Search

Commentary to: Docosahexanoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell lineTakashi Yamagami, Christopher D. Porada , Ronald S. Pardini , Esmail D. Zanjani , Graca Almeida-Porada

Background Grey Zone Lymphoma (GZL), with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (CHL), is a relatively new entity per the latest WHO classification. Limited clinical data exists on this rare lymphoma and the ideal management remains uncertain. We performed a comprehensive literature review of reported cases to better define its clinical characteristics and the natural history of this rare entity. Methods A comprehensive MEDLINE search was performed using key words “gray zone or grey zone or unclassifiable or indeterminate and lymphoma” through July of 2013. Cases were included in the analysis if they met the pathological definition of GZL as defined by the WHO criteria, based on the typical morphological and immunophenotypic pattern. Cases without primary patient data were excluded. Of the 554 abstracts reviewed from the primary MEDLINE search, 45 articles met study criteria for review. Of those, 8 articles involving 39 cases met criteria for inclusion in our analysis. Two additional cases were identified at our local institution. Comparison of complete response (CR) rates between ABVD-like and CHOP-like regimens was calculated using Fisher’s exact test. P-values Results Of the 41 cases included in this analysis, the median age of presentation was 33.5 (range 13-85) with a slight male predominance (59%). B symptoms were present in 77% of cases and 75% presented with early stage (I or II). Mediastinal lymphadenopathy was the most common site of disease (89%). Pathological data were available for analysis in all 41 patients. Sixty-eight percent of cases had a morphological appearance of CHL with Reed-Sternberg cells. Immunophenotype revealed positivity for CD20 (90%), CD30 (95%), CD15 (63%), CD45 (73%), CD79a (100%), BOB1 (72%), OCT2 (89%) and PAX5 (100%). Forty-one percent were positive for EBV based on EBER and/or LMP1 expression. Clinical outcome data were available for review for 20 of the 41 patients Treatment was variable and included either initial CHL regimens (ABVD, BEACOPP) or DLBCL regimens (CHOP, EPOCH, with or without rituximab). Seven patients received initial treatment with ABVD-like regimens, of which 4 did not show a response, 3 achieved a partial response (PR) and there were no reported complete responses. Of the seven patients treated with CHOP-like regimens, 5 had clinical outcome data available. Four patients achieved a CR, 1 patient achieved a PR (Fisher’s for CR rate P=0.01). All patients that achieved CR after CHOP-like regimens received consolidation radiation therapy. Seven patients underwent an autologous stem cell transplantation, of which there were two reported relapses within the first 6 months. The median follow up for the entire cohort was 15 months and the 2-yr overall survival (OS) was 87% with a median OS that was not reached. Conclusions GZL, with features intermediate between CHL and DLBCL, is a rare entity with variable prognosis. This lymphoma subtype commonly presents at an early stage with B symptoms and mediastinal involvement. A high proportion were EBV positive. None of the patients that received initial ABVD-like regimens achieved a CR. The response rates were higher in patients that received initial CHOP-like regimens, although the sample size was small. Additional studies are warranted to better understand the optimal treatment regimens in these patients. Disclosures: No relevant conflicts of interest to declare.

