Personal history of autoimmune disease and other medical conditions and risk of myelodysplastic syndromes.

BACKGROUND: Autoimmune diseases and hematopoietic malignancies are known to cluster within individuals, suggesting intertwined etiologies. A limited number of studies have evaluated pre-existing medical conditions as risk factors for myelodysplastic syndromes (MDS). We evaluated associations between autoimmune disease and other medical conditions and risk of MDS. METHODS: Cases were identified through the Minnesota Cancer Reporting System. Controls were identified through the Minnesota State driver's license/identification card list. History of autoimmune disease and other medical conditions was based on self-report; proxy interviews were not conducted. Unconditional logistic regression was used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CI). RESULTS: We included 395 cases and 694 controls. Cases were significantly more likely to report a diagnosis of any autoimmune disease when compared with controls (aOR=1.41, 95% CI: 1.05-1.89) after adjustment for age, sex, education, NSAID use, exposure to benzene and body mass index. When we evaluated specific autoimmune conditions, a statistically significant association was observed for hypothyroidism (aOR=2.16, 95% CI: 1.39-3.34) and odds ratios were elevated for inflammatory bowel disease (aOR=1.75) and systemic lupus erythematosus (SLE; aOR=3.65), although these associations did not reach statistical significance. Presence of an autoimmune condition did not impact overall survival (p = 0.91). CONCLUSION: Our results validate previous findings of an association between autoimmune disease and MDS. Further studies are required to determine whether this association is due to shared etiology, treatment for autoimmune diseases, or altered immune surveillance or bone marrow damage caused by the autoimmune condition.

The association between non-steroidal anti-inflammatory drugs (NSAIDs) and myelodysplastic syndromes in the Adults in Minnesota with Myelodysplastic Syndromes (AIMMS) Study.

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a chemopreventive effect in some cancers. We evaluated associations between NSAID use and MDS in a population-based case-control study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Secondary analyses stratified by sex and MDS subtype were also conducted.The analysis included 399 MDS cases and 698 controls. No significant associations between MDS and use of aspirin (OR = 0.87, 95% CI 0.67-1.14), ibuprofen (OR = 0.91, 95% CI 0.64-1.30), acetaminophen (OR = 1.29, 95% CI 0.90-1.84) or NSAIDs overall (OR = 0.92, 95% CI 0.68-1.23) were observed. No significant associations were observed in models stratified by sex or MDS subtype; however, the direction of the effect between NSAID use and MDS varied by MDS subtype. Our results do not support an association between NSAID use and MDS overall.

Risk factors for de novo and therapy-related myelodysplastic syndromes (MDS).

PURPOSE: Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS. METHODS: The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy. CONCLUSIONS: We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS.

Alcohol use is not a significant contributor to myelodysplastic syndromes.

PURPOSE: Myelodysplastic syndromes (MDS) are a class of clonal neoplastic disorders of largely unknown etiology, and published data remain inconclusive regarding the association between lifetime alcohol consumption and MDS risk. In these analyses, data from a population-based case-control study were used to investigate this association. METHODS: Eligible cases of MDS were identified through the Minnesota Cancer Reporting System; controls were matched by sex and age-decile. A central review process was used to confirm MDS diagnosis and classify subtypes. Unconditional and polytomous logistic regression were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to compare survival by category of lifetime alcohol consumption. RESULTS: In total, 398 cases of MDS and 698 controls were included. Alcohol consumption at 23-30, 31-49, and 50-65 years of age, recent consumption 1 year before diagnosis/interview, and lifetime consumption were not found to be significantly associated with MDS in males (OR range 0.63-0.99) or females (OR range 0.58-1.70). Analysis by MDS subtype further suggested there was not a significant association between recent alcohol consumption and odds of disease by subtype (OR range 0.39-1.13). Lifetime alcohol consumption was not significantly associated with survival after diagnosis of MDS CONCLUSIONS: Previously reported associations between alcohol consumption and MDS risk were inconsistent. Results from our analyses by sex and disease subtype do not support alcohol as a significant contributor to risk of MDS.

Factors predicting early mortality after new diagnosis of myelodysplastic syndrome: A population-based study.

