a primary clinical trial endpoint. Treatments such as lenalidomide can reduce red blood cell (RBC) transfusion burden (TB) and serum ferritin, but the long-term impact on OS remains undetermined.Patients and MethodsData from 3 trials evaluating lenalidomide in patients with LR-MDS (the phase 2 MDS-003 and phase 3 MDS-004 trials in del[5q]; the phase 3 trial MDS-005 in non-del[5q] patients) were pooled. Predictors of OS were assessed by multivariate analysis using time-dependent models for TB and RBC transfusion independence (RBC-TI), and a landmark analysis of RBC-TI at 17 weeks. Separate analyses using MDS-004 and MDS-005 data determined the relationship between OS and serum ferritin.ResultsMedian follow-up for MDS-003, MDS-004, and MDS-005 was 3.2, 3.0, and 1.7 years, respectively. In multivariate analyses, transfusion of ≥6 RBC units over 8 weeks was a significant predictor of shorter OS vs. 0 units in the time-dependent TB model (hazard ratio [HR] 4.65; 95% confidence interval [CI] 3.32-6.52; P < .0001). RBC-TI achievement was associated with prolonged OS in the time-dependent (HR 0.48; 95% CI 0.37-0.62; P < .0001) and landmark model (HR 0.57; 95% CI 0.44-0.75; P < .0001). Increased serum ferritin was associated with shorter OS (P < .0001).ConclusionThis analysis of prospective trial data in patients with LR-MDS confirms lenalidomide may improve OS by reducing TB and serum ferritin. OS should be considered as an endpoint in future lower risk MDS clinical trials.     

Influence of Acute Myeloid Leukemia Progression on the Prognosis of 831 Patients With Myelodysplastic Syndromes From the Argentine Database

BackgroundA large group of patients with myelodysplastic syndromes (MDS) will die of causes intrinsic to bone marrow failure. One third of patients will develop acute myeloid leukemia (AML), which is associated with an extremely poor outcome and a short survival. Our objectives were to analyze the prognostic variables and scoring systems in the attempt to determine the influence of progression on the overall survival of MDS patients.Patients and MethodsWe performed a retrospective analysis of 831 MDS patients, including those from the Argentine Registry.ResultsOf the 831 MDS patients, 158 (19.0%) experienced transformation, with a median overall survival of 17.9 months from diagnosis and 3.5 months after progression. The survival of patients with adverse karyotypes or greater risk, according to the International Prognostic Scoring System-revised (IPSS-R) or World Health Organization-based Prognostic Scoring System (WPSS) was not affected when stratified by patients with and without evolution to AML (P > .05). In contrast, the survival of lower risk patients was significantly reduced for those patients with progression to AML (P < .001) and those younger (P = .024) than those who died of non–AML-related causes. The intermediate-risk patients were heterogeneously distributed; however, an upgrade from a lower IPSS-R to a higher WPSS-hemoglobin risk category was associated with a worse outcome, not affected by progression (P = .420), with a median event-free survival of 16 months.ConclusionThe use of the IPSS-R and WPSS systems simultaneously might help in identifying those patients who require more aggressive treatment. Nevertheless, more efforts are needed to improve the identification of those lower risk patients whose survival is significantly reduced by progression to AML.     

Angiogenesis and Survival in Patients with Myelodysplastic Syndrome

Angiogenesis has been implicated in the pathogenesis and prognosis of myelodysplastic syndrome (MDS). In this study, we investigated the relationship between microvessel density (MVD), vascular endothelial growth factor (VEGF) expression, common morphological and clinical factors, and survival in patients with MDS. We examined the MVD of paraffin-embedded bone marrow sections from 70 MDS patients and 31 controls. VEGF expression was determined in 50 patients and 20 controls. The median MVD in MDS patients was significantly higher than that in controls (p = 0.025), whereas there was no difference in VEGF expression between MDS patients and controls. In univariate analysis, increased MVD was associated with a shorter survival time (p = 0.023). However, in multivariate analysis, MVD was not an independent predictor of survival. The VEGF expression did not influence survival in univariate analysis. Survival was independently influenced by platelet count (p = 0.0073), cytogenetic risk category (p = 0.022), and transfusion dependence (p = 0.0073). Neither MVD nor VEGF expression were predictors for progression to acute myeloid leukemia in univariate analysis. Progression to acute myeloid leukemia was independently influenced only by the cytogenetic risk category (p = 0.022). This study confirmed increased MVD in MDS. It does not support an independent prognostic role of angiogenesis in MDS.     