Introduction Based on the activity of ofatumumab in patients with indolent B-cell non-Hodgkin lymphoma (NHL) and the potential synergistic effect of bortezomib in combination with anti-CD20 antibody therapy, a phase II study to investigate the effect of the combination of ofatumumab and bortezomib in patients with relapsed indolent B-cell NHL who relapsed >6 months after receiving a rituximab-containing regimen was initiated. Methods Patients 18 years or older with a pathologically confirmed low-grade B-cell NHL who relapsed >6 months after a rituximab-containing regimen were included in our study. Other inclusion criteria were ECOG performance status 0.75, and platelets >50,000/uL). Exclusion criteria included HBV+, HIV+, transformed lymphoma, primary cutaneous lymphoma, central nervous system involvement, Results We present data on 10 patients enrolled between October 2010 and April 2013. Median age was 66 years (range 55-93 years); eight patients (80%) were 60 years or older. There were 7 (70%) men and 3 (30%) women. LDH was elevated in 8 patients (80%). ECOG performance status was 0 in 9 (90%) and 1 in 1 patient (10%). Six patients (60%) had a histological diagnosis of follicular lymphoma, 1 (10%) mantle cell lymphoma, 1 (10%) small lymphocytic lymphoma, 1 (10%) marginal zone lymphoma, and 1 (10%) low-grade B-cell lymphoma, not otherwise specified. Stage III/IV was seen in 5 patients (50%). Eight patients (80%) had a high-risk FLIPI score. Median time from initial diagnosis to current therapy was 65 months (range 20-204 months). Median time from last rituximab-containing regimen was 24 months (range 11-48 months). Median number of previous therapies was 2 (range 1-4). Three patients (30%) had previously received radiotherapy. One patient (10%) had previously undergone autologous stem cell transplantation. Response rates after induction therapy were: 1 (10%) complete response (CR), 3 (30%) partial response (PR), 3 (30%) stable disease, 1 (10%) progressive disease, and 2 (20%) not evaluable for response. With exception of 1 patient who continues on therapy, the patients who achieved a response or had stable disease after induction therapy showed progression of disease during maintenance. Median duration of response in patients who responded was 4 months (range 1-9 months). At the time of this report, 7 patients (70%) are alive with disease, 2 (20%) are alive without evidence of disease, and 1 (10%) has expired. Five grade 3 or 4 adverse events (AEs) occurred; grade 4: diarrhea (n=1) and hyperglycemia (n=1); grade 3: infusion reaction (n=1), nausea (n=1) and rash (n=1). No grade 3 or 4 peripheral neuropathy or hematological AEs were observed. The most common grade 1 or 2 AEs were: infusion reactions (n=6), anemia (n=5), thrombocytopenia (n=5), fatigue (n=4), diarrhea (n=4), hyperglycemia (n=4) and lymphopenia (n=4). No deaths have occurred while on therapy. Conclusions The combination of ofatumumab and bortezomib given weekly for 4 weeks induced a response in 40% and stable disease in 30% of the patients. However, most of the patients experienced progression of disease during the maintenance phase of the study. Furthermore, there were five grade 3 or 4 AEs associated with therapy. Based on this interim analysis, it was decided to stop enrollment. The combination of ofatumumab and bortezomib, however, appears potentially active and deserves further study. Different schemas of therapy with longer induction or different maintenance schedule could prove to be safer and more effective. Disclosures: No relevant conflicts of interest to declare.

Abstract 4589 Introduction: Spontaneous remission of chronic lymphocytic leukemia (SRCLL) has occassionaly been reported since the 1950s. About 40–50 cases have been reported in the English literature. The often quoted incidence of such a phenomena is estimated to be 1% of all CLL cases (Table 1). However, a review of these reports which have determined this incidence suggests that many patients did not have a true SRCLL. The authors have conducted a systemic search within their own institution database to determine the true incidence of SRCLL. Methods: After obtaining appropriate IRB approval, a systemic search was performed within the our institution's hematopathology databases for the diagnosis of chronic lymphocytic leukemia from year 2000 to 2012. Records and laboratory findings were reviewed for all cases. Records for patients with laboratory data suggestive of remission were reviewed to determine if they had received any form of therapy. All cases were included in the review if the diagnosis of CLL was firmly established by flow cytometry. SRCLL was defined as: 1) the patient's elevated lymphocyte number at diagnosis was >5 × 109/L and persisted for >6 months confirming the initial diagnosis of CLL, 2) the lymphocyte number subsequently normalized to Results: After reviewing 167 cases, only one case met our inclusion criteria, with an estimated incidence of 0.6%. Conclusion: Spontaneous remission of CLL is a rare phenomenon. This review suggests that the incidence of SRCLL is less then the previously often quoted incidence of 1% and may more appropriately approximate 0.6%. Disclosures: No relevant conflicts of interest to declare.

