Adina Cioc

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.

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.

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

Abstract:  Background:  Post‐transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. We examined the role of positron emission tomography (PET) scanning in PTLD.

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 patients 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. Pediatr Blood Cancer 2012; 59: 194–196.

Rituximab-Induced Changes in Hematolymphoid Tissues Found at Autopsy

The effect of rituximab on malignant B cells and normal circulating B cells has been previously studied. In contrast, data on the degree of depletion of nonneoplastic B cells induced by rituximab in lymph nodes and spleen is limited. For this purpose, clinical charts, autopsy records, lymph node and spleen sections, and immunoperoxidase stains were reviewed from 10 patients who had received 1 to 40 doses of rituximab before death. The percentage of nonneoplastic B cells was lower in the lymph node and spleen in rituximab-treated patients when compared with cyclophosphamide, doxorubicin, vincristine, and prednisone-treated patients and patients without lymphoma. The effect of rituximab on nonneoplastic B cells was observed as soon as 1 month after administration and with as few as 3 doses. Reappearance of normal numbers of B cells was not observed 1 to 12 months after the last dose of rituximab was administered. We conclude that rituximab induces prompt, consistent, profound, and prolonged depletion of B lymphocyte populations in human lymphoid tissue.

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 drivers 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.

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 drivers 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.

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. Diagn. Cytopathol. 2013;41:986–990.

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.

Pleural primary effusion lymphoma in an elderly patient

An 87-year-old man, recent immigrant from Korea, was admitted to the hospital due to decreased oral intake of food and fluids and abdominal discomfort. The patient had a history of severe dementia, diabetes, hyperlipidemia, hypertension, and chronic renal insufficiency. No history of malignancy, blood transfusions, drug abuse, high-risk sexual behavior, HIV, hepatitis B, or hepatitis C infection was obtained; however, no testing for HIV or other viruses was performed during this admission. Initial admission laboratory examinations were unremarkable except for hypernatremia, which was corrected by fluid administration, and an elevated lactate dehydrogenase (1,566 u/l, normal range 325–750). A computed tomography (CT) scan was largely unremarkable except for small bilateral renal cysts and a moderate-sized right-sided pleural effusion with associated compressive atelectasis as well as a pericardial effusion. No masses or lymphadenopathy were identified. A thoracentesis was performed and yielded 1 l of clear, dark-orange fluid. Fluid analysis showed a pH of 7.2, total protein levels of 5.2 g/dl, glucose levels of 43 mg/dl, triglycerides of 30 mg/dl, amylase levels < 30 U/l, and a lactate dehydrogenase level of 11771 u/l. Aerobic and anaerobic cultures as well as acid-fast bacteria (AFB) and fungal cultures were negative. Pleural fluid cell counts were 4,140 nucleated cells/microliter, of which 4% were neutrophils, 3% lymphocytes, and 93% other (malignant) cells. Wright-stained cytospin preparations, Papanicolaoustained Surepath preparations, and hematoxylin and eosin stained cellblock preparations were made from the pleural fluid. All preparations showed a dyshesive population of large pleomorphic cells with plasmablastic features in a background of red blood cells, small lymphocytes, and neutrophils. Many apoptotic bodies and occasional mitotic figures were present. In Wright-stained cytospin preparations (Fig. C-1) most cells measured 14–16 l, with a range of 11–30 l. Their nuclei were single, round, with smooth to slightly irregular membranes, measured 12–14 l (range 9–18 l) and harbored one to three round or irregularly shaped macronucleoli ranging from 3 to 5 l in size. The cytoplasm was variable, from a narrow rim around the nucleus to more abundant, pale to dark blue in the Wright-stained preparations, with a peripheral accentuation. Neoplastic cells with more abundant cytoplasm had eccentrically placed nuclei and a pale-staining perinuclear area reminiscent of the hof of plasma cells (Figs. 2C-A and C). Occasional cytoplasmic vacuoles were seen. Papanicolaou-stained (Figs. 2C-B and D) and H&E-stained preparations (Fig. 3C-A) accentuated the plasmacytoid appearance of the cells and the presence of macronucleoli and highlighted the thick chromatinic rim and coarse granularity of the nuclear chromatin. Flow cytometry was performed on the pleural fluid and showed that the large cells were negative for CD2, CD4, CD5, CD7, CD10, CD14, CD19, CD20, CD56, as well as for j and k immunoglobulin light chains. They showed dim expression of CD45, CD3, CD38, and CD138; however, the sample was considered not interpretable due to the poor viability of the neoplastic cells. Immunoperoxidase stains performed on the cellblock preparation showed that the neoplastic cells were negative for cytokeratin AE1/AE3 and S100, as well as for all B-cell markers (CD20, CD79a, PAX5) and most T-cell markers (CD2, CD4, CD5, CD7, CD8, CD45RO) applied. They were also negative for j and k light chains, CD10, bcl2, bcl6, and ALK1, but were strongly positive for CD3 Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota *Correspondence to: Stefan E. Pambuccian, M.D., Professor, Department of Laboratory Medicine and Pathology, Director of Cytopathology, University of Minnesota Medical Center, Fairview, C422 Mayo MMC 76, 420 Delaware Street SE, Minneapolis, MN 55455, USA. E-mail: pambu001@umn.edu Received 31 March 2011; Revision 2 June 2011; Accepted 22 June 2011 DOI 10.1002/dc.21793 Published online 19 September 2011 in Wiley Online Library (wileyonlinelibrary.com).