Citations

Abstract Background: In both polycythemia vera (PV) and essential thrombocythemia (ET), aspirin and/or hydroxyurea therapy provide adequate protection from thrombosis but not from disease transformation into acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF). In designing clinical trials with new drugs, including the use of small molecule JAK2 inhibitors, in either ET or PV, it is important to identify patients who are at a higher risk of early transformation into AML/MDS/MF as well as those in whom the long-term risk of these complications is too low to justify exposure to experimental drugs with unknown short-term and long-term toxicity profile. Methods: Information on an institutional database of 1061 patients with either PV (n=458) or ET (n=603) was updated in July of 2007. The World Health Organization criteria were used for diagnosis of PV, ET, AML, MDS, and MF. Two different approaches were used to assess both early and overall risk of AML/MDS/MF development in both ET and PV. In the first approach, three distinct groups were delineated and their presenting features compared; group A was comprised of patients who have remained AML/MDS/MF free after a minimum follow-up of 20 years whereas groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. In the second approach, prognostic factors for AML/MDS/MF-free survival were examined among the entire cohort of 1061 patients. Results : In ET, the number of patients that fulfilled the above-mentioned criteria for inclusion in groups A, B, and C were 40, 12, and 8; the three groups displayed significant differences in the prevalence, at diagnosis, of lower than normal hemoglobin level (8% vs. 58% vs. 38%; p=0.0004), male sex (18% vs. 58% vs. 50%; p=0.01), and arterial thrombosis at diagnosis (p=0.03), respectively. However, only the former two remained significant during multivariable analysis that included age as a covariate. In PV, the number of patients in groups A, B, and C were 23, 18, and 12; the only difference between the three groups was the association between group B and leukocytosis (p=0.02). Cox regression analysis of the entire 1061 ET/PV patients cohort, including 65 AML/MDS/MF events in ET and 36 AML/MDS events in PV, confirmed the inferior AML/MDS/MF-free survival in ET associated with lower than normal hemoglobin and AML/MDS-free survival in PV associated with leukocytosis (Figure). Conclusion : The current study identifies PV patients with leukocytosis as being the most appropriate and ET patients without anemia as the least appropriate for consideration of participation in experimental drug treatment trials. Figure Figure Figure Figure

Abstract Recent studies have shown decreased megakaryocyte expression of the thrombopoietin receptor (c-mpl) in patients with polycythemia vera (PV) but not in those with reactive erythrocytosis. We examined the diagnostic utility of this observation in 22 patients with PV, 7 patients with secondary erythrocytosis (SE), and 10 normal controls. Commercial antibodies against c-mpl were used with standard immunoperoxidase methods. Megakaryocyte c-mpl staining intensity was uniformly moderate-to-strong in the healthy controls and in all the patients with SE. In contrast, staining intensity in 9 patients with PV (41%) was uniformly weak. Furthermore, in 12 of the remaining 13 patients with PV, the c-mpl staining pattern in each case was heterogeneous and was associated with weak staining intensity in more than 20% of the megakaryocyte population. These preliminary data suggest that c-mpl immunostains may complement bone marrow histopathology in distinguishing PV from nonclonal causes of erythrocytosis.