OBJECTIVE: Little prospective data regarding factors determining patient outcomes in myelodysplastic syndromes (MDS) are available. To establish features of early mortality in MDS, we compare characteristics of patients dying within 1 year of diagnosis with those surviving longer. METHODS: We prospectively enrolled adults with a new MDS diagnosis in a population-based case-control study. Logistic regression was used to calculate odds ratios and 95% confidence intervals for potential predictors of early mortality. Subgroup analyses were conducted within the following groups: high-/very-high-risk IPSS-R; very-low-/low-/intermediate-risk IPSS-R; treated patients; and supportive care only patients. RESULTS: We observed early mortality in those with abnormal cytogenetics (OR: 3.36, 95% CI: 1.52-7.46), three or greater cytogenetic abnormalities (OR: 3.48, 95% CI: 1.51-7.99), treatment at a community medical center (versus academic) (OR: 2.55, 95% CI: 1.18-5.47), and with 2-3 concurrent medical comorbidities (OR: 2.14, 95% CI: 1.08-4.22). Similarly, in subgroup analyses, abnormal cytogenetics remained the main predictor of early mortality. CONCLUSION: Complex cytogenetics and prognostic risk category have been associated with early mortality without intervention. Our data confirm these associations in a large, prospectively followed cohort and highlight the significance of cytogenetic abnormalities and complexity regardless of IPSS-R risk categorization or treatment.

Chemical exposures and risk of acute myeloid leukemia and myelodysplastic syndromes in a population-based study.

Benzene exposure is one of the few well-established risk factors for myeloid malignancy. Exposure to other chemicals has been inconsistently associated with hematologic malignancies. We evaluated occupational and residential chemical exposures as risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) using population-based data. AML and MDS cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota driver's license/identification card list. Chemical exposures were measured by self-report. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CI). We included 265 MDS cases, 420 AML cases and 1388 controls. We observed significant associations between both MDS and AML and benzene (OR = 1.77, 95% CI 1.19, 2.63 and OR = 2.10, 95% CI 1.35, 3.28, respectively) and vinyl chlorides (OR = 2.05, 95% CI 1.15, 3.63 and OR = 2.81, 95% CI 1.14, 6.92). Exposure to soot, creosote, inks, dyes and tanning solutions and coal dust were associated with AML (range ORs = 2.68-4.03), while no association was seen between these exposures and MDS (range ORs = 0.57-1.68). Pesticides and agricultural chemicals were not significantly associated with AML or MDS. Similar results were observed in analyses stratified by sex. In addition to providing risk estimates for benzene from a population-based sample, we also identified a number of other occupational and residential chemicals that were significantly associated with AML; however, all exposures were reported by only a small percentage of cases (≤10%). While chemical exposures play a clear role in the etiology of myeloid malignancy, these exposures do not account for the majority of cases.

Association between mitochondrial DNA haplogroup and myelodysplastic syndromes.

Polymorphisms in mitochondrial DNA (mtDNA) are used to group individuals into haplogroups reflecting human global migration and are associated with multiple diseases, including cancer. Here, we evaluate the association between mtDNA haplogroup and risk of myelodysplastic syndromes (MDS). Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. Because haplogroup frequencies vary by race and ethnicity, we restricted analyses to non-Hispanic whites. We genotyped 15 mtSNPs that capture common European mitochondrial haplogroup variation. We used SAS v.9.3 (SAS Institute, Cary, NC) to calculate odds ratios (OR) and 95% confidence intervals (CI) overall and stratified by MDS subtype and IPSS-R risk category. We were able to classify 215 cases with confirmed MDS and 522 controls into one of the 11 common European haplogroups. Due to small sample sizes in some subgroups, we combined mt haplogroups into larger bins based on the haplogroup evolutionary tree, including HV (H + V), JT (J + T), IWX (I + W + X), UK (U + K), and Z for comparisons of cases and controls. Using haplogroup HV as the reference group, we found a statistically significant association between haplogroup JT and MDS (OR = 0.58, 95% CI 0.36, 0.92, P = 0.02). No statistically significant heterogeneity was observed in subgroup analyses. In this population-based study of MDS, we observed an association between mtDNA haplogroup JT and risk of MDS. While previously published studies provide biological plausibility for the observed association, further studies of the relationship between mtDNA variation and MDS are warranted in larger sample sizes. © 2016 Wiley Periodicals, Inc.

