Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) and the role of next-generation sequencing.

Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model.

Initially lymphocytic Sweet's syndrome in male patients with myelodysplasia: a distinguished clinicopathological entity? Case report and systematic review of the literature.

BACKGROUND: Sweet's syndrome (SS) is an acute febrile neutrophilic dermatosis. It can occur as an idiopathic, drug-induced or malignancy-associated entity. SS is also seen in patients with myelodysplastic syndrome (MDS) where it may present atypically, both clinically and histologically. In a few rare cases of MDS, lymphocytic infiltrates are the presenting feature of SS. METHODS: MEDLINE and Scopus were the data sources for our review. RESULTS: A clinicopathological subsetemerged of 12 male SS patients with MDS and a mean age of 67.3 years in which the initial SS lesions were lymphocytic infiltrates. However, from 0.5 to 8 years later, sequential biopsies revealed neutrophilic dermal infiltration typical of SS. CONCLUSION: Initially lymphocytic infiltrates in this subset could be attributed either to an early timing of the biopsy concerning the age of the lesion or to the dysgranulopoiesis syndrome. A possible relationship between the dysfunction of the receptor of the granulocyte-macrophage colony stimulating factor, the gene of which is located on the pseudoautosomal X-Y region, may exist in MDS patients with initially lymphocytic SS. This could explain the male gender of this subset and might establish initially lymphocytic SS as a distinguished clinicopathological entity for predicting the occurrence and even the prognosis of MDS.

Quantitation of human herpesvirus-6 (HHV-6) DNA in a cord blood transplant recipient with chromosomal integration of HHV-6.

Chromosomal integration of the human herpesvirus-6 (HHV-6) genome (CIHHV-6) is an important consideration if HHV-6 DNA is detected during the course of transplantation. A 4-year-old girl with refractory anemia with excess blasts type-2 was diagnosed with CIHHV-6 before a cord blood transplantation. HHV-6 DNA was serially quantitated by polymerase chain reaction assay in the transplant period. The possibility of HHV-6 reactivation in a transplant recipient with CIHHV-6 was suspected in our case.

[A case of interstitial pneumonia with smoldering adult T-cell leukemia].

A 66-year-old woman was admitted because of dry cough and dyspnea. Computed tomography showed ground-glass opacities and traction bronchiectasis in both lung fields. Then, ATL cells appeared in her peripheral blood, and the number of lymphocytes in BALF increased. Inverse PCR for HTLV-1 clonality of the peripheral blood revealed a polyclonal pattern, and she was given a diagnosis of smoldering adult T-cell leukemia. Using BALF flow cytometry, both CD4- and CD25-positive cells accounted for only 0.8%. Secondary interstitial pneumonia was diagnosed and we started therapy with prednisolone and cyclophosphamide. BALF flow cytometry may be useful in the differential diagnosis of ATL lung lesions.

[Haemosiderosis bulbi in a patient with myelodysplastic syndrome (MDS RAEB-1)]. / Haemosiderosis bulbi kod pacijenta s mijelodisplasticnim sindromom (MDS RAEB-1).

Haemosiderosis bulbi is a degenerative condition of the eye bulb caused by the toxic effects of an intracellular accumulation of haemosiderin. Haemosiderin is a product of the decomposition of haemoglobin. The most common and severe damage takes place in the epithelial cells of the eye tissues. Haemosiderosis bulbi is a complication of the long existing haemophthalmus, the intravitreal bleeding, which is neither spontaneously resorbed nor operatively removed. The condition is characterized by the loss of light perception and the reddish colour of the intrabulbar tissues. The cause of the haemophthalmus in our patient is protracted anaemia due to pre-existing myelodysplastic syndrome (MDS RAEB-1).

Transformation of adult myelodysplastic syndrome-refractory anemia to acute T-cell lymphoblastic leukemia.