Reduction in multi-lineage and erythroid progenitors distinguishes myelodysplastic syndromes from non-malignant cytopenias

We studied the diagnostic role of CFC assays in myelodysplastic syndromes (MDS) using CFC data from bone marrow (BM) and peripheral blood (PB) of 221 MDS patients, 51 patients with non-malignant causes of cytopenia and/or dysplasia and 50 normal controls. A consistent decrease in BM but not PB multi-lineage and erythroid progenitor frequencies was seen in patients with MDS compared to controls (P < 0.05). Automated distinction showed a sensitivity of 87 ± 6% and a specificity of 71 ± 11% in classifying MDS patients. In conclusion, a defect in early hematopoietic progenitor activity, in particular erythroid activity, distinguishes MDS from non-MDS.     

Over-Expression of Cancerous Inhibitor of PP2A (CIP2A) in Bone Marrow Cells from Patients with a Group of High-Risk Myelodysplastic Syndromes

Cancerous inhibitor of PP2A (protein phosphatase 2A) (CIP2A) is an inhibitor of PP2A, a phosphatase and tumor suppressor that regulates cell proliferation, differentiation, and survival. The aim of this study was to investigate whether CIP2A plays a role in the progression of myelodysplastic syndromes (MDS). Immunohistochemical analysis revealed that a fraction patients having refractory anemia with excess blasts (RAEB)-1 (4 out of 12) and RAEB-2 (10 out of 14) exhibited significant expression of CIP2A in bone marrow hematopoietic cells, while all patients with refractory cytopenia with unilineage or multilineage dysplasia (RCUD/RCMD) (0 out of 18) and the control group (0 out of 17) were negative. CIP2A was mainly expressed by the MPO-positive myeloid series of cells and partly by the CD34-positive cells in association with the expression of phosphorylated c-MYC (p-c-MYC) protein and the cell cycle-related proteins Ki-67, MCM2, and geminin. The percentage of p-c-MYC-positive cells in the bone marrow of CIP2A-positive MDS cases was significantly higher than that in CIP2A-negative MDS cases (P?<?0.01). The expression levels of mRNA for CIP2A and PP2A exhibited positive correlation in MDS/control bone marrow. These results suggest that up-regulated expression of CIP2A might play a role in the proliferation of blasts in the MDS bone marrow and in disease progression in at least some cases.     

A Prognostic Model of Therapy-Related Myelodysplastic Syndrome for Predicting Survival and Transformation to Acute Myeloid Leukemia

Introduction/BackgroundWe evaluated the characteristics of a cohort of patients with myelodysplastic syndrome (MDS) related to therapy (t-MDS) to create a prognostic model.Patients and MethodsWe identified 281 patients with MDS who had received previous chemotherapy and/or radiotherapy for previous malignancy. Potential prognostic factors were determined using univariate and multivariate analyses.ResultsMultivariate Cox regression analysis identified 7 factors that independently predicted short survival in t-MDS: age ≥ 65 years (hazard ratio [HR], 1.63), Eastern Cooperative Oncology Group performance status 2-4 (HR, 1.86), poor cytogenetics (−7 and/or complex; HR, 2.47), World Health Organization MDS subtype (RARs or RAEB-1/2; HR, 1.92), hemoglobin (< 11 g/dL; HR, 2.24), platelets (< 50 × 10⁹/dL; HR, 2.01), and transfusion dependency (HR, 1.59). These risk factors were used to create a prognostic model that segregated patients into 3 groups with distinct median overall survival: good (0-2 risk factors; 34 months), intermediate (3-4 risk factors; 12 months), and poor (5-7 risk factors; 5 months) (P < .001) and 1-year leukemia-free survival (96%, 84%, and 72%, respectively, P = .003). This model also identified distinct survival groups according to t-MDS therapy.ConclusionIn summary, we devised a prognostic model specifically for patients with t-MDS that predicted overall survival and leukemia-free survival. This model might facilitate the development of risk-adapted therapeutic strategies.     

