Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification-an approach to classification of patients with t-MDS.

In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained.

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.

Janus kinase 2 (V617F) mutation status, signal transducer and activator of transcription-3 phosphorylation and impaired neutrophil apoptosis in myelofibrosis with myeloid metaplasia.

An activating point mutation in Janus kinase 2 (JAK2 V617F) was recently identified in myelofibrosis with myeloid metaplasia (MMM). To further elucidate the pathogenic significance, we examined the JAK2 mutation burden, phosphorylation of JAK2 substrates and neutrophil apoptotic resistance. Immunoblotting revealed phosphorylation of signal transducer and activator of transcription-3 (STAT3) in all four JAK2 with high V617F mutant allele burden and seven of eight with intermediate mutant allele burden, but only one of eight with wild-type JAK2 (P<0.001). In contrast, STAT5 phosphorylation was undetectable in patient MMM neutrophils; and phosphorylation of Akt and extracellular signal-regulated kinases (ERKs) failed to correlate with JAK2 mutation status. Apoptosis was lower in MMM neutrophils (median 41% apoptotic cells, n=50) compared to controls (median 66%, n=9) or other myeloproliferative disorder patients (median 53%, n=11; P=0.002). Apoptotic resistance in MMM correlated with anemia (P=0.01) and the JAK2-V617F (P=0.01). Indeed, apoptotic resistance was greatest in MMM neutrophils with high mutant allele burden (median 22% apoptosis, n=5) than with intermediate burden (median 39%, n=23) or wild-type JAK2 (median 47%, n=22; P=0.008). These results suggest that mutant JAK2 contributes to MMM pathogenesis by constitutively phosphorylating STAT3 and diminishing myeloid cell apoptosis.

Comparison of clinical outcomes and prognostic utility of risk stratification tools in patients with therapy-related vs de novo myelodysplastic syndromes: a report on behalf of the MDS Clinical Research Consortium.

While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.

On the TRAIL of a new therapy for leukemia.

The cytokine TRAIL (tumor necrosis factor alpha-related apoptosis-inducing ligand) as well as agonistic antibodies that bind to the TRAIL receptors, death receptor 4 (DR4) and DR5, are undergoing preclinical and early clinical evaluation as potential therapeutic agents for a variety of hematological and nonhematological malignancies. Here, we briefly review the normal biological function of TRAIL, the mechanism of cytotoxicity of TRAIL receptor ligands, and their effects on normal myeloid progenitors, myelodysplastic marrow and leukemic cells, including acute myelogenous leukemia (AML) and chronic lymphocytic leukemia (CLL), in vitro. Recent observations suggesting that DR4 is the predominant receptor for the cytotoxic effects of TRAIL in CLL and that histone deacetylase inhibitors synergize with TRAIL in CLL in vitro are described and discussed. Collectively, the reviewed studies not only illustrate the potential therapeutic usefulness of TRAIL and the agonistic antibodies, but also highlight the need for additional preclinical evaluation of these agents.

Does quality of life impact the decision to pursue stem cell transplantation for elderly patients with advanced MDS?

The factors that influence utilization of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HCT) among medically fit older patients with advanced myelodysplastic syndromes (MDS) are largely unknown. The MDS Transplant-Associated Outcomes (MDS-TAO) study is an ongoing prospective observational study at the Dana-Farber Cancer Institute and Massachusetts General Hospital that enrolls transplant-eligible fit patients aged 60-75 years with advanced MDS and follows them through RIC HCT vs non-HCT treatment. In this analysis of 127 patients enrolled from May 2011 to June 2014, we examined the influence of age, gender, cytogenetics, International Prognostic Scoring System (IPSS) category, performance status, distance from HCT center and baseline patient-reported quality of life (QOL) from the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) on the likelihood of receiving RIC HCT using competing risk regression modeling. With a median follow-up of 16 months, 44 patients (35%) had undergone RIC HCT. In multivariable analyses, age (hazard ratio (HR) 0.87 per year, 95% confidence interval (CI): 0.81-0.92, P<0.001) and higher IPSS (intermediate-2/high; HR 2.29, 95% CI: 1.25-4.19, P=0.007) were significantly predictive of receipt of RIC HCT; neither global QOL score nor any QOL subscales scores were predictive. These data suggest that baseline patient-reported QOL has little influence on the decision to undergo RIC HCT for older patients with advanced MDS.

Comparison of risk stratification tools in predicting outcomes of patients with higher-risk myelodysplastic syndromes treated with azanucleosides.

Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.

Lymphadenopathy.

Lymphadenopathy can occur in any age group, in symptomatic or asymptomatic patients, and in a single site or at multiple sites. Lymphadenopathy is associated with numerous disorders. An abnormal lymph node may be observed or palpated by the patient, found by a health care worker, or discovered through radiologic evaluation. Lymphadenopathy may be a part of a complex case presentation, or the clinical cause may be straightforward. Patients with potentially curable malignant disorders may have lymphadenopathy as the first sign of their disease. This review of lymphadenopathy summarizes general considerations, discusses which patients might be considered for biopsy, reviews which nodes are most likely to be diagnostic, outlines initial diagnostic considerations on a region-by-region basis, and reviews a broad differential diagnosis for adenopathy.

