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Therapy of acute, high-dose whole-body exposures of humans to ionizing radiations is a complex medical challenge. Since 1944 more than 400 radiologic accidents have been registered with more than 3000 substantial radiation exposures and 127 fatalities. There are several potential interventions including supportive care, transfusions, preventative or therapeutic anti-infection drugs, molecularly-cloned myeloid growth factors and hematopoietic cell transplants. We discuss the use of the granulocyte and granulocyte-macrophage colony-stimulating factor (G-CSF and GM-CSF) to treat acute high-dose ionizing radiation exposures. Considerable data in experimental models including monkeys indicate use of these drugs accelerates bone marrow recovery and in some but not all instances increases survival. In ten accidents since 1996, 30 victims received G-CSF alone or with other growth factors. Twenty-six victims survived. In seven accidents since 1986, 28 victims received GM-CSF alone or with other growth factors; 18 victims survived. However, absent control or data from randomized trials, it is not possible to know with certainty what role, if any, receiving G-CSF or GM-CSF was of benefit. Given the favorable benefit-to-risk ratio of molecularly-cloned myeloid growth factors, their use soon after exposure to acute, high-dose whole-body ionizing radiations is reasonable.

Bone marrow damage is an important consequence of exposure to acute high-dose whole-body radiation. As such, haematologists can play an important role in managing this complication. However, these accident and incident scenarios are complex and often involve injuries to other organs and tissues from heat, projectiles and chemicals. In the case of a large-scale event there will likely be severe infrastructure disruptions and injury or death to medical personnel. Accurate estimates of dose and uniformity of exposure are needed to intelligently direct appropriate interventions, which range from antibiotics, antifungals and anti-virus drugs, molecularly-cloned haematopoietic growth factors and, in rare instances, haematopoietic cell transplants. These therapies are ones that haematologists often use in the context of anti-cancer therapy, especially therapy of haematological cancers like leukaemia. However, most haematologists have little knowledge of radiation biology and should consider updating this aspect of their expertise in continuing medical education. As in other areas of medicine, prevention is better than cure and haematologists should be active in decreasing risks of a nuclear war.

Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.

The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.

SummaryDiffuse large B-cell lymphoma (DLBCL) occasionally presents with circulat-ing malignant cells. The clinical characteristics and long-term outcomes ofthese patients have not been described. Twenty-nine newly diagnosedDLBCL presenting in leukaemic phase were identified between 1996 and2010, at two institutions. Median age was 48 years, and patients presentedwith leucocytosis, high lactate dehydrogenase levels, B symptoms, and highInternational Prognostic Index score. Extra nodal site involvement wasobserved in all patients and affected the bone marrow (100%), spleen(62%), pleura/lung (41%), liver (21%), bone (17%), bowels (7%) and cere-brospinal fluid (14%). Blood lymphomatous cells co-expressed CD19,CD20, CD22, CD38, CD45, HLA-DR and FMC7 in >90%, and kappa orlambda light chain restriction in >50%. Ninety per cent received rituximaband anthracycline-based chemotherapy. Overall, remission was complete in54% and partial in 31%; 15% had resistant disease. Median follow-up was47 months; 13 (45%) patients remain alive in complete remission. Medianprogression-free and overall survivals were 11·5 and 46·7 months, respec-tively. In summary, patients with DLBCL in leukaemic phase present withhigh tumour burden and frequent involvement of extra nodal sites. In thisuncommon DLBCL subgroup, anthracycline-based regimens with rituximabare associated with early morbidity and mortality, but yield approximately50% 4-year survival.Keywords: diffuse large B-cell lymphoma, leukaemic phase, outcomes,characteristics, treatment.

My favored treatment approach for patients with diffuse large B-cell lymphoma continues to evolve. Diffuse large B-cell lymphoma can now be cured in more than 50% of patients. This is a result of improved definitions of the disease, improved diagnostic capabilities, better staging and restaging techniques, a useful prognostic index to guide therapeutic decisions, and the development of increasingly effective therapies. Positron emission tomographic scans have improved the accuracy of both staging and restaging. Findings on a positron emission tomographic scan at the end of therapy are the best predictors of a good treatment outcome. Numerous subtypes of diffuse large B-cell lymphoma have been identified that require specific treatment approaches. For example, plasmablastic lymphoma typically lacks CD20 and does not benefit from treatment with rituximab. Diffuse large B-cell lymphoma originating in specific extranodal sites such as the central nervous system, testes, and skin presents special problems and requires specific treatment approaches. A subgroup of diffuse large B-cell lymphoma with a very high proliferative rate seems to have a poor outcome when treated with CHOP-R and does better with regimens used for patients with Burkitt lymphoma. New insights into the biology of these disorders are likely to further change treatment approaches. Recognition that diffuse large B-cell lymphoma is not one disease, but a variety of clinicopathologic syndromes provides the opportunity to further improve our ability to benefit patients.