Limited clinical efficacy of azacitidine in transfusion-dependent,growth factor-resistant,low- and Int-1-risk MDS: Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza)+erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo+granulocyte colony stimulation factors for >8 weeks and a transfusion need of ⩾4 units over 8 weeks were included. Aza 75 mg m⁻² d⁻¹, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ⩾one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza+Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n=3) and DNMT3A (n=4) were only observed in non-responders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations.     

Co-mutation landscape and clinical significance of RAS pathway related gene mutations in patients with myelodysplastic syndrome

Single gene mutations in the RAS pathway are uncommon and of unknown significance in myelodysplastic syndrome (MDS) patients, RAS pathway-related gene mutations (RASway^mut) as a whole may be significant and require further elucidation. The clinical and molecular data of 370 MDS patients who were newly diagnosed between 1 November 2016 and 31 August 2020 in our hospital were collected and retrospectively reviewed. RASway^mut were detected in 57 (15.41%) patients. Higher median percentage of marrow blasts (2% vs. 1%, P = 0.00), more co-mutated genes (4, interquartile range [IQR]: 2–5. vs. 2, IQR:1–4, P = 0.00), more higher risk patients according to international prognostic scoring system-revised (IPSS-R) (80.70% vs. 59.11%, P = 0.002) as well as higher acute myeloid leukemia transformation rate (35.09% vs. 14.38%, P = 0.02) were observed in patients with RASway^mut when compared to those with wild type RAS pathway-related genes (RASway^wt). The most frequent co-mutated genes were ASXL1 (28.6%), TET2 (23.2%), U2AF1, RUNX1, TP53 (14.3%); DNMT3A (12.5%), among which ASXL1 mutation rate were significantly higher than those with RASway^wt (p < 0.05). RASway^mut had no significant effect on response to disease-modifying treatment in MDS patients. However, Overall survivals (OS) of RASway^mut patients were significantly shorter than those with RASway^wt (16.05 m. vs. 92.3 m, P = 0.00), especially in patients with marrow blasts less than 5% (P = 0.002), normal karyotype (P = 0.01) and lower risk (P = 0.00). While multivariate prognostic analysis showed that RASway^mut co-mutated with TET2 was an independent poor prognostic factor for all MDS patients (P = 0.00, hazrad ratio [HR] = 4.77 with 95% confidence interval [CI]: 2.4–9.51) and RASway^mut patients (P = 0.02, HR 2.76, 95% CI 1.21–6.29). In conclusion, RASway^mut was associated with higher IPSS-R risk, higher incidence of leukemic transformation thus shorter OS in MDS patients, it could be viewed as a whole to predict poor prognosis. Co-mutation with TET2 may promote disease progression and was an independent poor prognostic factor in MDS patients.     

Identification of patients who may benefit from the prophylactic cranial radiotherapy among breast cancer patients with brain metastasis

Background To identify the candidates for prophylactic cranial radiotherapy (PCI) among the patients with early and advanced-stage breast cancer. Methods The demographic, pathologic and clinical features and survival results of 182 brain metastatic breast cancer patients treated with cranial radiotherapy were examined. Results Early stage patients who progressed with isolated brain metastasis had longer survival (13 months vs. 4 months P = 0.006). Lobular/mixed type histology (P = 0.033), high nuclear (P = 0.046) and high histological grade (P = 0.034) were the prognostic factors for isolated brain metastases. The most significant factor for the time to brain metastasis was the number of involved of lymph nodes (P = 0.004). In 60% of 148 patients with metastatic breast cancer, a progression with isolated brain metastasis was developed while the systemic disease was under control. Isolated brain metastasis progression was related to the presence of the hepatic metastasis at the first relapse (P = 0.001) and with ErbB-2 overexpression (P = 0.034). The time to the brain metastasis from the first extracerabral metastasis was associated with the high nuclear grade (P = 0.040) and with chemoresistance (P = 0.037). The median survival time after the brain metastases in chemosensitive patients was longer than in chemoresistant patients (8 months vs. 3 months P = 0.044). In chemoresistant patients (P = 0.0028) and/or in triple negative patients (P = 0.05) the development of the brain metastasis was early and the survival after brain metastasis was short. Discussions Since there is a tendency to early brain metastasis in early stage patients with high-grade, lobular/mixed type histology tumors and with a high number of involved lymph nodes, the value of PCI can be explored in these patients by a well designed prospective trial. Advanced stage chemosensitive patients with ErbB-2 over-expression and/or with hepatic metastasis at their first relapse may be candidates for PCI. There is no place for PCI in chemoresistant and triple-negative breast cancer patients.     

