Successful treatment with daratumumab for post-HSCT refractory hemolytic anemia.

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune-mediated thrombocytopenia 3.5 months following HSCT. After the failure of several treatments, he received daratumumab, an anti-CD38 specific antibody, and demonstrated fast and sustained response. The only side effect was delayed recovery of humoral immunity. Daratumumab, by targeting antibody-producing plasma cells, may be a valid treatment option for refractory post-HSCT AIC.

Radiofrequency ablation for patients with refractory symptomatic anaemia secondary to gastric antral vascular ectasia.

Background: Gastric antral vascular ectasia (GAVE) is a rare cause of gastrointestinal bleeding, often causing iron deficiency anaemia. Previous studies have looked at the management of this with argon plasma coagulation, laser therapy and endoscopic band ligation. Methods: This was a single-centre prospective study to evaluate the efficacy and safety of radiofrequency ablation (RFA) in patients with GAVE with persistent anaemia refractory to at least one session of first-line endoscopic therapy. Patients were treated with a through-the-scope (TTS) radiofrequency catheter at two endoscopic sessions six weeks apart. The primary outcome was change in haemoglobin at six months posttreatment. The secondary outcomes were reduction in blood or iron requirements, endoscopic surface area regression and complications. Results: Twenty patients were treated. The mean change in haemoglobin at six months was +12.6 g/l (95% confidence interval 11.7-24.3 g/l), paired t test p < 0.001. At six months, three of 14 individuals who had required blood transfusions had ongoing blood transfusions and five of 17 who had required iron had ongoing iron needs. Surface area regression was scored as 74% ± 25% but no correlation was seen between this and other outcomes. Three of 20 patients experienced pain which was managed with oral analgesia. Of the 14 patients who had reached 12-month follow-up, three required retreatment (21%). Discussion: This small study suggests that RFA is a safe and effective treatment for GAVE. Our study uses the TTS catheter compared to other studies, and demonstrates prolonged improvement in haemoglobin and reduction in blood and iron requirements with a novel assessment of surface area regression.

Gastric carcinoma subsequent to myelodysplastic syndrome with t (1; 19) chromosome translocation: A rare case report and its potential mechanisms.

RATIONALE: Myelodysplastic syndrome (MDS) is a heterogeneous malignant hematologic disease with median overall survival ranging from six months to more than ten years. Solid tumor rarely occurs in combination with MDS and the underlying pathogenesis and prognostic significance still remain controversial. PATIENT CONCERNS: Here we report a relative low risk myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia (MDS-RCMD) patient, with a rare t(1; 19)chromosome translocation. This patient also suffered from gastric carcinoma. DIAGNOSES: Gastric carcinoma, Myelodysplastic syndrome with t (1; 19) chromosome translocation. INTERVENTIONS: This patient received radical operation for gastric carcinoma and erythropoietin infusion. OUTCOMES: The patient took follow up visits every 2 to 3 months in past years and now he is in stable disease without further treatment. LESSONS: We reviewed the mechanism of MDS complicated by solid tumor and concluded the potential mechanisms of this patient. The interactions between potential factors may play a role in oncogenesis which, however, need an in-depth study of its operating mechanism.

Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia-Related Epistaxis and Gastrointestinal Bleeding.