Abstract 3336 Introduction: Heparin Induced thrombocytopenia (HIT) is a clinicopathological entity in which thrombocytopenia occurs in temporal relation to the initiation of heparin therapy. The diagnosis is made using clinical criteria and a scoring system (4T) can be applied to assess the probability of the diagnosis. A variety of sensitive tests are available but the most widely applied is an enzyme immunoassay (EIA), which detects and semi-quantifies antibodies of any class to the heparin-PF4 complex. The role of testing is largely supplementary, but recently focus has been placed on the epidemic of HIT overdiagnosis due to overreliance on laboratory tests irrespective of the clinical scenario. A newer EIA can measure the pathogenic IgG antibody only. This study examines the number of patients started on direct thrombin inhibitor (DTI) therapy for a presumptive diagnosis of HIT prior to the implementation of the IgG antibody and after its introduction at one large academic tertiary care center. Methods: All patients placed on the DTIs argatroban and lepirudin between October 2006-May 2009 in the pre IgG subtype antibody period and May 2009-February 2012 in the post IgG subtype period for a presumptive diagnosis of HIT were identified. Demographic data including age, sex, and primary service were recorded. All HIT antibody (Ab) immunoglobulin class EIA and IgG specific EIA optical density were recorded, as available. 4T criteria and rates of thrombosis were assessed retrospectively. Incidence of WHO Grade III (requiring transfusion) or IV (life threatening) bleeding was documented. Chi Square, Mann Whitney U, and Fisher's exact tests were used as appropriate for statistical analysis. Results: 89 patients pre availability of the IgG EIA assay and 100 patients post availability of the IgG EIA assay met inclusion criteria and were evaluated. Groups were matched in terms of sex and 4T pretest probability distribution as well as rates of thrombosis. Patients post IgG EIA availability were older and had lower mean total HIT Ab optical densities. Post IgG EIA patients were treated with DTI therapy 5 days less, which was statistically significant. The incidence of Grade III and IV bleeding episodes, however, was statistically similar between groups. In the pre IgG EIA group, 7 bleeds (4 Grade III, 3 Grade IV) occurred in patients with low pretest probability for HIT based on 4T criteria. In the post IgG EIA group, 8 bleeds (5 Grade III, 3 Grade IV) occurred in patients with low pretest probability for HIT based on 4T criteria. Conclusion: Implementation of the IgG HIT EIA resulted in a decrease in the number of days on a DTI without an observed change in serious bleeding events, indicating that such bleeding occurs early after initiation of DTI therapy. Further, patients pre and post availability of the IgG EIA were started on DTI therapy despite a low pretest clinical risk for HIT. The use of a test with a shorter turn-around time to exclude HIT or more rigorous enforcement of clinical guidelines will be required to minimize misdiagnosis and avoid therapy related morbidity. Disclosures: No relevant conflicts of interest to declare.

Abstract 4383 Introduction: Black cohosh (known as both Actaea racemosa and Cimicifuga racemosa), a member of the buttercup family is a perrenial plant that is native of North America. It has been widely used to relieve premenstrual problems, menstrual cramps and to control hot flushes and other menopausal symptoms. The mechanism of action of the black cohosh is not fully understood. Here, we report the case of a patient with pancytopenia related to the use of the black cohosh. Case Report: A 58 year old female patient with past medical history of dyslipidemia, presented with bruising after several months of taking black cohosh. Her complete blood count revealed a white blood cell count of 3.1×109/L (normal 3.5–11 ×109/l), hemoglobin of 10.6 g/dl (normal 11–15 g/dl), hematocrit of 31 % (normal 32–45%), mean corpuscular volume of 109 fL (normal 80–98 fl), platelets count of 37 000/μL (normal 150000–400000/μL). Her medications included lipitor, black cohosh and vitamin D. Her physical exam was remarkable only for bruising. Serum protein electrophoresis did not show any evidence of a monoclonal spike and a coomb’s test was negative. She had normal immunoglobulins level, haptogloin, LDH, liver function tests, iron studies, vitamin B12 and folate. Her prothrombin and activated partial thromboplastin times were within reference range. Her peripheral smear showed macrocytic red blood cells and decreased platelets. Her bone marrow biopsy and aspirate showed a hypocellular bone marrow (cellularity of 25–30%), with a predominance of erythroid precursors that exhibit shift toward immaturity and mild to moderate megaloblastoid changes, moderately decreased myeloid precursors, slightly decreased megakaryocytes, and normal iron stores, there was no increase in the bone marrow blasts (0.6%). She also had a flow sent for paroxysmal nocturnal hemoglobinuria, which showed normal levels of expression of CD55 and CD59 of the neutrophils and the red cells. Upon presentation, the black cohosh was stopped. Following this, her white count, hemoglobin and platelets improved slowly (figures 1,2,3,) without any further interventions, but it took over 2 years for her counts to normalize. Conclusion: Black cohosh is an over the counter herbal medicine that has been widely used by women to control premenstrual symptoms, menstrual cramping and menopausal symptoms. Many side effects have been described in the past but its effect on the bone marrow has never been studied. In our patient, Black cohosh caused pancytopenia that was reversible; however the recovery was very slow. Disclosures: No relevant conflicts of interest to declare.

6537 Background: The incidence of AML increases with advancing age; the median age of presentation for AML is 69 years. At present, there are limited treatment options available for elderly patient...

