Hanson, Curtis A.

SF3B1 mutations were recently reported in myelodysplastic syndromes (MDSs), especially in the presence of ring sideroblasts (RSs). We sought to define the interaction between SF3B1 mutations, morphology, karyotype, and prognosis in MDS with more than or equal to 15% RS (MDS-RS). We studied 107 patients with MDS-RS, including 48 with refractory anemia with RS (RARS), 43 with refractory cytopenia with multilineage dysplasia (RCMD)-RS, 11 with refractory anemia with excess blasts-1 (RAEB1)–RS, and 5 with RAEB2-RS. SF3B1 mutations were detected in 53 (∼ 50%) patients: 35 RARS (73%), 16 RCMD-RS (37%), and 2 RAEB1-RS (18%). In univariate analysis, the presence of SF3B1 mutations was associated with better overall (P < .01) and leukemia-free (P < .01) survival; however, in both instances, significance was completely accounted for by World Health Organization morphologic risk categorization. In other words, when RARS and RCMD-RS were analyzed separately, there was no additional prognostic value from the presence or absence of SF3B1 mutations.

Abstract DIPSS-plus (the Dynamic International Prognostic Scoring System-plus) includes 8 risk factors for survival in primary myelofibrosis. In the present study of 884 karyotypically annotated patients with primary myelofibrosis, we sought to identify 1 or 2 parameters that can reliably predict death in the first 2 years of disease. After a median of 8.2 years from time of referral to the Mayo Clinic, 564 deaths (64% of patients in the study) had been recorded. Risk factors associated with > 80% 2-year mortality included monosomal karyotype, inv(3)/i(17q) abnormalities, or any 2 of the following: circulating blasts > 9%, leukocytes ≥ 40 × 109/L, or other unfavorable karyotype. Patients with any 1 of these risk profiles (n = 52) displayed significantly shorter overall survival than those otherwise belonging to a high-risk category per DIPSS-plus (n = 298); respective median survivals were 9 and 23 months (hazard ratio 2.2, 95% confidence interval 1.6-3.1; P < .01). The present information complements DIPSS-plus in the selection of primary myelofibrosis patients for high-risk treatment approaches.

Abstract Annexin-1 and T-bet are recently described immunohistochemical stains that reportedly assist in the diagnosis of hairy cell leukemia (HCL). Our objective was to assess the sensitivity and specificity of a panel of immunohistochemical stains in distinguishing HCL from other B-cell neoplasms, particularly splenic and extranodal marginal zone lymphomas (SMZL and ENMZL, respectively). The study included 234 bone marrow biopsy specimens: 101 HCL, 13 SMZL, and 10 ENMZL cases were assessed with CD20, tartrate-resistant acid phosphatase (TRAP), DBA.44, a-1, T-bet, and cyclin D1, and 110 control cases were assessed with annexin-1 and T-bet. Our study showed that annexin-1 is a specific and sensitive marker for HCL; however, interpretation is limited by positivity within myeloid precursors. T-bet, DBA.44, and TRAP immunohistochemical stains lack sufficient sensitivity and specificity to differentiate HCL from either form of marginal zone lymphoma. However, our data suggest that the addition cyclin D1 to the immunostaining panel will increase the sensitivity and specificity of HCL diagnosis.

AbstractFree light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Monoclonal FLC and polyclonal FLC were associated with poor overall survival compared with patients with normal FLC. Results remained significant after adjusting for Rai stage. The FLC assay is a simple, widely available clinical test with similar prognostic utility as routinely used prognostic biomarkers for CLL. Among persons with FLC abnormalities, the type of abnormality affects prognostic significance.

Purpose The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction. Methods Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review. Results Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10 9 /L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population. Conclusion This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.

Abstract Survival in cytogenetically high-risk patients with acute myeloid leukemia or myelodysplastic syndromes is significantly worse in the presence of a monosomal karyotype (MK). The objective of the present study was to determine whether the same held true for primary myelofibrosis. Among 793 primary myelofibrosis patients seen at our institution, 62 displayed an unfavorable karyotype by way of complex karyotype (n = 41) or sole trisomy 8 (n = 21). Seventeen (41%) of the 41 patients with complex karyotype were classified as having an MK. Median survival was 6, 24, and 20 months in patients with MK, complex karyotype without monosomies, and sole trisomy 8, respectively (P < .0001). The corresponding 2-year leukemic transformation rates were 29.4%, 8.3%, and 0 (P < .0001); hazard ratios (95% confidence intervals) were 6.9 (1.3-37.3) and 14.8 (1.7-130.8). The prognostic relevance of MK was not accounted for by the Dynamic International Prognostic Scoring System. We conclude that MK in primary myelofibrosis is associated with extremely poor overall and leukemia-free survival.

Abstract POEMS is an uncommon syndromic disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes. There are few descriptions of the bone marrow pathology of POEMS; therefore, peripheral blood smears and bone marrow aspirates and biopsies from 87 patients (143 total, 67 pretreatment, 76 posttreatment cases) with POEMS were studied. Plasma cell clonality was analyzed by flow cytometry, immunohistochemistry, and/or in situ hybridization. Monotypic plasma cells were detected in 44 pretreatment cases (66%); the majority of plasma cells expressed λ light chain (91%). The monotypic plasma cells typically were present in a background of increased polytypic plasma cells. Lymphoid aggregates were found in 33 (49%) pretreatment cases and in most cases were rimmed by plasma cells (97%). Megakaryocyte hyperplasia (36 cases) and clusters (62 cases) were frequent; however, none of the 43 cases tested had the JAK2V617F mutation. In summary, we have identified a novel constellation of features that should strongly suggest POEMS syndrome as part of the differential diagnosis. The constellation of λ-restricted monoclonal gammopathy, plasma cell rimming around lymphoid aggregates, and megakaryocytic hyperplasia in a bone marrow is highly suggestive of this diagnosis, especially in the context of a peripheral neuropathy.