Correlation of tumor necrosis factor α (TNFα) with high Caspase 3-like activity in myelodysplastic syndromes

Increased intramedullary apoptotic death of hematopoietic cells is thought to contribute to the ineffective hematopoiesis in myelodysplastic syndromes (MDS). Furthermore, high amounts of tumor necrosis factor α (TNFα) have previously been correlated with apoptosis in MDS marrows. The present studies were undertaken to examine the status of two key downstream effectors of TNFα signaling, i.e. Caspase 1 and Caspase 3 enzymes, using a fluorometric assay in the bone marrow aspirate mononuclear cells (BMMNC) in relation to apoptotic DNA fragmentation detected by in situ end-labeling (ISEL) of DNA and with localization of TNFα in the corresponding biopsies from 14 MDS patients. Both Caspase 1 and 3 were detectable in freshly harvested BMMNC, albeit median Caspase 3 levels (47.5 units/mg protein) being almost 10 times higher than Caspase 1 (4.0 units/mg protein). Upon short-term culture for 4 h in a serum-supplemented medium in vitro a significant increase was seen in Caspase 3 activity (58.8±13.9 at 0 h vs. 177.8±55.2 units/mg protein at 4 h, n=14, P=0.017) and in percent cells labeled by ISEL (apoptotic index or AI%: 0.76%±0.25% vs. 3.99%±1.1%, n=14, P=0.004, respectively). Caspase 1 activity increased after 15 min in culture. Interestingly, TNFα levels measured by immunohistochemistry correlated with the net increase in Caspase 3 activity after 4 h (ρ=0.517, n=13, P=0.07) and the starting levels of Caspase 1 at 0 h correlated with the Caspase 3 levels attained at 4 h (ρ=0.593, n=13, P=0.033). Additionally when TNFα-positive bone marrows (8/14) were compared with the negative marrows (6/14) the Caspase 3 levels were significantly higher in the TNFα-positive marrows (189.6±66.2 vs. 25.0±14.6 units/mg protein, respectively, P=0.043). The increase in AI%, though not statistically significant, was also higher in the TNFα-positive marrows. Finally in HL60 cells the effects of different Caspase inhibitors and pentoxifylline (PTX) (interferes with lipid signaling of cytokines) on TNFα-induced apoptosis were evaluated. TNFα treatment significantly increased AI% (P<0.003) as compared to the untreated controls. A co-treatment with three Caspase inhibitors, zVAD.FMK (inhibitor of Caspases 1 and 3, 10 μM/l), Ac.YVAD.FMK (Caspase 1 inhibitor, 1 μM/l), Ac.DEVD.FMK (Caspase 3 inhibitor, 10 μM/l) as well as PTX (250 μM/l) significantly curtailed the AI% induced by TNFα The present studies thus identify the downstream effectors of TNFα-inducible apoptosis in MDS and so also the suppressors of TNFα apoptotic signaling. These results may have significant clinical implications in the therapy of MDS in the future.     

Predicting survival of patients with hypocellular myelodysplastic syndrome: Development of a disease-specific prognostic score system

BACKGROUND:

Although most patients with myelodysplastic syndrome (MDS) exhibit bone marrow hypercellularity, a subset of them present with a hypocellular bone marrow. Specific factors associated with poor prognosis have not been investigated in patients with hypocellular MDS.

METHODS:

The authors studied a cohort of 253 patients with hypocellular MDS diagnosed at The University of Texas MD Anderson Cancer Center between 1993 and 2007 and a cohort of 1725 patients with hyper‐/normocellular MDS diagnosed during the same time period.