Diffuse large B-cell lymphoma (DLBCL) includes two prognostically important subtypes, the germinal center B-cell (GCB) and the non-GCB types. The aim of this study was to evaluate immunohistochemical approaches for predicting the survival of patients with DLBCL following autologous hematopoietic stem cell transplantation (AHSCT). We identified 62 patients with DLBCL who either had an initial complete remission (17 patients) or received salvage chemotherapy for relapsed or refractory disease (45 patients), followed by AHSCT. Tissue microarrays were immunostained with monoclonal antibodies against GCET1, CD10, BCL6, MUM1, FOXP1 and LMO2. Using the Hans algorithm, we classified 50% of the cases as GCB type, whereas the Choi algorithm classified 58% as GCB type and LMO2 was positive in 69%. However, no significant differences were found in the 5-year overall or event-free survivals using any of these approaches. In conclusion, cell of origin fails to predict survival of DLBCL patients treated with AHSCT.

This article summarizes the issues involved in the treatment of patients with early-stage Hodgkin's lymphoma. Long-term follow-up reveals an increasing burden of complications in patients who received combined methods of treatment.

The disease we now call diffuse large B-cell lymphoma has gone by many names in the past. These have included reticulum cell sarcoma,[1][1] diffuse histiocytic lymphoma,[2][2] and, more recently, diffuse mixed lymphoma, diffuse large cell lymphoma, or immunoblastic lymphoma—terms from the Working

The proceedings of a workshop focusing on a project to evaluate the use of fluorodeoxyglucose-positron emission tomography (FDG-PET) as a tool to measure treatment response in non-Hodgkin lymphoma (NHL) are described. Sponsored by the Leukemia & Lymphoma Society, the Foundation of the National Institutes of Health, and the National Cancer Institute, and attended by representatives of the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and scientists and clinical researchers from academia and the pharmaceutical and medical imaging industries, the workshop reviewed the etiology and current standards of care for NHL and proposed the development of a clinical trial to validate FDG-PET imaging techniques as a predictive biomarker for cancer therapy response. As organized under the auspices of the Oncology Biomarker Qualification Initiative, the three federal health agencies and their private sector and nonprofit/advocacy group partners believe that FDG-PET not only demonstrates the potential to be used for the diagnosis and staging of many cancers but in particular can provide an early indication of therapeutic response that is well correlated with clinical outcomes for chemotherapy for this common form of lymphoma. The development of standardized criteria for FDG-PET imaging and establishment of procedures for transmission, storage, quality assurance, and analysis of PET images afforded by this demonstration project could streamline clinical trials of new treatments for more intractable forms of lymphoma and other cancers and, hence, accelerate new drug approvals.

Approximately 7350 new cases of Hodgkin lymphoma (HL) are diagnosed annually in the United States. The Incidence of HL has a bimodal pattern, with the highest incidence seen in young adults and in elderly patients. The disease is composed of 2 distinct entities: the more commonly diagnosed classical HL and the rare nodular lymphocyte-predominant HL. Classical HL includes the subgroups nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte rich. Selection of the appropriate therapy Is based on accurately assessing the stage of disease. Patients with early-stage disease are treated with combined modality strategies using abbreviated courses of combination chemotherapy followed by Involved-field radiation therapy, whereas those with advanced-stage disease receive a longer course of chemotherapy without radiation therapy. Currently, more than 80% of all patients with newly diagnosed HL are expected to be long-term survivors. Although many patients respond well to initial therapies and have durable long-term remissions, a subset of patients has resistant disease and experiences relapse even after subsequent high-dose chemotherapy and autologous stem cell transplantation. New therapies are clearly needed for these patients.

Non-Hodgkin lymphomas are a heterogeneous group of malignancies of the lymphoid system. Based on the World Health Organization classification of hematological and lymphoid tumors, these diseases have been classified as B-cell and T-cell neoplasms. B-cell lymphomas account for approximately 90% of all lymphomas, and the 2 most common histological disease entities are follicular lymphoma and diffuse large B-cell lymphoma. Approximately 55,000 to 60,000 new cases of non-Hodgkin lymphoma are diagnosed annually in the United States, a number that has nearly doubled during the past 3 decades. The Ann Arbor Staging Classification is used routinely to classify the extent of disease, and the International Prognostic Index has been used to define prognostic subgroups. Also, recent data have identified molecular and genetic markers of prognosis that may be used in the future to further refine treatment decisions. Treatment of these diseases is based on the histology and extent of disease. Patients with follicular lymphomas with early-stage disease generally are treated with radiation therapy, whereas those with stage III and IV disease requiring treatment usually are treated with chemotherapy, Immunotherapy, or radioimmunotherapy. These patients generally experience long survival, but only a minority are cured. For patients with diffuse large B-cell lymphoma, treatment of limited-stage disease generally includes doxorubicin-based chemotherapy combined with rituximab followed by involved field radiation therapy. Those with extensive disease are treated with rituximab combined with chemotherapy alone. Disease relapse is a problem, and high-dose therapy with stem cell support is the treatment of choice for chemosensitive relapsed aggressive lymphomas. Patients with chemoresistant disease or whose disease relapses subsequently should be treated with novel experimental therapies.

