Outcomes of bendamustine- or cyclophosphamide-based first-line chemotherapy in older patients with indolent B-cell lymphoma.

Clinical trials comparing bendamustine/rituximab (BR) with cyclophosphamide-based regimens (RCHOP/RCVP) have pooled various histologies of indolent B-cell lymphomas. We examined real-life outcomes of older patients with follicular (FL), mantle cell (MCL), or marginal zone/lymphoplasmacytic lymphoma (MZL/LPL), treated with these first-line regimens. We identified Medicare beneficiaries with FL, MCL, or MZL/LPL, who received either first-line BR or RCHOP/RCVP in 2009-2016, and matched groups using a propensity score. Outcomes of claims-based event-free survival (EFS), overall survival (OS), toxicity, secondary cancers, and costs were compared in the aggregate cohort (N = 2736), and in separately matched histology-specific subcohorts. In the aggregate cohort, EFS was better with BR than with RCHOP/RCVP (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87). Acute toxicity was lower with BR, including rates of hospitalizations (33% vs 45%), infections (21% vs 30%), cardiovascular events, and transfusions, yet OS did not differ (HR, 1.03; 95% CI, 0.91-1.17) and Medicare spending was higher. There was no difference in the cumulative incidence of secondary cancers (subhazard ratio, 1.11; 95% CI, 0.83-1.48). The EFS advantage of BR was pronounced in MCL (N = 690; HR, 0.64; 95% CI, 0.54-0.76), but less so in FL (N = 1330; HR, 0.83; 95% CI, 0.69-0.98) and absent in MZL/LPL (N = 574; HR, 0.92; 95% CI, 0.73-1.17). Despite improved EFS and lower toxicity, the shift from RCHOP/RCVP to BR in clinical practice did not improve OS for older patients with indolent B-cell lymphomas. Frequent infections and hospitalizations underscore the need for safer treatment approaches in this population. Secondary cancers do not appear to be increased after BR compared with RCHOP/RCVP.

Cellular immunotherapy for refractory hematological malignancies.

BACKGROUND: Acute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance. METHODS/DESIGN: The trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy. DISCUSSION: Cellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome. TRIAL REGISTRATION: NCT01685606.

Epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly: what we know so far.

Epstein-Barr virus-positive (EBV-positive) diffuse large B-cell lymphoma (DLBCL) of the elderly is a newly described lymphoproliferative disorder recently included as a "provisional" entity in the most current WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. The objective of this review is to provide a thorough and current summary of the existing knowledge of this subtype of DLBCL. We will review and discuss the incidence of EBV expression in DLBCL, the pathogenesis behind EBV-driven malignant transformation of B cells, the different EBV latency patterns associated with DLBCL, the distinct pathologic characteristics of EBV-positive DLBCL, the potential predictive and prognostic value of EBV tumoral status in patients with DLBCL, and potential strategies for the treatment of this rare entity, which is characterized by a suboptimal response to therapy and poor survival rate.

EBV-positive diffuse large B-cell lymphoma of the elderly: a case series from Peru.

EBV-positive diffuse large B-cell lymphoma (DLBCL) of the elderly is an entity recently included in the WHO classification of lymphoid tumors. We have reviewed our experience and clinical outcomes of this distinct subtype of DLBCL. Between 2002 and 2009, cases of DLBCL were identified from medical records of the Hospital Nacional Edgardo Rebagliati Martins in Lima, Peru, and underwent pathological evaluation including immunohistochemistry for CD20, CD10, bcl-6, MUM1/IRF4, and EBV-encoded RNA in situ hybridization. Clinical data were gathered, tabulated, and reported descriptively. Survival analyses were performed using Kaplan-Meier estimates. Out of 199 cases of DLBCL, 28 cases of EBV-positive DLBCL of the elderly were identified. The median age was 75 years with male predominance (1.5:1). B-symptoms were present in 43%, advanced stage in 50% and International Prognostic Index (IPI) score > 2 in 57% of patients; 68% of patients had a nongerminal center (NGC) phenotype. The complete response rates to R-CHOP and CHOP were 63% and 33%, respectively. The median overall survival (OS) for the group was 5 months. In the univariate analysis, age ≥70 years, lymphocyte count <1.0 × 10(9) /L, and advanced clinical stage were associated with worse OS in patients treated with chemotherapy with and without rituximab. EBV-positive DLBCL of the elderly is a clinically aggressive entity with a short OS and typically presents with advanced stage, high IPI score, and a NGC phenotype. Further studies are needed to investigate if rituximab-containing regimens are associated with better response and OS rates in EBV-positive DLBCL of the elderly.