Abstract 4126 Introduction: The immunohistochemical (IHC) profile as described by Hans and colleagues has emerged as a potential prognostic and predictive factor in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy. However, its role has not been completely elucidated. The main objective of this patient-level meta-analysis was to evaluate the IHC profile as a prognostic and predictive indicator in newly diagnosed DLBCL patients treated with R-CHOP. Secondary objectives were to identify potential novel prognostic factors in these patients. Methods: Patient-level clinical data was requested from 13 research groups that published studies on the role of the IHC profile in prognosis for DLBCL patients treated exclusively with R-CHOP. Six groups (46%) submitted their data, accounting for a total of 701 patients. The requested clinical data included age, sex, performance status, LDH levels, number of extranodal sites, clinical stage, expression of CD10, BCL-6 and MUM1, IHC profile, type of response, outcome and overall survival (OS). Logistical regression analyses were used to identify independent variables associated with overall and complete response rates. Univariate survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional-hazard regression test. P-values of Results: The median age was 63 years (range 16–90 years), 54% were men, 59% were 60 years or older, 24% had an ECOG ≥2, 55% had elevated LDH levels, 15% had ≥2 extranodal sites involved, 52% had stage III/IV and 48% had a non-germinal center (NGC) IHC profile. The overall response rate was 92% with complete responses seen in 78% and partial responses in 14%. The median follow-up was 34 months. In the logistical regression analysis, age ≥70, high LDH, ECOG ≥2, stage III/IV and a NGC profile were associated with improved overall response, and MUM1 expression, ECOG ≥2 and stage III/IV were associated with improved complete response. In the survival analysis, the estimated 5-year OS was 66% and the median OS was not reached. Age ≥60 years, elevated LDH levels and NGC IHC profile (Figure) were not associated with worse OS. In the multivariate analysis, age ≥70 years, male sex, ECOG ≥2 and clinical stage III/IV were independent prognostic factors for OS. A prognostic score was formulated using these 4 prognostic factors and then compared against the IPI and R-IPI scores. This novel score and the IPI score were the only independent factors for OS with HR 1.4 (95% CI 1.19–1.64) and 1.38 (95% CI 1.15–1.67) with p Conclusion: The IHC profile is not a prognostic indicator for OS, and it is predictive of overall response but not complete response in newly diagnosed patients with DLBCL treated with R-CHOP. Age ≥70, male sex, ECOG ≥2 and stage III/IV were independent prognostic factors for OS. A score consisting of these 4 factors showed a significant prognostic value in DLBCL patients treated with R-CHOP. Disclosures: No relevant conflicts of interest to declare.

Abstract 4223 Acquired amegakaryocytic thrombocytopenia is a rare disorder in which there is a marked decrease in bone marrow megakaryocytes leading to severe thrombocytopenia with preserved hematopoeisis in the remaining lineages. The clinical course is variable and no standardized treatment exists. Multiple cases in the literature report treatment using immunosuppressive agents including cyclosporine and antithymocyte globulin. In this case report, we describe the first successful use of rituximab in a patient with amegakaryocytic thrombocytopenia in the absence of any underlying autoimmune disorders. Our patient, an 86- year-old woman, presented with epistaxis, ecchymoses, and blood-tinged sputum. She had thrombocytopenia (platelets 6 × 109/L, MPV 8.3) with a normal hemoglobin and white blood cell count. Peripheral blood smear showed no obvious cause for thrombocytopenia. Bone marrow biopsy revealed focal lymphocytic infiltrates and severe megakaryocytic hypoplasia with nearly absent megakaryocytes. Cytogenetic and molecular analyses were normal, revealing no evidence of a clonal myelo- or lymphoproliferative disorder. The diagnosis of amegakaryocytic thrombocytopenia was made. She was started on prednisone 50mg per day. There was no significant improvement in her platelet count and she was then given IVIG without response. Repeat bone marrow biopsy showed persistent severe bone marrow hypoplasia with near absence of megakaryocytes. After 6 weeks of platelet transfusion dependence and steroids, she was tapered off her steroids and was given rituximab 375mg/m2 weekly for 4 doses. Three weeks after starting rituximab, her platelet counts began to recover and by day 37, her platelet counts normalized and remained within normal limits 12 months after treatment. This case demonstrates the possible utility of rituximab in treating patients with isolated acquired amegakaryocytic thrombocytopenia. Disclosures: No relevant conflicts of interest to declare.