OBJECTIVE: Myelodysplastic syndrome (MDS) is recognized as a preleukemic disorder with a variable risk of transformation to acute myeloid leukemia. Usually the blast cells in leukemia are transformed after MDS displays a myeloid phenotype. Lymphoid progression had been reported as myeloid-lymphoid hybrid or early B phenotype, but our patient transformed acute T-lymphoblastic leukemia, which is a rare lymphoid transformation. CLINICAL PRESENTATION AND INTERVENTION: We present a case of refractory anemia with excess of blast that transformed into acute T-cell lymphoblastic leukemia. MDS was diagnosed in a 69-year-old man in April 2007. Twelve month later, he developed T-acute lymphoblastic leukemia. The blasts were positive for expression of CD2, CD3, CD5, CD7, CD45, and HLA-DR, leading to a diagnosis of T-lymphoblastic leukemia. The patient was treated with chemotherapy, but he died of multiple organ failure. CONCLUSION: The mechanism of lymphoid transformation is not yet fully understood. This case clinically supports the nature of MDS as a pluripotent hematopoietic stem cell disorder. MDS often transforms into acute leukemia, usually of a myeloid phenotype. The transformation of MDS into acute lymphoblastic leukemia is extremely rare.

ETV6/GOT1 fusion in a case of t(10;12)(q24;p13)-positive myelodysplastic syndrome.

The ETV6/GOT1 fusion, resulting from t(10;12) (q24;p13), has been recently described in a myelodysplastic syndrome. We reported a second case of t(10;12)-positive myelodysplastic syndrome in whom fluorescent in situ hybridization confirmed the non-random translocation but molecular biology analyses revealed a ETV6/GOT1 chimera varying from the first case described.

Sinusoidal obstruction syndrome of the liver after hematopoietic stem cell transplantation: decision making for orthotopic liver transplantation.

Sinusoidal obstruction syndrome (SOS) is a specific complication of hematopoietic stem cell transplantation (HSCT) that can lead to substantial morbidity and treatment-related mortality. Heparin is frequently used as prophylaxis of and defibrotide as therapy for mild to moderate SOS. In severe cases of SOS these therapies are often ineffective, and orthotopic liver trans-plantation (OLT) may be the only option. Reports in the literature about the outcome of liver transplantation for SOS are contradictory. We describe our second case of OLT after HSCT. The patient died of intracranial hemorrhage 2 weeks after liver transplantation with good initial organ function. In the first case at our center, however, the patient survived more then 8 years. The reported short- to medium-range survival rate for OLT following HSCT is approximately 50%. On the basis of the experience at our center and the findings in a review of the literature, we developed a rational approach to the selection for liver transplantation of patients with life-threatening liver dysfunction after marrow transplantation.

Clinical efficacy of intravenous colistin therapy in combination with ceftazidime in severe MDR P. aeruginosa systemic infections in two haematological patients.

Nosocomial infections due to MDR P. aeruginosa are an increasing problem. Therapeutical options are few. We describe two haematological patients with severe neutropenia and systemic infection due to MDR P. aeruginosa treated successfully with colistin plus ceftazidime. Severe adverse events were not described.

Varying probability of the development of acute nonlymphoblastic leukemia in refractory anemia patients with an excess of blasts.

The cumulative leukemia-free survival rate of refractory anemia with excess of blasts was fitted to three parametric failure time models, i.e., the usual exponential and Weibull, and exponential mixture models. Among the three, the best fit model was the exponential mixture model, which was 119 times more likely to assume that samples came from the exponential mixture distribution than to assume that those were from the usual Weibull distribution. This strongly suggests that refractory anemia with excess of blasts consists of subgroups with very high and very low probability to develop acute nonlymphoblastic leukemia. The estimated proportion of the very low probability group was about 30%. Analysis by the exponential mixture model with covariates revealed that the probability of a patient to develop acute nonlymphoblastic leukemia could be estimated by three covariates, i.e., bone marrow blast percentage; abnormal granules of granulocytes; and mononuclear large megakaryocytes. The estimated probabilities ranged from 17 to 99%, according to the model.