Prognostic factors in chemotherapy-treated patients with HIV-associated Plasmablastic lymphoma.

BACKGROUND: Plasmablastic lymphoma (PBL) is a variant of diffuse large B-cell lymphoma commonly seen in the oral cavity of HIV-infected individuals. PBL has a poor prognosis, but prognostic factors in patients who have received chemotherapy have not been adequately evaluated. METHODS: An extensive literature search rendered 248 cases of PBL, from which 157 were HIV(+). Seventy cases with HIV-associated PBL that received chemotherapy were identified. Whenever possible, authors of the original reports were contacted to complete clinicopathological data. Univariate analyses were performed calculating Kaplan-Meier estimates and compared using the log-rank test. RESULTS: The mean age was 39 years, with a male predominance. The mean CD4(+) count was 165 cells/mm(3). Advanced clinical stage was seen in 51% and extraoral involvement was seen in 43% of the cases. The expression levels of CD20 and Epstein-Barr virus-encoded RNA were 13% and 86%, respectively. The overall survival duration was 14 months. In a univariate analysis, early clinical stage and a complete response to chemotherapy were associated with longer survival. There was no apparent difference in survival with regimens more intensive than cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). CONCLUSIONS: Patients with HIV-associated PBL have a poor prognosis. Prognosis is strongly associated with achieving a complete clinical response to CHOP or CHOP-like chemotherapy. The role of more intensive regimens is currently unclear. Further research is needed to improve responses using novel therapeutic agents and strategies.

Perioperative management of chronic anticoagulation in orthopaedic surgery.

The orthopaedic patient on chronic anticoagulation therapy is at risk of thromboembolism and hemorrhage in the perioperative period. To establish the most effective anticoagulation regimen, patients should be stratified according to the risk of arterial or venous thromboembolism. Timing of surgery, thromboembolic risk, and bleeding risk should be considered when developing an anticoagulation protocol. Retrievable inferior vena cava filters may be a viable alternative to bridging therapy in patients at high risk of venous thromboembolism and/or bleeding.

Marrow Hypocellularity, But Not Residual Blast Count or Receipt of Reinduction Chemotherapy, Is Prognostic on Day-14 Assessment in Acute Myeloid Leukemia Patients With Morphologic Residual Disease.

BACKGROUND: Induction chemotherapy for acute myeloid leukemia (AML) is based on the "7+3" cytarabine/anthracycline regimen. A nonhypocellular day 14 (D14) bone marrow sample with a blast count > 5% to 10% is suggestive of residual leukemia, for which a second course of induction chemotherapy has been recommended. Although the prognostic value of D14 bone marrow findings has been established, its use as a decision point is controversial because the benefit of repeat induction has been questioned. PATIENTS AND METHODS: In the present single-center retrospective study of 113 patients with newly diagnosed AML, we evaluated the role of cellularity on the clinical outcomes of patients with residual morphologic leukemia (blasts ≥ 5%). Among 64 patients with D14 bone marrow samples, 31 had residual morphologic leukemia. RESULTS: The complete remission (CR) rates were greater for the hypocellular (11 of 16) than for the nonhypocellular (4 of 15) patients (P = .03). The median overall survival (OS) for the hypocellular D14 patients was longer than that for the nonhypocellular patients (17 vs. 8 months; P = .02). No significant difference between the receipt of reinduction therapy and CR or OS was found on logistic or survival model analysis. The specificity for residual leukemia on D14 bone marrow samples was better for cellularity ≥ 20% and blasts ≥ 20% than for blasts ≥ 5%. CONCLUSION: The results of our study have shown that patients with < 20% cellularity and < 20% blasts on the D14 bone marrow assessment should continue observation until recovery rather than receive additional immediate therapy.