Abstract 4468 Introduction The diagnosis of HIT can be challenging. Short of the serotonin release assay, which can be difficult to get in a timely manner, the 4T method developed by Lo et al., in conjunction with the HIT elisa assay (EIA), is the best established criteria for the rapid diagnosis of Heparin Induced Thrombocytopenia (HIT). We sought to determine how often the 4Ts were being applied at a large academic institution. In addition, we sought to understand the outcome of patients started on direct thrombin inhibitors (DTIs) who did not meet the 4T/EIA criteria for HIT. Methods A retrospective case series identified patients placed on DTI for HIT treatment from 10/2006 to 5/2008. The 4T pretest probability was then applied retrospectively. HIT EIA Ab testing, optical densities, duration of DTI treatment, and bleeding incidence were recorded. Liberal and modified conservative criteria from Lo et al.'s study were used to define patients with HIT. Overdiagnosis of HIT was then recorded based on the above criteria. Results 76 patients were included for analysis. The average age was 61.4 years. Based on the 4T pretest probability, 30 patients were classified as low risk, 37 intermediate risk, and 9 high risk for HIT. The average HIT OD for low, intermediate, and high pretest probability was 0.49, 1.17, and 2.05. 76% and 36% of patients treated with DTIs for HIT met the liberal and modified conservative HIT definitions, respectively. 18 patients (24%) did not meet liberal HIT criteria but remained on DTI treatment for 1 to 60 days. Cost of DTI overuse in this subset was $84,960. Cost of DTI use in patients who did not meet modified conservative criteria was $462,246. All 16 patients who developed bleeding complications fulfilled a liberal diagnosis of HIT while only 6 of these patients fulfilled the modified conservative definition of HIT. Conclusions 1) The 4T method for diagnosing HIT is not being applied to a large percentage of patients in a tertiary academic center. 2) There is an overdiagnosis of HIT regardless of definition criteria with 24% of patients treated for HIT not meeting the liberal definition while 64% of patients did not meet the modified conservative definition. This overdiagnosis has both a significant monetary and morbidity cost. Disclosures: No relevant conflicts of interest to declare.

Abstract 2665 Introduction: Little is known on the racial differences in characteristics and outcomes of patients with a diagnosis with diffuse large B-cell lymphoma (DLBCL) treated with rituximab-containing regimens. The aim of this retrospective study is to compare the clinicopathological characteristics, prognostic factors and outcomes of Asian and Western patients with a diagnosis of de novo DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients and Methods: Patient-level data was collected from 8 centers (USA, Italy, Sweden, Finland, Croatia, Japan, Korea and China). This study was approved by the Institutional Review Board at each of the participant centers. All patients were diagnosed with de novo DLBCL and treated with R-CHOP administered every 3 weeks. HIV-positive and primary brain DLBCL were excluded. The requested clinical data included age, sex, performance status, lactate dehydrogenase (LDH) levels, number of extranodal sites, clinical stage, expression of CD10, BCL6 and MUM1/IRF4, response to chemotherapy, outcome and overall survival (OS). Patients were divided in Asian and Western, according to the country of report. Comparison between groups was performed with Mann-Whitney and Chi square tests for continuous and categorical variables, respectively. Univariate survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional-hazard regression test. P-values of Results: A total of 712 patients, 455 Asian and 257 Western patients were included in this study. Western patients were more likely to present with elevated LDH levels (70% vs. 48%; p1, elevated LDH levels and advanced clinical stage were significantly associated with a worse median OS in Westerners (p1, >1 extranodal sites and advanced clinical stage were significant adverse factors for Asians (p1 and advanced clinical stage were independent prognostic factors associated with a worse median OS in Westerners and Asians (p Conclusions: Asian and Western patients with de novo DLBCL present with distinct clinical and pathological characteristics, and although the CR rate to standard R-CHOP was higher in Westerners than in Asians, the final outcome, prognostic factors and median and 5-year OS rates are similar in both populations. Disclosures: Castillo: GlaxoSmithKline: Research Funding; Millennium Pharmaceuticals: Research Funding.

The etiology of venous thromboembolism in young patients is frequently associated with hereditary coagulation abnormalities, immunologic diseases, and neoplasia. The advent of radiological advances, namely Computed Tomography (CT) scans and venography has identified vena cava malformations as a new etiologic factor worthy of consideration. In this case report, we describe the unusual occurrence of venous thromboembolism in association with a duplicated inferior vena cava. Duplications of the inferior vena cava (IVC) are seen with an incidence of 0.2% to 3.0% in the general population. Embryogenesis of the IVC is a complex process involving the intricate formation and regression of numerous anastomoses, potentially leading to various anomalies. We present a 23-year-old Caucasian woman with IVC duplication who developed a deep venous thrombosis and multiple pulmonary emboli. Anomaly of the IVC is a rare example of a congenital condition that predisposes to thromboembolism, presumably by favoring venous stasis. This diagnosis should be considered in patients under the age of 30 with spontaneous occurrence of blood clots.