OBJECTIVE: To present a multiyear clinical experience with intravenous bevacizumab for the management of severe gastrointestinal bleeding and/or epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT). PATIENTS AND METHODS: All patients treated with intravenous bevacizumab for severe hereditary hemorrhagic telangiectasia-related bleeding from June 1, 2013, through January 31, 2017, were included in this report. Severity of epistaxis (determined using the Epistaxis Severity Score questionnaire); hemoglobin, iron, and ferritin levels; and quality of life data were collected serially in all patients. RESULTS: Intravenous bevacizumab was administered to 34 patients using a standardized treatment protocol. Anemia was primarily related to severe epistaxis (n=15, 44%), severe gastrointestinal bleeding (n=4, 12%), or both (n=15, 44%), with a median baseline hemoglobin level of 9.1 g/dL (range, 8.3-10.5 gm/dL; to convert to mmol/L, multiply by 0.62). Red blood cell (RBC) transfusions had been administered to 28 patients (82%). Of these, 16 patients (47%) were RBC transfusion dependent and had received a median of 75 RBC transfusions (range, 4->500 RBC units) before bevacizumab initiation. The median length of follow-up was 17.6 months from the beginning of bevacizumab treatment (range, 3-42.5 months). There was a significant reduction in epistaxis severity scores (P<.001) and RBC transfusion requirements (P=.007) after completion of the initial bevacizumab treatment cycle. New-onset or worsened hypertension was noted in 4 patients, with 1 patient experiencing hypertensive urgency with a temporary decline in renal function. CONCLUSION: Intravenous bevacizumab is an effective treatment option for patients with severe anemia related to epistaxis and/or gastrointestinal bleeding. Further studies are needed to establish a dose-response relationship as well as clinical, genetic, and biomarker predictors of response.

Synchronous colorectal cancer and multiple myeloma with chest wall involvement: Is this a coincidence?

Multiple primary malignant neoplasms (MPMNs) are rare malignant neoplasms that simultaneously or successively occur in the same patient as 2 or more primary malignancies. Currently, an increasing number of cases are being reported. In general, MPMNs more commonly occur as 2 solid tumors or 2 hematological malignancies. Cases of MPMN that involve a solid tumor and a hematological malignancy are rare. Here, we report a case of synchronous colorectal cancer (CRC) and multiple myeloma (MM) with chest wall involvement. After reviewing the literature, we believe that there may be a distinct syndrome involving CRC and MM. The patient in our case study suffered refractory anemia following surgery and 2 cycles of chemotherapy. Initially, the anemia was considered to be a common manifestation of CRC in this patient. Interestingly, although he received a blood transfusion, his hemoglobin levels remained low. He later developed hematuria, proteinuria, multiple osteoporosis in the costal bones, and thrombocytopenia. These new symptoms drew our attention, and we considered a diagnosis of synchronous primary CRC and MM, with the anemia as a symptom of MM. Based on the results of a bone marrow aspirate, MM was confirmed. Therefore, when CRC is associated with refractory anemia, we should not only assume that anemia is a classical symptom of CRC, a result of chronic blood loss, nutritional deficiencies, or myelosuppression due to chemotherapy, but we should also consider that it may reflect the possibility of a coexisting hematologic malignancy. As the treatment of these 2 malignancies is different, early diagnosis and treatment based on definitive diagnosis as early as possible will be beneficial to overall prognosis.

A phase 2, randomized, double-blind, multicenter study comparing siltuximab plus best supportive care (BSC) with placebo plus BSC in anemic patients with International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome.

Interleukin-6 (IL-6) may play an important role in the pathophysiology of anemia of inflammation associated with myelodysplastic syndrome (MDS). This double-blind, placebo-controlled, phase 2 study assessed the efficacy and safety of siltuximab, a chimeric anti-IL-6 monoclonal antibody, in patients with low- and intermediate-1-risk MDS who require transfusions for MDS anemia. Patients were randomized in a 2:1 ratio to siltuximab 15 mg kg(-1) every 4 weeks + best supportive care (BSC) or placebo + BSC for 12 weeks. The primary endpoint was reduction in red blood cell (RBC) transfusions to treat MDS anemia, defined as ≥50% relative decrease and ≥2-unit absolute decrease in RBC transfusions. Fifty and 26 patients were randomized to the siltuximab and placebo groups, respectively. The study did not meet its prespecified hypothesis, with six (12%) patients in the siltuximab group and one (3.8%) in the placebo group having reductions in RBC transfusions (P = 0.271). At the time of the planned futility analysis, the prespecified cutoff criteria were not met, and the study was terminated early due to lack of efficacy. No unexpected safety findings were observed. In conclusion, compared to placebo, treatment with siltuximab did not reduce RBC transfusions in transfusion-dependent patients with low- and intermediate-1-risk MDS. Future studies might explore siltuximab in patients with less iron overload and with elevated IL-6 levels and/or using higher doses for MDS.