Abstract Background. MBL is defined as a monoclonal expansion of B lymphocytes (&lt; 5 × 109/L) in the blood without associated lymphadenopathy or organomegaly; MBLs with a chronic lymphocytic leukemia (CLL) immunophenotype have been termed as CLL-like MBL. The prevalence of CLL-like MBL in the general population is 3.5-12% but increases with age; however, the frequency is even higher (∼13-18%) among unaffected relatives from CLL families (i.e., families with two or more CLL members). We and others have found that a small proportion of individuals with CLL-like MBL individuals and lymphocytosis will progress to CLL requiring treatment (∼1.1% per year). Because CLL and NHL have been shown to aggregate together within families, suggesting a shared pathogenesis, we evaluated the frequency of MBL in NHL families. Methods. Individuals were obtained from an ongoing study of NHL families (i.e., families with 2 or more NHL members). However, we limited to NHL families with at most 1 individual with CLL due to the known increased frequency of MBL in CLL families. Multi-color flow cytometry was performed on fresh peripheral blood samples. A CBC and differential count was simultaneously obtained using an automated blood cell counter. Five possible flow diagnoses were defined as: CLL-like MBL (CD5+CD20dim), atypical MBL (CD5+CD20bright), non-CLL like MBL (CD5−), and normal immunophenotype (NIPT). Medical records of NHL cases were reviewed to confirm disease. Results. A total of 30 individuals from 16 NHL families had available flow cytometry results. The mean age at flow analysis was 56 years (range 37− 83 years). We identified 5 individuals with MBL from 4 families: 3 of the 6 had CLL-like MBL, 1 had atypical MBL, and 1 had non-CLL like MBL. The remaining 25 individuals had a NIPT. Thus, the MBL rate in NHL families is 17% (5/30). Among the CD5+ MBL (both CLL-like and atypical MBL) individuals, all were female and the mean absolute lymphocyte count was 1.4 × 109/L. Of interest, 1 of the CLL-like MBL individuals is from a family where two members had monoclonal gammopathy of uncertain significance (MGUS). Conclusion: Our data show that MBLs of various phenotypes can be found at a higher prevalence in NHL families than that of the general population. Further, the frequency of MBL in NHL families is comparable to that of CLL families. Although more work is needed, our results suggest that MBL may be clustering within NHL families, and thus support a possible common inherited predisposition of NHL and CLL, with MBL signifying a shared early pathogenetic step. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1853.

Purpose The Dynamic International Prognostic Scoring System (DIPSS) for primary myelofibrosis (PMF) uses five risk factors to predict survival: age older than 65 years, hemoglobin lower than 10 g/dL, leukocytes higher than 25 × 10 9 /L, circulating blasts ≥ 1%, and constitutional symptoms. The main objective of this study was to refine DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status. Patients and Methods Mayo Clinic databases for PMF were used to identify patients with available bone marrow histologic and cytogenetic information. Results Seven hundred ninety-three consecutive patients were selected and divided into two groups based on whether or not their referral occurred within (n = 428; training set) or after (n = 365; test set) 1 year of diagnosis. Multivariable analysis identified DIPSS, unfavorable karyotype, platelets lower than 100 × 10 9 /L, and transfusion need as independent predictors of inferior survival. Hazard ratio (HR) –weighted adverse points were assigned to these variables to develop a composite prognostic model using the training set. The model was subsequently validated in the test set, and its application to all 793 patients resulted in median survivals of 185, 78, 35, and 16 months for low, intermediate-1 (HR, 2.2; 95% CI, 1.4 to 3.6), intermediate-2 (HR, 4.9; 95% CI, 3.2 to 7.7), and high-risk groups (HR, 10.7; 95% CI, 6.8 to 16.9), respectively (P < .001). Leukemia-free survival was predicted by the presence of thrombocytopenia or unfavorable karyotype (10-year risk of 31% v 12%; HR, 3.3; 95% CI, 1.9 to 5.6). Conclusion DIPSS plus effectively combines prognostic information from DIPSS, karyotype, platelet count, and transfusion status to predict overall survival in PMF. In addition, unfavorable karyotype or thrombocytopenia predicts inferior leukemia-free survival.

Abstract Prior genome-wide association (GWA) studies have identified 10 susceptibility loci for risk of chronic lymphocytic leukemia (CLL). To identify additional loci, we performed a GWA study in 407 CLL cases (of which 102 had a family history of CLL) and 296 controls. Moreover, given the strong familial risk of CLL, we further subset our GWA analysis to the CLL cases with a family history of CLL to identify loci specific to these familial CLL cases. Our top hits from these analyses were evaluated in an additional sample of 252 familial CLL cases and 965 controls. Using all available data, we identified and confirmed an independent association of 4 single-nucleotide polymorphisms (SNPs) that met genome-wide statistical significance within the IRF8 (interferon regulatory factor 8) gene (combined P values ≤ 3.37 × 10−8), located in the previously identified 16q24.1 locus. Subsetting to familial CLL cases, we identified and confirmed a new locus on chromosome 6p21.3 (combined P value = 6.92 × 10−9). This novel region harbors the HLA-DQA1 and HLA-DRB5 genes. Finally, we evaluated the 10 previously reported SNPs in the overall sample and replicated 8 of them. Our findings support the hypothesis that familial CLL cases have additional genetic variants not seen in sporadic CLL. Additional loci among familial CLL cases may be identified through larger studies.