Heterozygous Hemoglobin Sherwood Forest Causing Polycythemia.

Hemoglobin (Hb) Sherwood Forest is a rare high-affinity hemoglobin first described in 1977, arising from an Arg to Thr substitution at codon 104 of the beta chain. This hemoglobin variant has been identified in few individuals and has been associated with a compensatory erythrocytosis in the homozygous state. Prior scarce case reports have noted that heterozygotes for this variant are phenotypically normal. Here we present a patient who was evaluated in our hematology clinic for chronic erythrocytosis and was found to be heterozygous for Hb Sherwood Forest. No other primary or secondary cause of his polycythemia was identified. This is the first described case of heterozygous Hemoglobin Sherwood Forest causing erythrocytosis.

Low microchimeric cell density in tumors suggests alternative antineoplastic mechanism.

Microchimerism has generally been shown to protect against cancer (Gilmore et al. in Exp Hematol 36(9):1073-1077, 2008). The mechanism of how this occurs is an area of intense study, as it may lead to new cancer treatments. The leading theory is that microchimeric cells perform immune surveillance by directly fighting cancerous cells and that they also act as stem cells, repairing damaged tissue (Khosrotehrani et al. in JAMA 292:75-80, 2004). However, there is conflicting evidence to support this theory. Several small studies have found few microchimeric cells in tumor tissue (Gadi in Breast Cancer Res Treat 121(1):241-244, 2010; Cirello et al. in Int J Cancer 126:2874-2878, 2010), while another study contradicted these findings by showing microchimeric cells clustered around tumor tissue (O'Donoghue et al. in Reprod Biomed Online 16:382-390, 2008). To date, we have designed the largest and broadest study to investigate this question of whether microchimeric cells really do cluster at tumor tissue. We analyzed 245 samples from a broad range of cancer types. Using PCR for the male chromosome marker TSPY1, we identified only 12 out of 245 samples with microchimerism for a rate of 4.9% (95% confidence interval 2.2-7.6%). Five of these samples were confirmed using Y fluorescence in situ hybridization. This rate of 4.9% microchimerism is the lowest reported in any study. The low percentage of microchimerism observed in our broad study suggests that microchimeric cells do not invade tumors to fight off neoplasm.

Dicentric (17;20)(p11.2;q11.2): an uncommon cytogenetic abnormality in myeloid malignancies.

We report on two patients with myeloid disorders and complex karyotypes including a dicentric chromosome, dic(17;20)(p11.2;q11.2), resulting in the loss of most of 17p and 20q. The presence of the centromeres of chromosomes 17 and 20 in the dic(17;20), as well as the loss of TP53, were confirmed by fluorescence in situ hybridization. Deletions of 17p and 20q are recurrent abnormalities in hematologic disorders, particularly myelodysplastic syndrome and acute myeloid leukemia). However, a dic(17;20) is an uncommon finding. According to the few reports in the literature, dic(17;20) is associated with an unfavorable prognosis. The key mechanism might be the loss of TP53 as well as other tumor suppressor genes in 20q that may have a critical role in tumor genesis.

TAFRO Syndrome Associated with EBV and Successful Triple Therapy Treatment: Case Report and Review of the Literature.