A new diagnosis of myelodysplastic syndrome in hemochromatosis in an elderly man.

Hemochromatosis is associated with increased risk of hematological neoplasias, but studies showing hemochromatosis gene mutations in myelodysplastic syndrome (MDS) are scanty, particularly in the elderly. The onset of MDS in hemochromatosis usually occurs between 60 and 70 years of age, while cases with advanced age are very rare. We report a case of a 78- year-old man with hemochromatosis who developed refractory anemia with excess of blasts. Our case suggests that in the elderly with hemochromatosis, myelodysplasia should be considered a possible cause of anemia.

Morphological differentiation of severe aplastic anaemia from hypocellular refractory cytopenia of childhood: reproducibility of histopathological diagnostic criteria.

AIMS: To evaluate the reproducibility and reliability of the histomorphological criteria differentiating severe aplastic anaemia (SAA) and hypoplastic refractory cytopenia of childhood (RCC), the most frequently acquired hypocellular bone marrow conditions of childhood. METHODS AND RESULTS: We performed a double-blind interobserver study of 100 different cases of SAA and RCC among seven haematopathologists of the European Working Group of MDS in Childhood (EWOG-MDS) and the German SAA study. Cases with foci of typical myelodysplastic syndrome (MDS) morphology, such as patchy erythropoiesis with defective maturation, in an otherwise highly hypocellular or adipocytic bone marrow were classified as having RCC. Bone marrow samples without a patchy distribution, few scattered myeloid cells or haematopoietic aplasia were diagnosed as SAA. In only four of 100 cases did the reference pathologists not reach agreement regarding classification as SAA or RCC. The kappa index was 0.79. CONCLUSIONS: Our results show that the vast majority of SAA and RCC cases can be reliably differentiated by morphological means alone. A clear differentiation between SAA and RCC at presentation is mandatory for optimizing therapy strategies, and might be responsible for the fact that, in the German childhood SAA study, the probability of developing clonal disease after immunosuppressive therapy has dropped to 3%.

Refractory anemia as a presenting feature of microscopic polyangiitis: a rare vasculitis in children.

Microcytic anemia refractory to usual supplementation is an important clue to an alternative diagnosis. Accompanying pulmonary and renal involvement during the disease course suggests a multisystem disease. Small-vessel vasculitis should be suspected in any patient who presents with a multisystem disease that is not caused by an infectious or malignant process. Among these, antineutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis is a distinct subclass involving anti-neutrophil cytoplasmic antibody (ANCA) as the common pathogenesis. Microscopic polyangiitis is a rare form of such vasculitis in children characterized by pulmonary-renal syndrome with pauci-imune rapidly progressive glomerulonephritis and a poor outcome.

Blue rubber bleb nevus syndrome causing refractory anaemia.

Blue Rubber Bleb Nevus Syndrome (BRBNS) is a rare angiomatosis characterized by distinctive cutaneous and gastrointestinal venous malformations that result in gastrointestinal haemorrhage and iron-deficiency anaemia secondary to the bleeding episodes. We hope to emphasize the possibility of recurrent melaena in BRBNS and heighten physicians' awareness about the disease to contribute to its early detection.

High-throughput characterization of 10 new minor histocompatibility antigens by whole genome association scanning.

Patients with malignant diseases can be effectively treated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Polymorphic peptides presented in HLA molecules, the so-called minor histocompatibility antigens (MiHA), play a crucial role in antitumor immunity as targets for alloreactive donor T cells. Identification of multiple MiHAs is essential to understand and manipulate the development of clinical responses after allo-SCT. In this study, CD8+ T-cell clones were isolated from leukemia patients who entered complete remission after allo-SCT, and MiHA-specific T-cell clones were efficiently selected for analysis of recognition of a panel of EBV-transformed B cells positive for the HLA restriction elements of the selected T-cell clones. One million single nucleotide polymorphisms (SNP) were determined in the panel cell lines and investigated for matching with the T-cell recognition data by whole genome association scanning (WGAs). Significant association with 12 genomic regions was found, and detailed analysis of genes located within these genomic regions revealed SNP disparities encoding polymorphic peptides in 10 cases. Differential recognition of patient-type, but not donor-type, peptides validated the identification of these MiHAs. Using tetramers, distinct populations of MiHA-specific CD8+ T cells were detected, demonstrating that our WGAs strategy allows high-throughput discovery of relevant targets in antitumor immunity after allo-SCT.