Autoimmune hemolytic anemia in a patient with autosomal dominant chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is a heterogeneous immunodeficiency syndrome characterized by recurrent candidal infections of the skin, nails, and mucous membranes. The syndrome can be associated with autoimmune conditions, especially endocrine disorders. Typically, inheritance is autosomal recessive, and abnormal T-cell-mediated immunity is thought to be the underlying deficit. We describe a 27-year-old man with chronic mucocutaneous candidiasis inherited in an autosomal dominant fashion, in whom both lymphocyte blastogenesis and delayed-type skin reactivity to Candida antigens were normal. Notable features of the case include autoimmune hemolytic anemia, probable hypoparathyroidism, and hypogonadal hypogonadism.

Hereditary red blood cell disorders in middle eastern patients.

Hereditary disorders of erythrocytes are common in many areas of the world, including the Middle East. In some regions of the Middle East more than 10% of the population are carriers of a gene for one of these conditions. When patients from the Middle East seek medical care in the West, an unrecognized but clinically important erythrocyte disorder can result in serious complications during routine medical care, such as a drug-induced hemolytic crisis. This article reviews the most important and most common inherited red blood cell disorders in Middle Eastern patients, including glucose-6-phosphate dehydrogenase deficiency, the thalassemias, and sickle cell disorders. We discuss when to suspect such conditions, how to determine their presence, and how to avoid potential complications related to them. Although a detailed discussion of treatment of erythrocyte disorders is beyond the scope of this article, some general management principles are described.

Amifostine alone and in combination with erythropoietin for the treatment of favorable myelodysplastic syndrome.

Ten anemic patients with favorable myelodysplastic syndrome (MDS) were first treated with two 5-week courses of amifostine alone (each course consisted of 200 mg/m(2) of the drug given intravenously three times a week for 3 weeks), followed by an additional two courses combined with subcutaneous erythropoietin (EPO) (150 U/kg, three times a week for 8 weeks). The study patients either had previously failed to respond to treatment with EPO or had pretreatment serum EPO levels of more than 100 mU/ml. None of the patients experienced a complete or partial response in anemia or other cytopenias. We conclude that amifostine alone or in combination with EPO has limited therapeutic activity in MDS.

Myelodysplastic syndrome and pregnancy: the Mayo Clinic experience.

Although the myelodysplastic syndrome (MDS) is most common in the elderly, younger patients, including women of child-bearing age, may be affected. The association of MDS with pregnancy appears to be very rare: fewer than 25 cases have been reported. We report the outcomes of seven pregnancies in four women seen at the Mayo clinic between 1983 and 2000. Three of the women were found to have MDS when an abnormal complete blood count was detected during routine prenatal care. The fourth patient had an apparently congenital MDS, and suffered three spontaneous abortions before undergoing premature menopause as a result of pelvic irradiation for vulvar cancer. We discuss some of the unique concerns regarding pregnant patients with MDS. As women give birth at older ages and as more young persons survive cancer, MDS and pregnancy are likely to be seen together with increasing frequency.

Hydroxyurea-associated platelet count oscillations in polycythemia vera: a report of four new cases and a review.

Cyclic oscillations in the peripheral blood platelet count were recently described in two patients with polycythemia vera (PV) receiving therapy with hydroxyurea (HU). This phenomenon can make proper HU dosing very challenging and may be especially problematic in PV patients who are at risk for thrombohemorrhagic complications. In this report, we describe four new cases of HU-associated platelet oscillations in patients with PV and extend our observations on one of the two previously reported cases. We also review cyclic thrombocytosis within the broader context of periodic hematopoiesis. A thrombopoietin-mediated negative feedback loop is central to most models of periodic thrombopoiesis, but this is probably an oversimplification. It is possible that HU destabilizes the delicate balance of thrombopoietin/c-Mpl signaling in megakaryocytic lineage hematopoiesis that is already markedly altered in PV; this hypothesis remains speculative. For patients who develop oscillatory variation in their platelet counts associated with HU use, keeping the HU dose constant may result in damping or termination of the cycles. However, this strategy is not always successful.

"Congo" red: out of Africa?

CONTEXT: Congo red is the essential histologic stain for demonstrating the presence of amyloidosis in fixed tissues. To the best of my knowledge, nothing has been written about why the stain is named "Congo." OBJECTIVE: To understand the etymology and history of the Congo red histologic stain. DESIGN: Primary sources were consulted extensively, including 19th-century corporate documents, newspapers, legal briefs, patents, memoirs, and scientific papers. SETTING: Sources were obtained from multiple university libraries and German corporate archives. RESULTS: To Europeans in 1885, the word Congo evoked exotic images of far-off central Africa known as The Dark Continent. The African Congo was also a political flashpoint during the Age of Colonialism. "Congo" red was introduced in Berlin in 1885 as the first of the economically lucrative direct textile dyes. A patent on Congo red was filed by the AGFA Corporation of Berlin 3 weeks after the conclusion of the well-publicized Berlin West Africa Conference. During these important diplomatic talks, German Chancellor Otto von Bismarck presided over a discussion of free trade issues in the Congo River basin. A challenge to AGFA's Congo red patent led to a precedent-setting decision in intellectual property law. CONCLUSIONS: The Congo red stain was named "Congo" for marketing purposes by a German textile dyestuff company in 1885, reflecting geopolitical current events of that time.