Abstract Abstract 2906 Poster Board II-882 Background: The World Health Organization (WHO) classification system recognizes indolent SM (ISM) as an entity characterized by low systemic mast cell (MC) burden but frequent skin involvement. The WHO system also recognizes 2 provisional ISM sub-variants: smoldering SM (SSM) and bone marrow (BM) mastocytosis (BMM). The two are respectively characterized by increased systemic MC burden (presence of ≥ 2 ‘B-findings') and BM MC infiltration in the absence of skin or multiorgan visceral lesions. The prognostic relevance of this sub-classification remains unclear. Methods: The study population was drawn from a larger cohort of 342 adult SM patients (Blood. 2009 Jun 4;113(23):5727). Clinical data and BM histology were reviewed, and the diagnosis of ISM and its subclassification confirmed per the 2008 WHO proposal. The primary objectives of the study were to: (i) describe the clinical characteristics of a large cohort of ISM patients, within the context of the WHO classification; (ii) evaluate the prevalence of molecular and cytogenetic abnormalities; (iii) evaluate whether ISM subclassification is prognostically relevant on the basis of survival and risk of transformation to acute leukemia or aggressive SM (ASM). Results: (i) Clinical characteristics: 159 ISM patients were evaluated (69 males; median age 49 years, range 19-84); 22 (14%) had SSM, 36 (23%) BMM, and 101 (63%) ‘ISM-other' (ISMo). By definition, ‘B-findings' were absent in BMM patients. ‘B-findings' in SSM (and ISMo) patients was as follows: hepatosplenomegaly and/or lymphadenopathy 91% (21%), BM MC >30% or serum tryptase level >200ng/mL 68% (8%), and hypercellular BM or dysmyelopoiesis without cytopenias 50% (2%). SSM patients were older (p<0.01) and more frequently displayed constitutional symptoms (p<0.01), and anemia (p<0.01). MC mediator-release symptoms (p=0.01), including anaphylaxis (p<0.01), were more frequent in BMM. The following MC-mediators were studied: serum tryptase (57%), beta prostaglandin F2alpha (45%), urine methylhistamine (32%), and urine histamine (21%) – significant differences were noted amongst the ISM subgroups with the following relationship: SSM>ISMo>BMM (p<0.01). (ii) Molecular and cytogenetic abnormalities: Complete karyotype information was available for 55 patients; only 1 patient (with ISMo) had an abnormal karyotype. Fifty nine patients were screened for KITD816V and JAK2V617F; JAK2V617F was universally absent, and distribution of KITD816V was not significantly different amongst the ISM subgroups: SSM (100%), BMM (92%), and ISMo (69%). (iii) Survival and risk of disease transformation: At a median follow of 27 months (range <1-417), 26 deaths were recorded (ISMo 14, SSM 10, and BMM 2), and the combined median survival was 198 months: ISMo 301 months, SSM 120 months, and BMM (not reached) (p<0.01; Figure). Transformation to acute leukemia and ASM was seen in 1 patient (SSM) and 3 patients (2 SSM and 1 ISMo), respectively. Conclusions: Among WHO-defined ISM patients, SSM is associated with significantly shorter survival whereas BMM and ISMo are prognostically similar. If these observations are confirmed by others, consideration may be given to classifying SSM as a distinct subcategory of SM, instead of a sub-variant of ISM as it currently stands. Disclosures: No relevant conflicts of interest to declare.

Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3+/CD8+/CD57+ cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.

Abstract Background: The prognosis of patients with T-cell large granular lymphocyte (LGL) leukemia is diverse, with some patients experiencing rapid progression of the disease while others surviving decades. Despite multiple case reports and a number of case series reported in literature, prognostic factors in this leukemia are unknown and no staging/prognostic system has been developed. Aim: To identify factors predicting the prognosis of patients with newly diagnosed T-cell LGL leukemia. Methods: We reviewed the presentation, laboratory data and the clinical course of patients with newly diagnosed T-cell LGL at seen at the Mayo Clinic, Rochester. T-cell LGL was diagnosed in patients with at least 2 of these criteria: morphological evidence of LGL leukemia on bone marrow biopsy or blood smear; LGL immunophenotype; evidence of clonal T-cell receptor gene rearrangements. Results: 286 patients seen at Mayo Clinic Rochester between 6/1986 and 5/2005 met diagnostic criteria (52% male, median age at presentation 64 years (range 27–88)). Lymphadenopathy, splenomegaly, and hepatomegaly were present in 9%, 4% and 1.5% of the patients respectively. Median hemoglobin was 11.7 g/dL (range 3.5 – 17.1). Median absolute neutrophil count (ANC) was 1.51 × 109/L (range 0.0 – 20 × 109/L) and median absolute lymphocyte count (ALC) was 2.2 × 109/L (range 0.1 – 24). Median LGL count on peripheral smear was 0.81 × 109/L (range 0.06–10.8 × 109/L). Cytogenetic studies were done for 122 patients, of which, only 9 were abnormal. 87 patients (29%) had associated autoimmune conditions: rheumatoid arthritis (n=29), Felty’s syndrome (n=11), other connective tissue disorders (n=9)). Pure red cell aplasia, aplastic anemia, idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia were seen in 17, 5, 8, 1 patients respectively. Median follow up was 50 months (range 1–229) and estimated median survival was 74.3 months. In multivariate analysis, the only independent risk factors were: anemia (hemoglobin<12 g/dl), hazard ratio (HR) 1.75, (95%CI 1.22–2.52, p= 0.0023), severe neutropenia (<0.1 × 109/L), HR 2.11 (95%CI 1.053–4.25) and lymphopenia (ALC< 1 × 109/L), HR 1.93 (95%CI 1.21–3.07). We developed a simple prognostic scoring system based on the above identified independent risk factors, stratifying patients in 3 groups: 0 - no risk factors present, 1 -one risk factor, 2 - two or more risk factors present. The median survival was 105, 55 and 5 months for score of 0, 1 and 2 respectively, p=0.004 (Figure). Conclusion: The prognosis of patients with newly diagnosed T-cell LGL is variable. The presence of anemia, severe neutropenia and lymphopenia are independent poor prognostic factors in T-cell LGL. Combining these factors allows the identification of patients at a high risk of death from the disease. Further studies are needed to prospectively validate these findings and establish if the high risk group would benefit from aggressive therapy. Figure Figure.