Obesity over the life course and risk of acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Overweight and obesity are known risk factors for a number of cancers, with recent evidence suggesting that risk of hematologic cancer is also increased in obese individuals. We evaluated associations between body mass index (BMI) at differing time points during the life course in population-based case control studies of acute myeloid leukemia (AML) and myelodysplatic syndromes (MDS). METHODS: Cases were identified by the Minnesota Cancer Surveillance System. Controls were identified through the Minnesota State driver's license/identification card list. BMI was calculated using self-reported height and weight at ages 18, 35, and 50 years and two years prior to interview, and categorized as normal (18.5-25 kg/m(2)), overweight (25-29.9 kg/m(2)), obese class I (30-34.9 kg/m(2)), and obese class II/III (35+ kg/m(2)). All analyses were stratified by sex. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: We included 420 AML cases, 265 MDS cases and 1388 controls. Obesity two years prior to diagnosis was associated with AML in both males and females (OR=2.22, 95% CI 1.28, 3.85 and OR=1.85, 95% CI 1.08, 3.15 for BMI≥35 vs. BMI 18.5-24.9, respectively). In contrast, associations between obesity and MDS were observed only in females. Weight change in adulthood was not consistently associated with either outcome. CONCLUSION: Our results extend the emerging literature suggesting that obesity is a risk factor for hematologic malignancy and provide evidence that that the association remains regardless of timing of obesity. Obesity in adulthood is a modifiable risk factor for both MDS and AML.

Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota.

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis, and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process, and we sought to better characterize hematopoietic cell transplantation (HCT) outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with HCT. Patients enrolled in a population-based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age- and risk-matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48 vs. 21 %, log-rank p value 0.009). Non-HCT patients were more likely to have comorbidities, and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques, more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.

Differences in community and academic practice patterns for newly diagnosed myelodysplastic syndromes (MDS) patients.

PURPOSE: The heterogeneous nature of myelodysplastic syndromes (MDS) complicates therapeutic decision making, particularly for newly diagnosed disease. Factors impacting the treatment plan in this early period of disease course are poorly defined. This study determines whether therapeutic choices for newly diagnosed MDS are associated with location of treatment (community or academic), prognostic risk category, and patient age. METHODS: The adults in Minnesota with myelodysplastic syndromes (AIMMS) database was utilized in this statewide, prospective population-based study conducted by the University of Minnesota (UMN), Mayo Clinic, and Minnesota Department of Health. Adult (age 20+ years) cases of MDS newly diagnosed starting in April 2010 were invited to participate. This analysis includes patients enrolled during the first study year with 1-year follow-up data. Treatment choices (supportive, active, and transplant) were stratified by the international prognostic scoring system (IPSS) and the revised-IPSS (IPSS-R), then separated into groups by location of care and age (<65 or 65+ years). Academic-based care was any contact with the UMN and Mayo Clinic; community-based care was all other clinical sites. RESULTS: Stratification by IPSS and IPSS-R showed supportive care decreased and active care increased with advancing risk categories (p<0.0001). Comparing treatment setting, community-based care had 77% supportive and 23% active treatment; academic-based care was 36% supportive, 41% active, and 23% transplant (p<0.0001). By age groups, patients <65 years with intermediate, high, or very high risk disease by IPSS-R received 97% active care/transplant, compared to only 52% of patients age 65+. CONCLUSIONS: Younger patients and those treated at academic centers had a more aggressive treatment approach. Whether these treatment differences convey improved disease control and mortality, and therefore should be extended more frequently to older and community-based patients, is the subject of ongoing prospective study.

De novo CD5-positive primary cardiac diffuse large B-cell lymphoma diagnosed by pleural fluid cytology.

Primary cardiac lymphomas are exceedingly rare. The presence and extent of the intracardiac mass is determined by echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI); however, the diagnosis is established by endomyocardial biopsy or by pericardial or pleural effusion cytology. We describe the pleural effusion cytologic features of a primary cardiac lymphoma in a 55-year-old woman who presented with progressive shortness of breath, fatigue, mild dizziness, dull chest ache, and lower extremity edema. Transthoracic echocardiography, CT, and MRI showed a large mass centered in the right atrium and extending into the right ventricle, associated with pericardial effusion and bilateral pleural effusions. Cytologic examination of the pleural fluid showed very large pleomorphic malignant cell, some of which were binucleated and multinucleated and had anaplastic features. Flow cytometry showed a kappa monotypic population of large cells coexpressing CD5, CD19, and CD20; and immunoperoxidase stains performed on the cell block sections showed that the large neoplastic cells were positive for CD20, PAX5, CD5, and MUM1 and showed a very high proliferation rate (over 90%) by Ki67 staining. The cytologic, flow cytometry, and immunohistochemistry findings established the diagnosis of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma (DLBCL), anaplastic variant, which was confirmed by the subsequent endomyocardial biopsy. This is, to the best of our knowledge, the first report of de novo CD5-positive primary cardiac diffuse large B-cell lymphoma, and the first report of the anaplastic variant of DLBCL diagnosed by effusion cytology.