Refractory cytopenia with unilineage dysplasia: analysis of prognostic factors and survival in 126 patients.

According to the revised WHO classification of 2008, dysplasia in > or = 10% of one bone marrow lineage and one cytopenia constitutes the low-risk category of unilineage cytopenia and unilineage dysplasia (UCUD). We retrospectively reclassified, according to WHO, low-risk MDS from our database and found 126 subjects with these features at diagnosis: 79 patients were categorized as refractory anemia (RA), 23 patients as refractory neutropenia (RN), and 24 as refractory thrombocytopenia (RT). We did not find differences between the three subgroups as regards sex, median age, and cytogenetic aberrations. Lower PMN count (0.8 x 10(9)/L) was observed in the RN category, as well as lower platelet count in the RT category (51 x 10(9)/L). Moreover, we found a lower rate of patients requiring RBC transfusions, during the disease course, in the RT category (45.8%) as compared to RA (62%) and RN (69%) groups (p = 0.05); a lower incidence of infections at diagnosis in the RT category (20.8%) compared to RA (32%) and RN (43%) categories (p = 0.03); and a higher incidence of hemorrhagic symptoms at diagnosis in the RT category (41.6%) and RN category (26%) as compared to the RA group (5%) (p = 0.001). Application of different scoring systems (Bournemouth and Spanish scores, WPSS) revealed a low OS in high-risk patients within the RT category, compared to RA and RN categories, although unlikely to reflect the consequences of low OS found in the former category. Statistically significant differences were also evidenced in the incidence of acute myeloid leukemia (AML) evolution and overall survival: 7/79 (8%) patients with the RA category evolved to AML in a median time of 89 months, whereas 4/23 (17%) of the RN category and 1/24 (4%) of the RT category experienced disease progression, in a median time of 33.8 and 12.8 months, respectively (p = 0.03). The RT category had a lower overall survival (15.9 months) as compared to RA (48.2 months) and RN (35.9 months) categories (p < 0.001). In conclusion, in our study, application of the revised 2008 WHO classification confirmed the importance of separating patients with unilineage dysplasia for prognostic disease assessment; from our results it seems that the RT category has a worse outcome.

[Re-evaluation of classification of myelodysplastic syndromes with low percentage bone marrow blasts].

OBJECTIVE: To apply the WHO criteria and the minimal diagnostic criteria to the classification of myelodysplastic syndromes (MDS) with low percentage (< 0.050) bone marrow (BM) blasts. METHODS: Two hundred and ten MDS patients with less than 0.050 BM blasts diagnosed between 1988 and 2005 according to FAB criteria were retrospectively reclassified with WHO criteria (2001) and minimal diagnostic criteria. RESULTS: According to the WHO criteria, 5 patients were diagnosed as refractory anemia (RA), 7 as refractory anemia with ringed sideroblasts (RARS), 76 as refractory cytopenia with multilineage dysplasia (RCMD), 9 as RCMD-RS, 35 as MDS-unclassified (MDS-U), 3 as 5q - syndromes, and the rest 75 patients could not be classified suitably. Among the latter 75 patients 16 BM smears showed dysplasia in more than 2 cell lineage but only unilineage cytopenia in peripheral blood (PB). Nine of them were reclassified as RCMD after followed up for more than half a year. Forty-four BM smears showed erythroid dysplasia only, but bicytopenia or pancytopenia in PB. Twenty-seven of them were classified as RCMD after follow-up. Fifteen BM smears not showed dysplasia in any myeloid lineage were reclassified as MDS (5 patients), HS-MDS (5 patients) and idiopathic cytopenia of uncertain significance (ICUS) (5 patients) according to the MDS minimal diagnostic criteria. CONCLUSION: According to WHO criteria (2001), RA is the least diagnosis in MDS. The minimal diagnostic criteria for MDS classification of patients not fulfilled the standard criteria of MDS.