TAFRO syndrome is a rare constellation of symptoms: thrombocytopenia, anasarca, reticulin fibrosis of the bone marrow, renal dysfunction, and organomegaly. Its pathogenesis involves an excessive and inappropriate cytokine storm, most notably from IL-6, causing multiorgan failure; however, its etiology is undetermined. Starting in 2012, TAFRO syndrome was first identified in Japan as an atypical variant of Castleman's disease. Previous reports include various different treatment protocols with inconsistent survival outcomes. Here we report the first known American, EBV positive but HIV and HHV-8 negative, male with TAFRO syndrome. He was successfully treated with an unusual three-drug regimen including tocilizumab, etoposide, and rituximab. We review the literature of TAFRO syndrome, discuss its possible viral etiology, and propose an original treatment regimen.

Cryoglobulinemic membranoproliferative glomerulonephritis associated with mucosa-associated lymphoid tissue lymphoma treated with rituximab.

Cryoglobulinemia and mucosa-associated lymphoid tissue (MALT) lymphoma are diseases characterized by B-cell dysregulation and overproduction of antibodies. Vasculitis and cutaneous manifestations are common, but renal involvement is rare. A 65-year-old woman with type 1 cryoglobulinemia and MALT lymphomas of the right lacrimal and parotid glands successfully treated by excision and chemoradiotherapy, presented with dyspnea on exertion, edema, and hematuria. Renal biopsy findings revealed type 1 cryoglobulinemic glomerulonephritis. She underwent treatment with high-dose oral prednisone and intravenous rituximab with subsequent return of creatinine to baseline levels. To our knowledge, this is the first report of a patient in whom type 1 cryoglobulinemia, multiple MALT lymphomas, and MPGN with IgM cryoglobulin deposits coexist. Evidence for rituximab is sparse with widely varying protocols and mixed results. There is a need for high quality evidence in the treatment of these conditions.

Attending Physician Attitudes Toward Choice of Oral Anticoagulant for the Treatment of Venous Thromboembolism.

Until recently, warfarin has been the primary treatment of venous thromboembolism (VTE). Limited data are available regarding physician attitudes toward anticoagulant choice in the setting of novel oral anticoagulant (NOAC) availability. This study sought to evaluate attending physician attitudes toward NOACs. A survey was sent to attending physicians from internal medicine (primary care and hospitalist medicine), family medicine, cardiology, and hematology-oncology asking about their preference and reasoning for choice of oral anticoagulant for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). Warfarin was the most common choice of initial treatment of both DVT (85.6%) and PE (89%). Among the specialties surveyed, cardiologists were more likely to use rivaroxaban as initial treatment of VTE as compared to other specialties including internal medicine or hematology (p=0.011 for DVT and 0.004 for PE). Cost-effectiveness and lack of a reversal agent were cited as the major disadvantages for NOAC use.

Differences in the clinical course of heparin induced thrombocytopenia before and after the availability of HIT IgG class testing.

INTRODUCTION: To determine whether the HIT IgG class platelet factor 4 (PF4) enzyme immunoabsorbant assay (EIA) influenced the duration of parenteral direct thrombin inhibitor (pDTI) therapy or bleeding risk in patients started on pDTI for a presumed diagnosis of HIT. MATERIALS/METHODS: 187 patients started on pDTI for presumed HIT were assessed in two time periods before (period 1, n=88 patients) and after the introduction of an IgG-specific assay (period 2, n=99 patients). RESULTS: Patients in period 2 were treated with pDTI therapy for a median of 5 days less (p<0.0001) however the incidence of Grade III and IV bleeding episodes was not different. Bleeding was observed to occur early during the hospital course at a median of 2-3 days after initiation of the pDTI. The average pDTI drug acquisition cost was markedly decreased in period 2 when compared to period 1 (p<0.0001). CONCLUSIONS: Implementation of the IgG class HIT EIA resulted in a decrease in the number of days on a pDTI and a decrease in the average pDTI acquisition cost per patient without an observed change in serious bleeding events.