Follicular lymphoma transformed to "double-hit" B lymphoblastic lymphoma presenting in the peritoneal fluid.

Lymphomas showing both MYC/8q24 rearrangement and IGH@BCL2/t(14;18)(q32;q21), also referred to as "double-hit" or "dual-hit" lymphomas (DHL) are rare B-cell malignancies with a germinal center B-cell immunophenotype and heterogeneous cytologic and histologic features. Such lymphomas may arise de novo or through transformation of follicular lymphomas and are classified either as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL)" (most commonly), DLBCL, or, rarely, as B-lymphoblastic lymphoma. We report a case of B-lymphobastic lymphoma arising through transformation of follicular lymphoma diagnosed on peritoneal fluid cytology, flow cytometry, and cytogenetic studies in a 53-year-old man who presented with abdominal pain, shortness of breath, night sweats, extensive lymphadenopathy, pleural effusion, and ascites. Cytologic examination of the ascitic fluid showed two distinct populations of neoplastic lymphoid cells, a predominant population of larger cells with fine powdery ("blastic") chromatin, visible to prominent nucleoli and occasional small cytoplasmic vacuoles and a less numerous population of smaller cells with centrocytic morphology. Flow cytometry also showed two distinct monotypic B-cell populations, both expressing CD10, and TdT-positivity was demonstrated immunohistochemically. Fluorescence in situ hybridization (FISH) demonstrated both MYC rearrangement and IGH/BCL2 gene fusion and cytogenetic analysis showed a complex karyotype including both t(14;18)(q32;q21) and t(8;22)(q24.1;q11.2). Since DHL pursue an aggressive clinical course, respond poorly to therapy, and have a poor outcome, it is important to suspect the diagnosis when encountering neoplastic lymphoid cells that are difficult to classify in effusion cytology specimens and to order the appropriate immunophenotyping and cytogenetic studies.

Favorable outcome of allogeneic hematopoietic cell transplantation for 8p11 myeloproliferative syndrome associated with BCR-FGFR1 gene fusion.

We report the case of a child who presented with nonspecific symptoms suggestive of a rheumatologic disorder, whose bone marrow had a complex translocation involving the FGFR1 locus. Hematopathologic findings were subtle and did not definitively indicate malignancy. Because he responded poorly to initial treatment with hydroxyurea, and in light of the progressive clinical course associated with the 8p11 myeloproliferative syndrome, he underwent an unrelated-donor hematopoietic stem cell transplant. This patient's atypical presentation highlights the importance of obtaining cytogenetic analysis at the time of bone marrow sampling and considering this uncommon entity in the differential diagnosis of hematologic disorders.

Diagnosis of myelodysplastic syndrome among a cohort of 119 patients with fanconi anemia: morphologic and cytogenetic characteristics.

Predisposition to myelodysplastic syndrome (MDS) and acute leukemia is a hallmark of Fanconi anemia (FA). Morphologic criteria for MDS in FA are not well established, nor is the significance of clonal chromosomal abnormalities. We reviewed bone marrow samples of 119 FA patients: 23 had MDS, with the most common subtype refractory cytopenia with multilineage dysplasia. The presence of MDS was highly correlated with the presence of clonal abnormalities. Neutrophil dysplasia and increased blasts were always associated with the presence of a clone, in contrast with dyserythropoiesis. The most frequent clones had gains of 1q and 3q and/or loss of 7. Karyotype complexity also correlated with MDS. One third of patients with 3q as a sole abnormality had no MDS; patients with 3q and an additional abnormality all had MDS. The data provide a rationale for integrating cytogenetic findings with independently evaluated morphologic findings for monitoring bone marrow status in FA.

Allogeneic stem cell transplantation for adults with myelodysplastic syndromes: importance of pretransplant disease burden.