Association of gastrointestinal stromal tumor and acute myeloid leukemia preceded by myelodysplastic syndrome with refractory anemia.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs are believed to be related to mutational activation of receptor tyrosine kinases, KIT, or platelet-derived growth factor receptor-alpha. The coexistence of GISTs with other neoplasms has been extensively addressed in the literature. The most common second neoplasms are colorectal cancer, prostate cancer, and neoplasms derived from lymphoid tissue. In this case report, we describe a patient affected by GIST and acute myeloid leukemia preceded by myelodysplastic syndrome with refractory anemia. The clinicopathological characteristics of the patient are discussed and the literature is reviewed.

Prognostic analysis of refractory anaemia in adult myelodysplastic syndromes.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) display a very diverse pattern. In this study, we investigated prognostic factors and survival rate in adult patients with MDS refractory anaemia (MDS-RA) diagnosed according to French-American-British classification and evaluated the International Prognostic Scoring System (IPSS) for Chinese patients. METHODS: A multi-center study on diagnosis of MDS-RA was conducted to characterize the clinical features of Chinese MDS patients. The morphological criteria for the diagnosis of MDS-RA were first standardized. Clinical data of 307 MDS-RA patients collected from Shanghai, Suzhou and Beijing from 1995 to 2006 were analyzed using Kaplan-Meier curve, log rank and Cox regression model. RESULTS: The median age of 307 MDS-RA cases was 52 years. The frequency of 2 or 3 lineage cytopenias was 85.6%. Abnormal karyotype occurred in 35.7% of 235 patients. There were 165 cases (70.2%) in the good IPSS cytogenetic subgroup, 44 cases (18.7%) intermediate and 26 cases (11.1%) poor. IPSS showed 20 (8.5%) categorized as low risk, 195 cases (83.0%) as intermediate-I risk and 20 cases (8.5%) as intermediate-II risk. The 1-, 2-, 3-, 4- and 5-year survival rates were 90.8%, 85.7%, 82.9%, 74.9% and 71.2% respectively. Fifteen cases (4.9%) transformed to acute myeloid leukaemia (median time 15.9 months, range 3 - 102 months). Lower white blood cell count (< 1.5 x 10(9)/L), platelet count (< 30 x 10(9)/L) and cytogenetic abnormalities were independent prognostic factors by multivariate analysis, but age (= 65 years), IPSS cytogenetic subgroup and IPSS risk subgroup were not independent prognostic factors associated with survival time. CONCLUSIONS: Chinese patients were younger, and had lower incidence of cytogenetic abnormalities, more severe cytopenias but a more favourable prognosis than Western patients. The major prognostic factors were lower white blood cell count, lower platelet count and fewer abnormal karyotypes. The international prognostic scoring system risk group was not an independent prognostic factor for Chinese myelodysplastic syndrome patients with refractory anaemia patients.

[Overview of the clinical reference guides for the idiopathic hematopoietic disorders].

The research committee for idiopathic hematopoietic disorders, which has been supported by the government over the past 35 years, has recently worked out a series of reference guide for the management of diseases under investigation to provide aids for better understanding of pathophysiology of diseases and appropriate clinical decision making. Such attempts covered aplastic anemia, Fanconi anemia, pure red cell aplasia, autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria, myelodysplastic syndromes and primary myelofibrosis, and included diagnostic criteria and severity classification as well as clinical pictures derived from nationwide survey studies. Therapeutic measures were evaluated according to the concepts of evidence-based medicine, when applicable. This report presents an overview of these guides and summarizes key issues in each disease entity.