RESULTS:

Patients with hypocellular MDS presented more frequently with thrombocytopenia (P < .019), neutropenia (P < .001), low serum β‐2 microglobulin (P < .001), increased transfusion dependency (P < .001), and intermediate‐2/high‐risk disease (57% vs 42%, P = .02) compared with patients with hyper‐/normocellular MDS. However, no difference in overall survival was observed between the 2 groups (P = .28). Multivariate analysis identified poor performance status (Eastern Cooperative Oncology Group ≥2), low hemoglobin (<10 g/dL), unfavorable cytogenetics (?7/7q or complex), increased bone marrow blasts (≥5%), and high serum lactate dehydrogenase (>600 IU/L) as adverse independent factors for survival.

CONCLUSIONS:

A new prognostic model based on these factors was built that segregated patients into 3 distinct risk categories independent of International Prognostic Scoring System (IPSS) score. This model is independent from the IPSS, further refines IPSS‐based prognostication, and may be used to develop of risk‐adapted therapeutic approaches for patients with hypocellular MDS. Cancer 2012. © 2012 American Cancer Society.     

Phase I/II study of decitabine in patients with myelodysplastic syndrome: A multi‐center study in Japan

The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with MDS with red cell transfusion dependence or 5–30% blasts in marrow and with an International Prognostic Scoring System score of intermediate‐1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m² daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m² and experienced no dose limiting toxicity during the first cycle. Thirty‐four patients received 20 mg/m². Grade 3 or greater non‐hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m², complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4–8), and duration of remission was 474+ days (range 294–598+). The 2‐year rate of acute myeloid leukemia‐free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high‐risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).     

Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow‐up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty‐one (71.0%) patients received ASCT2 and had better progression‐free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.     

Clinical Outcomes of Decitabine Treatment for Patients With Lower-Risk Myelodysplastic Syndrome on the Basis of the International Prognostic Scoring System

IntroductionDecitabine has shown clinical benefits in patients with intermediate (INT)-2 or high-risk myelodysplastic syndrome (MDS), determined according to the International Prognostic Scoring System (IPSS), but the benefits have not been well demonstrated in patients with lower-risk (IPSS low or INT-1) disease. Recently, it was proposed that the prognosis for patients with IPSS lower-risk disease is heterogeneous, with a substantial proportion of these patients having poor survival.Patients and MethodsThis study included patients with IPSS lower-risk MDS from the DRAMA (An Observational Study for Dacogen Long-Term Treatment in Patients With Myelodysplastic Syndrome; NCT01400633) and DIVA (A Study for Dacogen Treatment in Patients With Myelodysplastic Syndrome; NCT01041846) studies, which were prospective observational studies on the efficacy and safety of decitabine treatment in patients with MDS. Using the Lower-Risk Prognostic Scoring System [LR-PSS], we classified IPSS lower-risk MDS. Patients in each LR-PSS category were divided according to overall response (OR) to decitabine treatment, and survival outcomes were compared.ResultsOne hundred sixteen patients were enrolled: LR-PSS category 1 (n = 12; 10.3%), category 2 (n = 56; 48.3%), and category 3 (n = 48; 41.4%). Survival outcomes differed among the 3 categories (P = .046). The overall survival according to OR showed a significant difference in total patients (P = .008) and category 3 patients (P = .003). We analyzed predictive factors for OR, but no variable was found to significantly affect OR.ConclusionDecitabine treatment showed a survival benefit in the higher-risk group of IPSS lower-risk MDS patients who responded to treatment, and classification using the LR-PSS category was helpful for this subgroup, indicating that decitabine treatment might alter the natural course of disease in these patients.     

Acute myeloid leukemia and myelodysplastic syndrome following breast cancer: increased frequency of other cancers and of cancers in multiple family members

Adjuvant chemotherapy and radiation therapy for breast cancer are associated with therapy-related acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS), but little is known about additional risk factors. Thirty-four patients with AML (n = 26)/MDS (n = 8) following breast cancer (cases) were compared with 2029 breast cancer patients without AML/MDS (controls). Cases were older at breast cancer diagnosis (mean 60.2 years versus 54.5 years; p = 0.01) and more commonly had additional cancers (29% versus 4.9%; p < 0.0001) and ≥4 first-degree relatives with any type of cancer (OR: 5.37, CI: 1.44–19.9). Thus risk factors for AML/MDS following breast cancer include older age, other cancers and multiple first-degree relatives with cancer.