Factors influencing leukemic transformation in refractory anemias with excess of blasts, with ringed sideroblasts, and without ringed sideroblasts.

The association between leukemic transformation and various features recorded at presentation in patients with refractory anemia with excess of blasts and with or without ringed sideroblasts was analyzed in 255 patients using the proportional hazard model. Features associated with higher transformation rates were: higher values of blasts in peripheral blood or bone marrow; serum haptoglobin; vitamin B12; megakaryocytes in bone marrow; morphological abnormalities in granulo- or megakaryocyte series; male sex; circulating megakaryocytes in peripheral blood; older age; and lower ringed sideroblast proportion. Multivariate analysis was also performed using the following predictor variables: presence or absence of refractory anemia with excess of blasts; sex; abnormal granules in granulocytes; age; and mononuclear large megakaryocytes. Patients were divided arbitrarily into low (hazard ratio, less than 0.45), intermediate (hazard ratio, 0.45-1.85) and high (hazard ratio, greater than 1.85) risk groups. The cumulative leukemia-free rates in the low and intermediate risk groups showed long plateau phases at 95 and 71%, respectively, while in the high risk group, the rate was 10% at 5 years. For clinical purposes, the low risk group should be considered to have nonpreleukemia and the high risk group to have preleukemia.

Ruxolitinib in steroid refractory graft-vs.-host disease: a case report.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited. CASE PRESENTATION: A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 × 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54. CONCLUSIONS: At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

Azacitidine versus decitabine in patients with refractory anemia with excess blast-Results of multicenter study.

The present study aimed to compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndrome (MDS). A total of 88 patients diagnosed with refractory anemia with excess blast (RAEB) treated with azacitidine (n=57) or decitabine (n=31) were evaluated. Comparisons between azacitidine and decitabine groups were performed in the whole cohort, and in a 1:1 propensity score-matched cohort in order to reduce the simple selection bias. Patients who received azacitidine or decitabine had comparable overall response rates in both the unmatched (49.1% vs. 64.5%, p=0.166) and the propensity-matched cohorts (52% vs. 68%, p=0.248). The cumulative incidence of AML transformation at one year was comparable between azacitidine and decitabine in the unmatched (24.0% vs. 31.3%, p=0.26) and in the propensity-matched cohorts (18.7% vs. 31.5%, p=0.11). There was no difference in terms of transfusion requirement, febrile neutropenia episodes or the need for antifungal use during the treatment cycles in the propensity-matched cohort. The median overall survival was 20.4 months for azacitidine and 16.8 months for decitabine (p=0.59). Finally, we found that at least a four-cycle treatment with any HMA was a favorable factor. In conclusion, both azacitidine and decitabine have similar efficacy and toxicity profiles in the treatment of MDS-RAEB.

Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome.

One hundred ninety-six patients with acute myelogenous leukemia (AML) were treated with intensive induction chemotherapy using similar daunorubicin/cytarabine/thioguanine regimens. Treatment results of 44 patients who had a documented preleukemic syndrome or cytopenia present for more than 2 months before developing over AML were compared with 152 patients with de novo AML. Eighteen (41%) patients with preleukemia evolving into AML achieved complete remission compared with 111 (73%) patients with de novo AML (P less than .01). Patients with preleukemia-AML had a significantly longer period to recovery of granulocytes. Multivariate analysis indicated that presence of a previous preleukemic syndrome and advancing age were independent poor prognostic indicators for achieving remission. For patients who achieved remission, disease-free survival and overall survival were also inferior for patients with previous preleukemia; disease-free survival was 17 +/- 17% at 3 years compared with 29 +/- 10% in patients with de novo AML (P = .02). These data indicate that intensive chemotherapy has limited efficacy in patients with AML following a preleukemic syndrome. Durable remissions may be achieved in some patients.