Allogeneic stem cell transplantation is the only known curative therapy for myelodysplastic syndromes (MDS). We present the transplant outcomes for 84 adult MDS patients, median age 50 (18-69 years), undergoing allogeneic hematopoietic stem cell transplantation (HSCT) at the University of Minnesota between 1995 and 2007. By WHO criteria 35 (42%) had refractory anemia with excess blasts (RAEB-1 or 2), 23 (27%) had refractory cytopenia with multilineage dysplasia (RCMD) or RCMD and ringed sideroblasts (RCMD-RS), and the remaining 26 (31%) had refractory anemia (RA), myelodysplastic syndrome-unclassifiable (MDS-U), chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative disease (MDS/MPD), or myelodysplastic syndrome-not otherwise specified (MDS-NOS). Graft source was related in 47 (56%), unrelated donor (URD) marrow in 11 (13%), and unrelated cord blood (UCB) in 26 (31%). The conditioning regimen included total body irradiation (TBI) in 94% of transplantations; 52 (62%) myeloablative (MA) and 32 (38%) nonmyeloablative (NMA) regimens. Cumulative incidence of neutrophil engraftment by day +42, acute graft-versus-host disease (aGVHD) by day +100, and chronic GVHD (cGVHD) by 1 year were 88% (80%-96%, 95% confidence interval [CI]), 43% (36%-50%, 95% CI), and 15% (10%-20%, 95% CI), respectively. One-year treatment-related mortality (TRM), relapse, disease-free survival (DFS), and overall survival (OS) were 39% (28%-50%, 95% CI), 23% (12%-32%, 95% CI), 38% (28%-48%, 95% CI), and 48% (38%-58%, 95% CI) respectively. Cumulative incidence of relapse at 1 year in patients with pre-HCT complete remission (CR) or <5% blasts was improved at 18% (8%-28%, 95% CI) compared to 35% (16%-54%, 95% CI) in patients with 5%-20% blasts (P = .07). Additionally, with MA conditioning, the incidence of relapse at 1 year trended lower at 16% (6%-26%, 95% CI) versus 35% (18%-52%, 95% CI) in NMA (P = .06), and a statistically significant decrease in relapse was noted in patients entering HCT with CR or <5% blasts with an incidence of 9% (0%-18%, 95% CI) (MA) versus 31% (11%-51%, 95% CI) (NMA) (P = 0.04). For those patients with > or =5% blasts, MA conditioning did not significantly decrease relapse rates. One-year TRM was similar between MA and NMA conditioning. For patients entering transplant in CR or with <5% blasts, prior treatment to reach this level did not impact rates of relapse or transplant-related mortality when all patients were analyzed; however, when broken down by conditioning intensity, there was a trend toward improved DFS in those NMA patients who were pretreated. Finally, 1-year DFS was similar using related donor peripheral blood stem cell (PBSC)/marrow, URD marrow, or UCB grafts. These data suggest that (1) blast percentage <5% at HSCT is the major predictor of improved DFS and relapse and prior treatment to reach this disease status may have value in leading to improved DFS; (2) MA conditioning is associated with lower relapse risk, particularly in patients with CR or <5% blasts, but is not able to overcome increased disease burden; (3) NMA conditioning yields equivalent TRM, DFS, and OS, and is reasonable in patients unsuited for MA conditioning; (4) the donor sources tested (PBSC, bone marrow [BM], or UCB) yielded similar outcomes.

Positron emission tomography scanning in the setting of post-transplant lymphoproliferative disorders.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. We examined the role of positron emission tomography (PET) scanning in PTLD. METHODS: All patients treated for PTLD from 2001-2006 who also underwent PET scans were reviewed. RESULTS: Nineteen PTLD patients were included. Seventeen patients had PET scans for staging at diagnosis. Of these, two patients with primary central nervous system lymphoma and one patient with only bone marrow involvement after complete surgical resection of a bowel lesion had no abnormalities on CT or PET scan. The remaining patients had measurable, extracranial disease by CT scan and PET scan. The median maximum standard uptake value was 8.2 (range 3-30). Thirteen patients had a PET scan following treatment. Eleven of 13 patients had a complete response (CR). Two of 13 patients had persistent disease following therapy; in one of these patients, relapsed disease was documented by PET scan alone. Of the 11 patients with CR, three patients relapsed shortly thereafter. In each case, at the time of relapse, the PET scan confirmed recurrent disease regardless of histopathologic subtype. CONCLUSIONS: PET scans may have a role in the staging and follow-up of patients with PTLD. Additional prospective studies are warranted.