The management of primary mediastinal large B-cell lymphoma (PMBCL) requires a balance between optimizing chances of cure and reducing risk of long-term toxicities. The combination of rituximab to cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP) followed by mediastinal radiation results in a plateau in progression-free survival after first few years of follow-up. In rituximab era, a negative positron emission tomography (PET) scan performed after the completion of immunochemotherapy has a high predictive value for durable remission. Consequently, end-of-therapy PET may be utilizable to avoid radiation without compromising survival. Additionally, intensified chemotherapy alone has shown excellent survival. PMBCL is frequently associated with amplification of programmed death ligand (PDL) 1/2 and constitutive activation of JAK–STAT and NFKB pathways; these may serve as promising therapeutic targets. Clinical trials that integrate novel therapies into upfront immunochemotherapy and utilize end-of-therapy PET scan to guide mediastinal radiation have potential to further enhance survival and prevent long-term toxicities.

Preliminary results of new therapies in the areas of cytotoxic agents and immunotherapy for advanced indolent lymphomas have been encouraging. Long-term follow-up on high-dose therapy suggests a potential role for this modality in this group of lymphomas. In aggressive lymphomas, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) continues to hold ground as first-line therapy when compared against other regimens. Several studies reinforce past findings that patients with chemosensitive relapse are better candidates for high-dose therapy. In relapsed or refractory disease, selected compounds appear to have activity as single agents and others have shown activity in combination therapy. Despite high treatment-related mortality rates, allogeneic transplantation in relapsed aggressive lymphoma warrants further investigation. Last, as patients are surviving longer, complications of therapy are having to be addressed.

The incidence of non-Hodgkin's lymphomas continues to rise and the number of deaths attributable to these malignancies currently rank in the top five causes of cancer-related deaths in the United States. Recent insights into the pathogenesis and molecular characterization of these disorders have led to improvements in a clinicopathologically relevant classification system, as well as in the ability to accurately diagnose specific entities. Several new treatment modalities have been developed which may improve the outcome for selected patients. A better understanding of the biology of non-Hodgkin's lymphomas will hopefully translate into different therapies with improved outcomes. This article describes a new system for classifying the non-Hodgkin's lymphomas, highlights key aspects of the pathogenesis of non-Hodgkin's lymphomas and briefly reviews clinical and therapeutic approaches to the most common of these lymphomas.

The purpose of this to evaluate in a phase I/II study the efficacy and toxicity of a multi-dose administration of 131I labeled CD22 monoclonal antibody (131I-MAb-LL2) in escalating dose cohorts administered to relapsed non-Hodgkin's lymphoma (NHL) patients. Twenty-one patients with relapsed NHL received one of four dose levels of 131-MAb-LL2 administered in a twice weekly pattern. Starting with dose level 2, the patients also received 20 mg of unlabeled LL2 prior to each radiolabeled dose administered. Previously stored autologous peripheral blood progenitors were reinfused in case of prolonged cytopenias. Patients could repeat the same treatment if they had stable disease or a response to the first therapy at 8 weeks, and had not received their peripheral blood progenitors with the first cycle. Combining all of the dose cohorts, there were 5 complete responses or complete responses (undetermined) and 2 partial responses for a total response rate of 7/21 (33%). There was no dose response effect with responses documented at all dose levels. Expected toxicities were hematopoietic, requiring stem cell re-infusion in 5 patients. Other toxicities included hypothyroidism in 3 patients, and human anti-mouse antibody formation (HAMA) in 4 patients. In conclusion, 131I-MAb-LL2, when administered in a multi-dose fashion with 20 mg unlabeled antibody pre-dosing, resulted in a response rate of 33% in heavily pre-treated NHL patients. Non-hematologic toxicities were mild and few in number. Further evaluation of this treatment is warranted and further dose escalation will be possible.

Hodgkin's lymphoma (HL) is a clonal lymphoid malignancy that affects over 7000 patients in the United States annually. The disease remains one of the great success stories in the recent history of cancer treatment. More than 80% of HL patients will be expected to be long-term survivors because of recent advances in radiation therapy and combined chemotherapy. However, for the subset of patients who relapse after initial therapy, HL remains a challenging disease. Indeed, for patients who relapse after salvage high-dose chemotherapy and autologous stem cell transplant, effective therapeutic options remain limited, and further new therapies are warranted. This article provides a review of the current literature regarding salvage therapy for HL.

At the present time, the majority of patients who develop Hodgkin's disease can be cured with radiotherapy and/or chemotherapy. A long follow up of cured patients has shown that the cumulative toxicity from treatment related complication rivals the mortality from Hodgkin's disease. In addition to late fatal complications, delayed adverse effects of therapy on the thyroid, reproductive system, and bones are burdens many patients have to bear. Future treatment regimens for Hodgkin's disease will be designed attempting to minimize these complications. Follow up of those patients now in remission should focus on the prevention of morbidity and mortality by anticipating and preventing late complications.

Febrile neutropenia, a common side effect of myelosuppressive chemotherapy in patients with cancer, can result in prolonged hospitalization and broad-spectrum antibiotic use, often prompting treatment delays or dose reductions of drug regimens. Prophylactic use of myeloid growth factors (mainly the colony-stimulating factors filgrastim and pegfilgrastim) in patients of heightened risk can reduce the severity and duration of febrile neutropenia. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Myeloid Growth Factors provide recommendations on the use of these agents mainly in the oncology setting based on clinical evidence and expert consensus. This version includes revisions surrounding the issue of timing of pegfilgrastim administration. It also includes new sections on tbo-filgrastim, a recently approved agent that is biologically similar to filgrastim, and the role of myeloid growth factors in the hematopoietic cell transplant setting.

Tissue samples from 93 de novo diffuse large B-cell lymphoma patients seen between 1995 and 2009 randomly receiving either standard combination chemotherapy (CHOP, n=48) or the identical program with rituximab (n=45) were subtyped using an investigational immunohistochemical (IHC) based tissue microarray (TMA) and contrasted to the approximately corresponding categories as defined either by Hans and associates using a three marker panel into germinal or non-germinal centre subtypes or by Choi and colleagues with two additional antibodies into germinal centre (GCB) or activated B-cells (ABC). Each of these primary subdivisions was further evaluated for expression of BCL2 and LMO2 both of which are recognised to predicate response. The addition of rituximab to the uniform drug regimen did not show any significant improvement in 5 years overall (63% versus 59%, p 0.68) or event-free survival (42% versus 39%, p 0.94), for CHOP versus R-CHOP comparisons. Similarly no differences were evident in subtype analysis. Interestingly however, when segregated on the Choi criteria, cytotoxic drugs alone showed a non-significant trend in improved survival (74% versus 55%, p 0.32) as well as event-free survival (44% versus 40%, p 0.42) for the germinal centre as opposed to the activated B-cell subtype. Nevertheless not even a small difference could be demonstrated in the presence of the anti CD 20 monoclonal antibody. According to Choi, both regimens (chemotherapy or immunotherapy antibody) revealed similar results to the Hans algorithm on 5 years OS as well as 3 year EFS when comparing GCB versus ABC or non-GCB subgroups. BCL2 and LMO2 marker expression of the respective immunohistochemical (IHC) subtype, despite small sample size, revealed the following. Analysis by Choi criteria on survival for BCL2, no matter for which subsets (GCB or ABC) or treatment modality (chemotherapy with or without the addition of rituximab) showed no difference in 5 years OS or EFS. In contrast, a significant difference for better EFS (p=0.0015) in the BCL2 positive group of the ABC subgroups subtypes treated with rituximab containing chemotherapy. For LMO2 similar results on survival outcome were seen thus showing no difference in 5 years OS or EFS - regardless of subtype or treatment modality. Also here, this was contrasted by better EFS (p=0.039) in the LMO2 positive group of ABC subtypes when treated with the rituximab containing regimen. The use of the IHC based TMA methodology has shown to be a simple, cost effective and a robust alternative to gene expression profiling (GEP) which is currently regarded as the gold standard for the classification in lymphomas. It provides a useful prognostic tool in stratifying DLBCL or other entities in future, even when frozen tissue samples are not available for GEP analysis. With the current budgetary limitations in South African public hospitals chemotherapy protocols for lymphoproliferative disorders exclude agents such as rituximab. Local therapeutic drug committees consider the approximately 15% overall survival benefit seen at 5 years for DLBCL when rituximab is added to combination chemotherapy as too marginal for justifying the arising additional expenses. Accordingly, demonstration that a specific molecular subtype accounts for superior outcome, when using these regimens, is needed. Such an option would provide convincing evidence for the use of immunochemotherapy in a resource constrained setting.

Background T-cell lymphomas make up approximately 10–15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. Diagnosis The diagnosis of aggressive peripheral T-cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than for aggressive B-cell lymphomas, with a range of 72–97% for the aggressive PTCLs. Risk Stratification Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, PET scans appear to be useful as they are in aggressive B-cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large cell lymphoma—particularly young patients with the anaplastic lymphoma kinase positive subtype. Risk Adapted Therapy Anaplastic large cell lymphoma is the only subgroup to have a good response to a CHOP-like regimen. Angioimmunoblastic T-cell lymphoma has a prolonged disease-free survival in only ∼20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL-NOS (not otherwise specified) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T-cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy. Am. J. Hematol. 88:911–918, 2013. © 2013 Wiley Periodicals, Inc.

Background: Serum lactate dehydrogenase is a non-specific marker for lymphoma whose prognostic significance is well established for both indolent and aggressive lymphomas at the time of diagnosis. The performance characteristics of this enzyme in predicting relapse in patients with diffuse large B-cell lymphoma has not been well studied. Methods: This study compared serum lactate dehydrogenase levels in 27 patients with diffuse large B-cell lymphoma who relapsed after sustaining a complete response versus 87 patients who did not relapse. For relapsed patients, the serum lactate dehydrogenase level at relapse was compared with the level three months before (considered baseline). For non-relapsed patients, the last two levels during follow-up were compared. For statistical analysis the T-test was used to compare differences in mean values between groups. The sensitivity, specificity, positive and negative predictive values for serum lactate dehydrogenase in detecting relapse compared to confirmatory imaging were calculated. Results: At relapse, only 33% patients had increases in serum lactate dehydrogenase above the upper limit of normal. The mean increase was 1.2-fold above the upper limit of normal for relapsed vs. 0.83 for those who did not relapse (p-value = 0.59). The mean increase in serum lactate dehydrogenase, from baseline, was 1.1-fold in non-relapsed vs. 1.3 in relapsed patients (p-value = 0.3). The likelihood ratio of relapse was 4.65 for patients who had 1.5-fold increases in serum lactate dehydrogenase above baseline (p-value = 0.03). The sensitivity, specificity, positive and negative predictive values of 1.5-fold increases for detecting relapse, compared to clinical and imaging findings were 0.18, 0.95, 0.55, and 0.79, respectively. Conclusion: A 1.5-fold increase in serum lactate dehydrogenase, over a period of 3 months, is associated with increased likelihood of relapse from diffuse large B-cell lymphoma.

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk–benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States.

The treatment of Burkitt lymphoma has advanced over the last 50 years due to the pivotal work of Dr. Denis Burkitt and his colleagues. Once treated with monotherapy out of necessity, high intensity short duration chemotherapy with CNS prophylaxis is now the standard of care. The success of this treatment strategy in pediatric patients directed the therapy used in adult patients. In all patients, rapid diagnosis and initiation of therapy is critical to assure optimal results. As cure rates for patients continue to improve, management of treatment toxicities such as acute tumor lysis syndrome continues to be an important point of emphasis.

miRNA deregulation has been implicated in the pathogenesis of mantle cell lymphoma (MCL). Using a high-throughput quantitative real-time PCR platform, we performed miRNA profiling on cyclin D1–positive MCL (n = 30) and cyclin D1–negative MCL (n = 7) and compared them with small lymphocytic leukemia/lymphoma (n = 12), aggressive B-cell lymphomas (n = 138), normal B-cell subsets, and stromal cells. We identified a 19-miRNA classifier that included 6 up-regulated miRNAs and 13 down regulated miRNA that was able to distinguish MCL from other aggressive lymphomas. Some of the up-regulated miRNAs are highly expressed in naive B cells. This miRNA classifier showed consistent results in formalin-fixed paraffin-embedded tissues and was able to distinguish cyclin D1–negative MCL from other lymphomas. A 26-miRNA classifier could distinguish MCL from small lymphocytic leukemia/lymphoma, dominated by 23 up-regulated miRNAs in MCL. Unsupervised hierarchical clustering of MCL patients demonstrated a cluster characterized by high expression of miRNAs from the polycistronic miR17-92 cluster and its paralogs, miR-106a-363 and miR-106b-25, and associated with high proliferation gene signature. The other clusters showed enrichment of stroma-associated miRNAs, and also had higher expression of stroma-associated genes. Our clinical outcome analysis in the present study suggested that miRNAs can serve as prognosticators.

The term non-Hodgkin's lymphoma (NHL) refers to a diverse group of illnesses that have in common a high frequency of chemotherapy sensitivity. In fact, high-grade NHL was among the first cancers to be cured with chemotherapy. Although the curability of patients with low-grade NHL remains debatable, all patients with intermediate- and high-grade NHL should be approached with curative intent, even if they present with advanced disease. Our ability to treat patients with NHL is steadily improving. There have been significant advances in our understanding of the biology of the disease and our ability to predict treatment outcome. New treatments and innovative uses of already available treatments are regularly reported. This paper reviews the highlights of the past year's literature regarding the treatment of patients with NHL.

Most patients who need peripheral blood stem cell transplantation do not have peripheral venous access that would allow apheresis for stem cell collection. Subclavian apheresis catheters have an unacceptably high incidence of thrombosis-related access failure. A technique has been developed for translumbar placement of permanent, subcutaneously tunneled, silicone rubber apheresis catheters into the inferior vena cava, and 40 of these catheters have been placed in 36 patients for stem cell collection. Twenty-six catheters have been left in place for venous access during the transplantation procedure. These catheters had a very low rate (2.3%) of apheresis-related related complications. Access failure was attributed to thrombosis in 10 catheters (25%) and to mechanical complications in another 9 (22%), but access was regained in all but 4 of these cases. The catheters functioned well as venous access devices during transplantation, only rarely developing complications during that time. Venograms performed at the time of removal of 16 catheters showed no case of caval occlusion. A residual fibrin sheath was found around 14 catheters. There was no clinical or computed tomographic scan evidence of bleeding after placement or removal of the catheters. Percutaneously placed, translumbar inferior vena cava apheresis catheters provide a safe and effective route for the collection of peripheral blood stem cells for transplantation, and they can be left in place for venous access during transplantation.

Modern high-dose therapy with autologous bone marrow transplantation (ABMT) used for the management of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL) began about a decade ago. ABMT may avoid the problems of finding a suitable donor for transplantation and graft- versus-host disease while eradicating a disease or providing long-term, disease-free survival to patients. Outcome depends on the grade of the disease. Efforts to reduce the morbidity and mortality associated with high-dose therapy, to identify the optimal high-dose therapy for each histologic type of lymphoma, and to better identify those patients most likely to benefit continue.

Routine imaging in remission is performed for patients with many types of cancer in an attempt to detect early, asymptomatic relapse. In patients with lymphoma in the United States, imaging is often performed as routine practice, frequently required in clinical trials, and recommended in treatment guidelines. This is all in the absence of proof that these images improve overall survival or provide other benefits. In Journal of Clinical Oncology (JCO), Voss et al report a trial that included routine surveillance imaging for children and adolescents with Hodgkin’s lymphoma in remission. Most relapses were detected by changes in symptoms, physical findings, or laboratory results; there was no evidence that detection of relapse by routine imaging changed survival. This report by Voss et al addresses an issue that is equally pertinent to adult patients with lymphoma. Because many patients with lymphoma relapsing after complete remission have a chance for a durable second remission with salvage therapy (ie, usually autologous hematopoietic stem-cell transplantation), it is reasonable to consider the possibility that early detection of relapse in asymptomatic patients might increase the chance for cure. To achieve this goal, screening for early relapse with surveillance imaging would need to be accurate and not associated with excessive toxicity or cost. Although the sensitivity and specificity of the imaging technique affect its accuracy, the largest impact is related to the prevalence of the condition in the population being screened. There are many reports of the sensitivity and specificity of computed tomography (CT) scanning in detecting lymphoma. Although these range from well less than 50% to 100%, a reasonable average would be a sensitivity of approximately 60% to 65% and specificity of approximately 90% to 95%. It is more difficult to be certain of the sensitivity and specificity for positron emission tomography (PET)/CT scanning, although it seems that the sensitivity is higher, and the specificity is lower. The most important variable is the prevalence of lymphoma in the population being screened. A study by Radford et al in patients with Hodgkin’s lymphoma in remission found that relapse was detected during one in 68 follow-up visits to an oncologist. In our clinic, the frequency of detecting relapse for patients with diffuse large B-cell lymphoma in remission is between one in 40 to 50 visits. Thus, applying the data from the Radford et al study, the chance that an abnormality on a routine surveillance CT scan would represent lymphoma would be approximately 10%, and applying the data from Nebraska for diffuse large B-cell lymphoma, the chance would be approximately 20%. Of course, these calculations almost certainly overestimate the utility of these images, because in most patients, relapse is detected by obvious changes in clinical status—often in patients returning to clinic between planned visits. The potential value of routine surveillance CT scanning in aggressive non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, and Hodgkin’s lymphoma has been evaluated in numerous reports. A report by Liedtke et al found that patients with relapsed diffuse large B-cell lymphoma detected by surveillance CT scan were likely to have low-volume disease, and the lymphoma was likely to be chemosensitive. However, they found only a nonsignificant trend toward better survival. Studies of Hodgkin’s lymphoma, including that reported by Voss et al, have not shown improved treatment outcome with routine imaging using CT scans. There are fewer reports on using surveillance CT scans for follicular lymphoma in remission. This lymphoma typically grows slowly, and asymptomatic relapse might be present for an extended time. Gerlinger et al described 71 patients who achieved complete remission from relapsed follicular lymphoma through autotransplantation and were observed with annual surveillance imaging. Surveillance imaging detected relapse in 16 patients, and routine clinical evaluation found relapse in 18 patients. The relapses detected by surveillance imaging did not require therapy for a longer time compared with the clinical relapses, but overall survival was not affected. The impact of surveillance PET/CT scans on identifying early relapse in patients with lymphoma has also been studied. In general, surveillance PET/CT scanning to detect relapse has a higher falsepositive rate than CT scans and has not had an impact on survival. A report from Denmark described 53 patients with Hodgkin’s lymphoma who underwent 127 surveillance PET/CT scans. The positive predictive value was 19%, and the negative predictive value was 100%. Lambert et al reported using PET/CT scans to screen for early relapse in patients after allogeneic transplantation and found that PET/CT scans in this setting detected relapse earlier than CT scans and allowed for early administration of donor lymphocyte infusions. There are several potential risks of routine surveillance imaging in patients with lymphoma. These include the possibility of inducing a second cancer because of the radiation dose, the risk of biopsies necessary to document relapse after a positive image, and potential anxiety and fear associated with these images, which could lower quality of life. The risk of causing cancer through medical imaging has recently been highlighted; reports suggested that medical imaging might be a significant cause of cancer in the United States. This seems to be a particular concern in young patients. Shenoy et al tried to calculate the risk of subsequent cancers after surveillance images in patients of different ages and sexes. The anticipated incidence of second cancers JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 21 JULY 2

Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported.We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors.Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%).Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.

Although high-dose chemotherapy and a blood cell or bone marrow autotransplant are commonly used to treat people with diffuse large-cell lymphoma, there is controversy whether this is better than conventional-dose chemotherapy. Subject-selection and time-to-treatment biases preclude comparison of data from uncontrolled trials and there are few date from randomized trials. We used a Delphi-panel group judgment process to determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow transplant. Results were compared to those of randomized trials. Nine lymphoma experts from diverse geographic sites and practice settings were panelists. Boolean MEDLINE searches of lymphoma and chemotherapy and an autotransplant formed the dataset. Panelists were asked to rate appropriateness of high-dose chemotherapy and an autotransplant compared to conventional-dose chemotherapy. Clinical variables were permuted to define 80 clinical settings rated by the panelists on a 9-point ordinal scale. Results were used to determine an appropriateness index reflecting the mean and distribution of ratings. The relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. In people with initial diffuse large-cell lymphoma, autotransplants were never rated appropriate. They were rated uncertain in all settings except in people never receiving chemotherapy and in those with a complete response to chemotherapy and an international prognostic index < 3, where they were rated inappropriate. In people with recurrent lymphoma, autotransplants were rated appropriate in those with a complete or partial response to chemotherapy, uncertain in those with a less than partial response and in those not receiving re-induction chemotherapy and inappropriate in people with CNS lymphoma. These conclusions agree with results of randomized trials.

With the increasing concern over the high cost of health care, policy makers have incorporated economic analyses into phase III clinical trials as the randomized clinical trials can provide important information on the efficacy and potential cost-effectiveness of new pharmaceutical agents. Economic analyses of single-hospital experience during phase III trials of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy for high dose chemotherapy with autologous stem cell support found significant shortening of neutropenia with GM-CSF at each hospital, but shortened hospitalization (and lower costs) at only two of three hospitals. In this study, we added data from three additional hospitals and found that the 103 patients who received GM-CSF had, on average, 5.7 days shorter durations of severe neutropenia than the 95 patients who received placebo (p < 0.0001) and 3.4 days shorter in hospitalization (p = 0.06). However, the duration of hospitalization, the primary determinant of health care costs, was shorter for GM-CSF patients in only four of the six centers and the duration of hospitalization of placebo patients was shorter at the other two centers. Careful analyses must be carried out when phase III clinical trial results are used to derive estimates of cost-effectiveness of new pharmaceutical agents. The interpretation of economic analyses of phase III clinical trials raises issues related to the perspective of the investigators, study design, collection of data on resource utilization, learning curve effects and generalizability of the results to other settings.

Although clinical trials are being used to evaluate economic outcomes of new agents, there are methodological problems. Decisions based on these analyses may lead to inefficient use of medical resources. Randomized clinical trials provide important information on the efficacy of new pharmaceutical agents for cancer patients. Policy makers are likely to require both economic and clinical data in order to approve pharmaceuticals for widespread use. Clinical trials provide an opportunity to evaluate economic outcomes for new agents. However, the interpretation of economic analyses of clinical trials raises issues related to perspective of the investigators, study design, collection of data on resource utilization, and generalizability of data to other settings. In this paper, we review these issues and illustrate problems associated with analyses of economic data from a recent phase III trial of hematopoietic growth factors. Clinical results were similar in both Paris and New York in this phase III trial. However, economic results differed markedly between the hospital in Paris and the hospital in New York. While significant savings in terms of fewer days in the hospital and fewer laboratory tests and radiographs for the granulocyte-macrophage colony-stimulating factor (GM-CSF) patients were noted at the New York hospital, resource savings were not identified at the hospital in France. Caution must be used when reimbursement policies are based on economic analyses of clinical trials. Policy decisions must be based on studies that are carefully conducted, analyzed, and interpreted from both a clinical and an economic perspective.

Bone marrow specimens from 317 patients with non-Hodgkin's lymphoma (NHL) obtained at initial staging were evaluated for the presence of lymphoma or benign lymphoid aggregates. Thirty-two percent (102 patients) had lymphoma in their bone marrow, and 9% had benign lymphoid aggregates. Bone marrow lymphoma was present in 39% of low-grade, 36% of intermediate-grade, and 18% of high-grade lymphomas. The bone marrow was involved in 25% of patients with diffuse large-cell or immunoblastic NHL (ie, diffuse histiocytic lymphoma of Rappaport). Bone marrow involvement did not affect survival of patients with low-grade NHL, but survival was significantly shorter (P = .03) for patients with intermediate- and high-grade NHL with bone marrow involvement. Bone marrow involvement was equally common in B-cell and T-cell NHL (31% v 32%). However, patients with T-cell NHL and bone marrow involvement had shorter survival than B-cell NHL with marrow involvement (P = .02) or T-cell NHL without marrow involvement (P = .05). A high incidence of morphologic discordance between lymph node and bone marrow was observed (ie, 40%), always with a more aggressive subtype in the lymph node than in the bone marrow. Presence of large-cell lymphoma in the bone marrow predicted for short survival. Survival for patients with small-cell lymphoma in their bone marrow did not differ significantly from patients with negative bone marrows. We conclude that bone marrow involvement in large-cell NHL, especially in those of T-cell origin, portends a poor prognosis. However, the subgroup of patients with an aggressive histologic subtype of NHL in a lymph node biopsy and small-cell NHL in the bone marrow do not have a poorer outlook than those without bone marrow involvement.

Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.

The development of new classification schemes and prognostic analyses for lymphomas has helped to identify patients at high risk for relapse who may benefit from intensification of primary therapy. Conventional salvage therapy for relapsed follicular or low-grade lymphomas now includes monoclonal antibody therapy. The combination of chemotherapy and monoclonal antibody therapy may improve outcomes for patients with advanced-stage aggressive non-Hodgkin's lymphomas. Confirmatory randomized trials are now in progress. Therapy for Hodgkin's disease continues to evolve toward the most efficacious programs, which also minimize the long-term probability of toxicity. The combination of high-dose chemotherapy and stem cell transplantation is probably the most effective therapy for patients with relapsed or refractory Hodgkin's disease.

We investigated if high dose melphalan and total body irradiation could be administered to adult patients with acceptable toxicity. Nineteen adult patients with relapsed disease, 15 of them having hematologic malignancies, were treated with high-dose melphalan ( 100 mg/m 2 –140 mg/m 2 ) divided over 2 consecutive days followed by a rest period of 4 , days before receiving total body irradiation, 850 rad administered in five fractionated doses over 3 , days . Subsequently 11 patients received autologous, seven allogeneic and one syngeneic, bone marrow transplantation. All patients had severe myelosuppression and the major extramedullary toxicity was mucositis. There were three early deaths, two related to septicemia and one to graft-versus-host disease with associated cytomegalovirus pneumonitis. All patients were heavily pretreated, and 16 were demonstrating progressive disease on alternative salvage therapies at the time of bone marrow transplantation. Two of the 16 evaluable patients (12.5%) achieved complete remissions, and 10 (63%) achieved partial remissions for a total response rate of 75% . One patient is a long-term disease-free survivor (over 1 yr ). An occasional patient may be cured by this approach. The combination of melphalan, an alternative alkylating agent to cyclophosphamide and total body irradiation are associated with moderate gastrointestinal toxicity in heavily pretreated adult patients. The combination warrants further investigation in a less heavily pretreated population to determine more accurately the complete response rate.

Evaluation and management of victims of exposure to myelosuppressive radiation in a military, terrorist, or accidental event is challenging. The hematopoietic syndrome with marrow suppression and pancytopenia follows intermediate intensity radiation exposure and as such produces a clinical syndrome similar to that after myelosuppressive chemotherapy or stem cell transplantation. Therefore, hematologists, oncologists, and transplantation physicians have the opportunity and challenge to plan for care of irradiation victims. Management of the hematopoietic syndrome, as a component of acute radiation sickness, requires understanding its manifestations and implementation of clinical biodosimetry to provide appropriate therapeutic support. Hematopoietic growth factors may be of value if administered early as a component of supportive care. Planning for urgent stem cell transplantation for those with intermediate- to high-dose radiation (4-10 Gy) may be required. Establishing contingency plans for triage, assessment, supportive care, and treatment resembles the development of phase II trials, with defined eligibilities, treatment plans, and incorporated data collection to assess results and plan further improvements in care. The hematology/oncology community is most suited to participate in such contingency planning, and the necessary elements for its success are reviewed.