Siragusa, Sergio

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4122 Background: We have previously identified sole +9, 13q- or 20q- as “favorable” and sole +8 or complex karyotype as “unfavorable” cytogenetic abnormalities in primary myelofibrosis (PMF) (Blood 2010; 115: 496). The purpose of the current study, which includes more than twice the number of patients included in previous studies, was to identify additional prognostically-relevant cytogenetic abnormalities in PMF and refine cytogenetic risk categorization for overall and leukemia-free survival. Methods: Clinical and laboratory data were collected from consecutive patients with PMF seen at our institution and in whom cytogenetic information at or within 1 year of diagnosis was available. Diagnosis of PMF and acute myeloid leukemia were according to the World Health organization (WHO) criteria. Results: A total of 433 patients with PMF were included in the current study. Median age at diagnosis was 65 years. IPSS risk distributions were low in 12% of patients, intermediate-1 in 25%, intermediate-2 in 24% and high in 39%. JAK2V617F mutational frequency was 60%. Cytogenetic findings were normal in 275 (64%) patients. Among the 158 (36%) patients with abnormal karyotype, 109 (69% of abnormal cases) represented sole abnormalities, 23 (15%) two abnormalities and 26 (17%) three or more (i.e. complex) abnormalities. In an effort to identify cytogenetic categories of similar prognosis, each one of 12 operational cytogenetic categories was separately compared with both normal and complex karyotype. Accordingly, we were able to devise a two-tired cytogenetic risk stratification with highly significant differences in overall and leukemia-free survival (Figures 1 and 2): unfavorable (complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement) and favorable (all other cytogenetic findings including normal karyotype). Median survivals of patients with favorable and unfavorable karyotype were 5.2 and 2.0 years, respectively (p<0.0001). The corresponding 5-year survival rates were 51% and 8% (HR 3.1, 95% CI 2.2–4.3; p<0.0001). Multivariable analysis confirmed the IPSS-independent prognostic value of cytogenetic risk categorization (p<0.0001; HR 2.1, 95% CI 1.5–3.1) and also identified thrombocytopenia (platelet count < 100 × 109/L) as another independent predictor of inferior survival (p<0.0001; HR 1.9; 95% CI 1.4–2.6). A similar multivariable analysis showed that cytogenetic risk profile (p=0.001; HR 4.1, 95% CI 1.7–9.6) and platelet count (p=0.04; HR 2.3, 95% CI 1.0–5.0), but not IPSS (p=0.27), predicted leukemia-free survival; the 5-year leukemic transformation rates for unfavorable and favorable karyotype were 46% and 7%, respectively (HR 5.5, 95% CI 2.5–12.0; p<0.0001). These results, in terms of both overall and leukemia-free survival analysis, did not change when patients receiving allo-SCT were censored at the time of their transplant. Among patients with favorable karyotype; the incidences of leukopenia and thrombocytopenia were highest in patients with sole 20q- (41% and 38%, respectively) and lowest in those with sole 13q- (0% and 0%, respectively). Conclusions: The current study provides the rationale and necessary details for incorporating cytogenetic findings and platelet count in future prognostic models for PMF. The study also revealed a highly significant association between sole 20q- and both leukopenia and thrombocytopenia, which suggests a 20q- haploinsufficient gene effect. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 2803 Poster Board II-779 Background. The rate of asymptomatic amyloidosis (asym-amyloidosis) detected in patients with newly diagnosed multiple myeloma (MM) or smoldering multiple myeloma (SMM) is unknown. This topic is significant because unrecognized AL may be associated with increased mortality may change the patient's management. The objective of the present investigation was to evaluate the number and clinical significance of asym-amyloidosis in MM and SM patients at the time of the diagnostic bone marrow (BM) biopsy for MM. Materials and Methods. The study population was selected from the Mayo Clinic Dysproteinemia database and consisted of consecutive patients with an established diagnosis of MM or SMM without recognition of symptomatic AL. Bone marrow biopsies at diagnosis of MM or SMM were retrospectively stained with Congo Red and reviewed by a single pathologist. A patient was considered to have asym-amyloid if Congo Red staining with apple green birefringence was found. Results. Biopsies from 144 (M 84, F 59) patients were evaluated: 77 had a diagnosis of MM and 67 of SMM. The median age was 59 (range 26-84) years. No differences were found regarding hemoglobin, platelets, prothrombin time, serum and urine proteins, serum albumin, alkaline phosphate, creatinine and β2-microglobulin among MM and SMM patients. At a median follow-up 76 months (range 0-216), 32% patients were alive, 65% dead and 2.7% lost to follow-up. Immunoglobulin isotypes were as follows: 96/144 (67%) had IgG 23/144 (16%) IgA, 12/144 (8%) had light chain only, 1/77 (1%) had IgD, none had IgM and 12/144 (8%) had biclonal or indeterminate; 84/144 (58%) were κ restricted. The presence of amyloid was found in only 2 cases (1%, 95% CI – 0.6 to 3.2), 1 in MM and 1 in SMM group. Neither of these patients had or developed signs or symptoms suggestive of organ involvement by amyloid. Among the 142 other patients without amyloid deposition in their index bone marrow, 1 (0.7%, 95% CI -0.6 to 2.0) developed symptomatic AL after 119 months of follow-up. Characteristics of these three patients are shown in table 1. Conclusions. We found only 2 cases (1%) of amyloidosis in the 144 cases of MM or SMM. Our estimates are lower than the rates which have been reported by others, perhaps because of our high level of suspicion for amyloid at our Amyloidosis Center. These data do not support the need for searching for asym-amyloidosis in patients with newly diagnosed MM or SMM as long as they have no clinical features of AL. Disclosures: Off Label Use: Hydroxyurea use in myelofibrosis. Gertz:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Witzig:Novartis: Research Funding. Kumar:celgene: Honoraria; millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees.