Expert Hematologists Research Articles

MANAGEMENT OF MYELODYSPLASTIC SYNDROMES IN ADULTS: GUIDELINES FROM THE BELGIAN HAEMATOLOGICAL SOCIETY

Myelodysplastic syndromes (MDS) represent a heterogeneous group of haematological disorders characterized by ineffective haematopoiesis and an increased risk for leukemic transformation. In recent years several new therapeutics have emerged that have demonstrated to alter the natural course of the disease. This document summarizes the state of the art in diagnosis and treatment of this heterogeneous disease, as proposed by a group of expert haematologists in the field of MDS from the Belgian Haematological Society. Its main purpose is to guide clinicians in daily practice to treat patients with this disease, within the limitations of current reimbursement modalities in Belgium.

The incidence of myelodysplastic syndromes in Western Greece is increasing

Descriptive epidemiology of the myelodysplastic syndromes (MDS) is always interesting and may reveal time-dependent and geographical variations, as well as occupational exposure. Epidemiological data in Greece are not available by now. We have collected and analyzed medical records of all patients with a documented diagnosis of MDS, performed by an expert hematologist and/or hematopathologist, in the geographical area of Western Greece, during the 20-year period, defined between 1990 and 2009. We have then calculated and described demographic and clinical features of the diagnosed MDS patient population, and assessed the incidence and prevalence rates of MDS in Western Greece, during the above-mentioned period. A total of 855 patients with newly diagnosed MDS have been identified. Refractory anemia was the most common subtype in both FAB and WHO classification systems and in both genders. Del-5q and RARS were more commonly encountered among females, and the dysplastic subtype of chronic myelomonocytic leukemia among males. Trisomy 8 was the most common single cytogenetic abnormality. The crude mean annual incidence rate of MDS was 6.0 per 100,000 inhabitants aged ≥15 years old (all subtypes according to FAB), and it was 4.8 per 100,000 when CMML and RAEB-T were excluded. Crude incidence rate was higher in rural than in urban areas, but this finding was not confirmed after age standardization. Age-standardized mean annual incidence rate in men was 7.9/100,000 and in women 3.4/100,000. A continuously increasing incidence rate of MDS has been observed throughout the study period.

Baby on board: what you need to know about pregnancy in the hemoglobinopathies

Abstract Pregnancy poses a unique challenge to patients with sickle cell disease and β-thalassemia, who often have exacerbations of hemolysis or anemia during the gestational period, experience higher rates of obstetric and fetal complications, and may have distinct underlying comorbidities related to vasculopathy and iron overload that can endanger maternal health. Optimal management of pregnant women with hemoglobinopathies requires both an understanding of the physiologic demands of pregnancy and the pathophysiology of disease-specific complications of inherited blood disorders. A multidisciplinary team of expert hematologists and high-risk obstetricians is therefore essential to ensuring appropriate antenatal maternal screening, adequate fetal surveillance, and early recognition of complications. Fortunately, with integrated and targeted care, most women with sickle cell disease and β-thalassemia can achieve successful pregnancy outcomes.

Prognostic Impact of Clinician-Based Interpretation of FDG-PET/CT Reports Obtained in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma.

AbstractAbstract 2646▪▪This icon denotes a clinically relevant abstract Background:PET/CT scan is a widespread modality in both clinical settings and clinical trials in the evaluation of diffuse large B-cell lymphoma (DLBCL). The concordance among interpreters of PET/CT scan is important for basing clinical decisions on these results. In order to act properly on the results, the response evaluation according to interpretation of PET/CT reports has to correlate with specific clinical end points including outcome. As of today we have no evidence for that and clinical studies are only based on the assessment of nuclear medicine-physicians. Aim:To evaluate the clinician-based interpretation of PET/CT reports in newly diagnosed DLBCL at mid-therapy(I-PET) and end-therapy(E-PET) in terms of concordance and prognostic impact. Method:Patients were considered eligible for inclusion in this retrospective study if they fulfilled the following criteria: I) newly diagnosed with de novo DLBCL, II) age ≥15 years, III) treated with R-CHOP or R-CHOP like treatment with or without addition of CNS prophylaxis and radiotherapy and IV) evaluated with PET/CT at mid-therapy and/or end-therapy. Patients with primary CNS lymphoma and composite lymphoma histology, HIV-associated lymphoma and transplant related lymphoproliferative disease were excluded from this study. All DLBCL patients diagnosed between September 2005 and December 2009 at eight Danish hematology centers were screened for eligibility.Nine expert hematologists were asked to interpret PET/CT reports. Each report was independently evaluated by three hematologists. The assessments of reports were performed without any clinical information. PET/CT reports were labeled positive or negative if all three interpreters independently agreed. All others were considered indeterminate. Results:A total of 434 patients and 617 PET/CT reports were included in the study. The distribution of PET/CT report interpretation is shown in Table 1.The median follow-up time was 3.4 years (range 0.3 – 6.7 years). The progression free survival (PFS) and overall survival (OS) for the I-PET reports were not significantly different between the indeterminate and negative results (p=0.6). However, patients with an indeterminate result had a worse PFS and OS according to the E-PET reports (p=0.09 and p=0.006, respectively). Patients with a positive I-PET and/or E-PET report both had a significantly lower PFS (p<0.0001) and OS (p<0.0001) compared to the two other groups. Survival curves are shown in Figure 1. Discussion:PET/CT evaluation in newly diagnosed DLBCL needs not only acceptable predictive values for outcome prediction to reinforce the decision to modify treatment strategy, but also high concordance between the clinicians who make the decisions. Failing to achieve this will make PET an unsuitable tool for this purpose. In the present study, we found a high number of indeterminate evaluations according to both I-PET and E-PET reports. There was no significant prognostic difference between the negative and the indeterminate group of the I-PET. However, we observed a significant difference in outcome between patients with a negative and indeterminate E-PET. Patients with a positive E-PET and I-PET had a very poor prognosis.This study demonstrates that binary visual PET response criteria for de novo DLBCL leads to a considerable amount of indeterminate interpretations in the clinician based setting. The study also underlines the importance of consistent PET reports and a multidisciplinary approach for the evaluation of treatment response in DLBCL.Table 1:Distribution of 617 PET/CT reports by hematologist interpretationIndeterminateNegativePositiveI-PET (n=241)59% (n=142)30% (n=73)11% (n=26)E-PET (n=376)37% (n=186)41% (n=153)10% (n=37)Table 2:Survival estimates according to results of I-PET and E-PETI-PET (n=241)Indeterminate (n=142)Negative (n=73)Positive (n=26)2YRS PFS estimate (95% CI)85% (78-90%)90% (81-95%)52% (31-69%)2 YRS OS estimate (95% CI)87% (81-91%)89% (79-94%)58% (37-74%)E-PET (n=376)Indeterminate (n=186)Negative (n=153)Positive (n=37)2YRS PFS estimate (95% CI)86% (80-90%)95% (90-97%)36% (21-52%)2 YRS OS estimate (95% CI)89% (84-93%)97% (92-99%)41% (25-56%) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Acquired Inhibitors: A Special Case of Bleeding in Older Adults

This literature review is intended to familiarize physicians and healthcare providers of older adults with the potential causes of acute bleeding in older adults and to review diagnostic approaches that can produce prompt identification of acute bleeding and facilitate timely treatment. Adverse events from anticoagulant treatment and nonsteroidal anti-inflammatory drug (NSAID) and aspirin use and abuse are among the most common causes of bleeding in older adults. Diagnoses infrequently considered—mild congenital hemophilia, acquired hemophilia, von Willebrand disease, and platelet dysfunction—can contribute to acute bleeding in older adults. The approach to management of bleeding varies. Management of acute bleeding in older adults can be challenging because these patients often have chronic comorbidity and have been prescribed long-term concomitant medications that can complicate diagnosis and treatment. Prompt recognition of acquired hemophilia, referral to an expert hematologist, and timely initiation of treatment could improve outcome in older patients who experience bleeding episodes resulting from this condition.

Cost-Effectiveness of Lenalidomide in Multiple Myeloma Patients with 1 Prior Therapy in England and Wales,

Abstract 4181 Introduction:Lenalidomide plus dexamethasone (Len+Dex) is approved by EMA for patients with multiple myeloma (MM) who have received at least 1 prior therapy. In the wake of NICE's guidance on Thalidomide and Bortezomib TA 228 for 1st-line treatment of MM, Len+Dex may be the only available novel therapy option with potential to extend survival beyond traditional therapies for patients failing the NICE recommended initial treatments; thalidomide or bortezomib both in combination with melphalan and prednisone. Therefore, economic modelling was undertaken to evaluate the cost-effectiveness of Len+Dex from the perspective of the National Health Service (NHS), England and Wales. Methods:An Excel-based individual simulation model was developed to account for disease history which affects time-to-progression (TTP) and overall survival (OS) in relapse refractory MM patients. The OS for each individual within the model was calculated as the combination of that patient's TTP and post progression survival (PPS). The TTP efficacy was derived from a subgroup analysis of patients from the MM-009/010 pivotal trials who had received only 1 prior therapy. The derived equation for TTP included parameters for treatment response, Len+Dex treatment effect and certain baseline characteristics of patients with only 1 prior therapy. The PPS for patients within the model was also derived from the MM-009/010 trials; however, since 47% of patients on Dex switched to Len+Dex at progression, there was a significant Len+Dex effect in the Dex PPS. To account for this, the Dex PPS was calibrated using the longer follow up from the UK Medical Research Council (MRC) trials. Resource use for monitoring and adverse events was obtained via a survey of expert hematologists in the UK. Costs were taken from NHS sources and included a Patient Access Scheme where patients received Len free of charge beyond 26 cycles of use. Utility values were taken from published literature and applied to patients prior to progression (based on their best response rate achieved) and after progression. The robustness of the model results were assessed by sensitivity analyses whereby individual model parameters were varied across their confidence intervals (CI). Results reported include life-years (LY), quality-adjusted life-years (QALY), costs, cost per LY gained and cost per QALY gained. NICE technology appraisal methodology guidelines were followed when modelling over a lifetime horizon and applying a 3.5% discount rate for future benefits and costs. All costs presented are in British pounds. Results:Len+Dex had a substantial increase in health-related outcomes compared to Dex alone, with LYs of 5.37 vs. 2.15 and QALYs of 3.69 vs. 1.49, respectively. The associated drug costs for Len+Dex over the patients' lifetime were higher: however, survival benefits accrued over the same time period offset the cost differences between the two regimens, resulting in a cost per LY gained of 20,639 and per QALY gained of 30,153. The model results remained robust to sensitivity analysis conducted on most parameters and utility estimates. The only parameter that affected the results was the adjustment factor for Dex survival when varied across its 95% CI (see table). Discussion:These results indicated that Len+Dex at 2nd line is cost-effective for a novel drug in an orphan disease compared to Dex alone. Despite Len+Dex only being recommended by NICE for use in MM patients with 2 or more prior therapies (with the recent NICE decision to allow thalidomide and Velcade in de novo patients), treatment alternatives for 2nd line therapy with novel agents is more limited. It is important for clinicians to consider the costs and benefits of 2nd line therapy. This analysis demonstrated that Len+Dex is cost-effective for 2nd line patients and meets the commonly quoted cost per QALY threshold of 30,000. Modelled Results:Len/DexDexDifferenceClinical OutcomesMedian TTP (in months)14.094.639.46Life-years5.372.153.22QALYs3.691.492.20Cost Outcomes (British pound)Medication61,98814161,847Monitoring6,9142,8804,034AE Management777175602Incremental cost-effectiveness (British pound)ICER-LYICER-QALY% difference from base case QALYBase case20,63930,153–Upper 95% CI DEX OS27,22538,97529.3%Lower 95% CI DEX OS17,50425,82014.4% Disclosures:Schey:Celgene: Consultancy. Stern:United BioSource Corporation: Employment; Celgene: Consultancy. Dhanasiri:Celgene: Employment. Brown:United BioSource Corporation: Employment; Celgene: Consultancy.

Dual modality search and retrieval technique analysis for leukemic information system.

Medical Information System (MIS) deals with standardized method of collection, storage, retrieval and evaluation of patient data. Computational Intelligence (CI) technique has many abilities in data processing and structuring, pattern matching, forming knowledge base, reasoning and decision making. MIS for leukemia cells was developed at University of Malaya for the Hematology Department of Hospital Ampang, Malaysia. CI techniques were used for syntactical and contextual image retrieval of leukemic images. A logical approach was used to systematically develop content based image retrieval system that supports decision making in clinical hematopathology. The developed system is based on open source. Pages were designed and developed using Java Server Pages (JSP) and Java with MySQL as the database for the domain and image repository. Several Java-based tools were used for image processing, neural network based pattern classification and recognition, and for the hybrid system. The classification rates for individual white blood cells varied between 97% for training data and 95% for testing data depending on the individual cell type- monocyte, lymphocyte, eosinophil, basophil and neutrophil. This result is cross-validated by an expert hematologist. Key words: Medical information system (mis), leukemia image retrieval, image processing, feature classification, pattern recognition, hematology.

Favourable Outcome of B-Cell Non Hodgkin Lymphomas Associated with Hepatitis C Virus - ANRS HC13 LYMPHO-C Observational Study

AbstractAbstract 3116 Background:Hepatitis C virus (HCV) associated B-cell non-Hodgkin's lymphoma (B-NHL) is a rare entity that constitutes a model of chronic immune stimulation related lymphomas. They are preferentially Marginal Zone Lymphomas (MZL) and Diffuse Large B Cell Lymphoma (DLBCL) subtypes. In order to study the characteristics of HCV-related B-NHL, we pursue a prospective multicentric observational study in France. We present here the characteristics and evolution of the patients included in this study. Patients and methods:Adult patients with a history of HCV associated B-NHL were included in the study. HCV infection was defined by a positive viral load at diagnosis of NHL. Patients with HIV infection were excluded from the study. Each patient was followed every 6 months during 5 years. Data collection included clinical presentation, treatment and evolution of NHL and HCV infection. Pathological and cytological materials were centralized and reviewed by a group of expert hematopathologists, haematologists and immunologists. Results:The data of the 64 consecutive patients included between nov 2006 and march 2010 in 20 centers are presented. Median age is 62 years (ranging from 39 to 87 years). There is a predominance of men: sex ratio 1.37 (m37/f27). HCV genotypic distribution does not differ from expected in France: 1: 52% (30/56), 2: 25% (14), 3: 11% (6), 4: 12% (7), 7 missing data.Twenty-six cases were included at diagnosis of B-NHL, 33 during follow-up of NHL and 5 at relapse. The median interval between NHL diagnosis and last follow-up is 22 months (range 0–152). The histological subtype distribution is DLBCL 39% (22), MZL 37% (21), FL 16% (9), CLL 4% (2), mantle cell lymphoma 4% (2). Remarkably, there is a continuum between MZL and DLBCL, with 6 cases with ongoing transformation. Eight cases are not classified due to small disease infiltration or lack of material. Expert review led to reclassification in few cases from DLBCL to MZL and from FL to MZL.Among the 22 patients with DLBCL, 3 have no follow-up. The median follow-up of the remaining 19 patients is 21 months. Those patients were treated with polychemotherapy combined with rituximab (R) in all cases except one. Treatment was followed by long lasting complete remission (CR) in all cases except three: a 59 y woman relapsed after Richter syndrome following CLL, a 85 y man progressed on therapy and a 40 y woman with liver DLBCL was resistant to 3 lines of R-chemotherapy. These three patients died from disease progression. During follow-up, 9 patients were treated with antiviral treatment followed by virologic response in all cases but one.The 21 patients with MZL are 8 splenic MZL including one with transformed DLBCL, 7 nodal MZL, 3 extra-nodal, and 3 Waldenstrom macroglobulinemia; 15 out of 19 cases were associated with positive rheumatoid factor (RF) and/or cryoglobulinemia. Two patients had no follow-up. The median follow-up of the remaining 19 patients is 40 months. The efficacy of antiviral treatment alone on HCV-associated MZL was confirmed in 8 patients and had a RF. The other patients were treated with R-chemotherapy (4), R+antiviral (2), R (2), oral chemotherapy (1) or “watch and wait” (1). The patient with splenic high grade transformation was treated by splenectomy alone and is still in CR. During follow-up, one patient relapsed and is currently treated with R-chemotherapy, two patients died including one after progression to DLBCL.Among the 9 patients with FL, one had no follow-up, 6 long-lasting CR were obtained following R-chemotherapy, one following three lines of treatment. One other CR was obtained following R-antiviral therapy. Three other patients received antiviral therapy during follow-up with efficacy in one case. Among the two patients with mantle cell lymphoma, one had no follow-up, the other one is on long term CR 6 years following first line chemotherapy (R-CHOP/R-DHAP). Conclusions:This study strengthens the heterogeneity of HCV-related lymphomas and the need for systematic expert review. Overall, these patients have a favourable outcome. Cases with MZL frequently respond to antiviral treatment and one case with FL to R-antiviral. Combined therapy of R- antiviral seems a good option and should be evaluated for low grade lymphomas. Patients with DLBCL should receive R-CHOP therapy and should be referred in hepatology department for antiviral treatment after chemotherapy due to frequent virologic responses and follow up of liver functions. Disclosures:No relevant conflicts of interest to declare.

High Frequency of Marginal Zone Lymphomas Among Patients Coinfected with Human Immunodeficiency Virus and Hepatitis C Virus - ANRS CO16 LYMPHOVIR Cohort Study

AbstractAbstract 4156 Introduction:Human Immunodeficiency Virus (HIV) and hepatitis C virus (HCV) infections are both associated with an increased risk of B-cell non-Hodgkin lymphoma (B-NHL). They are known to be preferentially diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma subtypes in HIV infection, while marginal zone lymphoma (MZL) and DLBCL represent the main subtypes in HCV infected patients. The absence of increased risk of B-NHL in HIV-HCV co-infected patients compared to HIV infected patients was reported in epidemiological studies, but the clinico-pathological characteristics of B-NHL in the setting of such co-infection particularly in the era of HAART remains unclear. Patients and methods:We present the data of adult patients with B-NHL and HIV-HCV co-infection from the French ANRS CO16 Lymphovir cohort. This multicentric prospective cohort includes HIV infected patients with lymphoma. Each patient is followed every 6 months during 5 years. At each follow-up, a blood sample is withdrawn allowing ancillary studies. Data collection concerns clinical presentation, treatment and evolution of B-NHL and HIV and HCV infections. Pathological and cytological materials are centralized in order to allow their review and a concerted analysis by a group of expert hematopathologists (MR, SP, DC), haematologists and immunologists. Results:Among the 49 patients with B-NHL included in the cohort, 6 were HIV-HCV coinfected, [5 men and 1 woman, median age 47 years (range 36–67)]. They were included between october 2007 and august 2009 in 6 French centres. Transmission risk was intravenous drug abuse (n=4) and heterosexual transmission (n=2). Median duration from HIV diagnosis to B-NHL was 11 years (range 1–20), and the median nadir CD4 T-cell count was 194/mm3 (range 151–746) (nadir not available for 2 patients). Only one patient had developed AIDS before the diagnosis of NHL. HCV genotypic distribution was: genotype 1 (n=3), 2 (n=1), 4 (n=1), and not available (n=1). Median HCV viral load was 6.0 log (range 5.4–7.1). One patient had compensated cirrhosis and none of the patients were tested for cryoglobulinemia. Immunological assays showed the presence of monoclonal IgM Kappa in 1 patient and no positive rheumatoid factor.At the diagnosis of B-NHL, 4 patients received HAART and had an undetectable HIV load. In contrast, none of the patients were treated for HCV infection. The median interval between B-NHL diagnosis and last follow-up is 17 months (range 0.1–32 months). The histological subtype distribution is 4 MZL -including 2 extranodal MZL of MALT, 1 splenic lymphoma with villous lymphocytes (SLVL) and 1 lymphoplasmacytic lymphoma- and 2 EBV-negative DLBCL. All patients have extranodal involvement, including digestive tract (n=3), liver (n=2), bone marrow (n=2) and spleen (n=1). Median CD4 T-cell count at B-NHL diagnosis was 582/mm3 (range 235–1322) in MZL patients and 274/mm3 (200 and 347) in DLBCL patients.Following diagnosis, all patients were treated with HAART, associated with peg-interferon plus ribavirin in 1 patient. The 2 patients with DLBCL received R-CHOP, associated with methotrexate in 1 case. One patient with a partial response exhibited a neuromeningeal relapse and was treated with COPADM and CYVE regimen, allowing a complete and sustained response. The other patient died of serious infection after 2 courses of chemotherapy. Among patients with MZL, one patient received R-CVP and one received chlorambucil, allowing a complete response in both patients. The patient with SLVL received HAART then peg-interferon plus ribavirin, allowing normalization of lymphocytes count (5.89 at baseline vs. 1.69 × 109/L at 12 weeks of anti-HCV therapy) with a correlation between HCV virological and hematological response. Patient with lymphoplasmacytic lymphoma died of cardiac ischemia before the initiation of chemotherapy. Conclusions:This study describes the resurgence of MZL in HIV-HCV co-infected patients with restored immunity under HAART. Such B-NHL, very rarely described in HIV patients, occurs mainly in patients with control of HIV without history of AIDS but with active HCV infection. Histological subtypes and localizations resemble more to that observed in HCV infected patients than in HIV infected patients. These findings suggest the role of chronic antigenic stimulation by HCV and/or HIV and question about the interest of HCV antiviral therapy on NHL in co-infected patients. Disclosures:No relevant conflicts of interest to declare.

Clinico-Pathological Characteristics of B-Cell Non Hodgkins Lymphomas Associated with Hepatitis C Virus ANRS HC13 LYMPHO-C Observational Study.

Abstract 1927Poster Board I-950 Introduction:Hepatitis C virus (HCV) associated B-cell non-Hodgkin's lymphoma (B-NHL) is a rare entity that constitutes a model to study chronic immune stimulation related lymphomas. They are known to be preferentially Marginal Zone Lymphomas (MZL) and Diffuse Large B Cell Lymphoma (DLBCL) subtypes. Conflicting results are reported on the association between Follicular Lymphoma (FL) and HCV. In order to study the physiopathology of HCV-related B-NHL, we pursue a multicentric observational study in France. We present here the clinicopathological characteristics of the patients included. Patients and methods:Adult patients with a history of HCV associated B-NHL are included in the study. HCV infection is defined by a positive viral load at diagnosis of NHL. Patients with HIV infection are excluded from the study. Each patient is followed every 6 months during 5 years. At each follow-up, a blood sample is withdrawn allowing ancillary studies. Data collection concerns clinical presentation, treatment and evolution of NHL and HCV infection. Pathological and cytological materials are centralized in order to allow their review and a concerted analysis by a group of expert hematopathologists, haematologists and immunologists. Results:The data of the 54 consecutive patients included between november 2006 and april 2009 in 20 french centers are presented. Median age is 63 years (ranging from 39 to 87 years). There is a predominance of men: sex ratio (m/f) is 1.45 (32/22). Included women are older than men (p<0.01), median age being 71 among women and 60 years among men. HCV genotypic distribution does not differ from expected in a HCV infected population in France: 1: 51% (25/49), 2: 29% (14/49), 3: 8% (4/49), 4: 12% (6/49), 5 missing data. Transmission risk groups, known in 50% (27/54) of cases, are transfusion (18), drug abuse (5), endemic origin (2), and tattoo/acupuncture (2). Two patients are co-infected with HBV. Twenty-four patients out of 42 tested (57%) had positive cryoglobulinemia at diagnosis of NHL. This proportion did not differ with gender nor with genotype.Fifteen cases were included at diagnosis of B-NHL. The 39 other cases were included during follow-up of NHL. The median interval between NHL diagnosis and last follow-up is 15 months (range 0-13y). The histological subtype distribution is DLBCL 39% (21), MZL 35% (19), FL 13% (7), CLL 6% (3). Remarkably, there is a continuum between MZL and DLBCL, 6 cases with ongoing transformation. Four cases could not be classified due to small disease infiltration or lack of material. We confirm the link between cryoglobulinemia and MZL, 12+ out of 17 tested, 6+/12 in DLBCL versus 2+/5 in FL and 1+/2 in CLL. Nodal involvement is infrequent (5 out of 21 cases of DLBCL, 2/19 MZL, 4/7 FL). Extranodal involvements predominated in spleen (15 including 8 MZL), lung (6), digestive tract (4), liver (3), heart (1), skin (6) and bone marrow (4). The efficiency of antiviral treatment is confirmed in 5 cases with MZL, and remarkably, was followed by a good response in one case with FL. However, most patients in this observational study received treatment with Rituximab (R) either alone (5 cases with MZL), or combined with chemotherapy (including 15 cases with DLBCL and 4 with FL) or with antiviral treatment. This was associated with good clinical responses in most cases and low toxicity. Indeed, only 5 patients died during follow-up – two from disease progression - a 85 y man and a 40 y woman with liver DLBCL who was resistant to 3 lines of R-chemotherapy. The other patients died of sepsis (2), and cardiac ischemia (1). Conclusions:This study strengthens the heterogeneity of HCV-related lymphomas. The observation of cases with MZL and, remarkably, of one case with FL responding to antiviral treatment suggests that they are both linked to chronic immune stimulation. Therefore, the concept of antigen-driven lymphomagenesis seems more heterogeneous than initially anticipated: it could involve a T independent response in MZL, and a T dependent response in FL. The ongoing pathophysiological study will improve further understanding of the mechanisms by which antigen-driven lymphoproliferation arise. Disclosures:No relevant conflicts of interest to declare.

Defibrotide (DF) in the Treatment of Severe Hepatic Veno-Occlusive Disease (VOD) with Multi-Organ Failure (MOF) Following Stem Cell Transplantation (SCT): Results of a Phase 3 Study Utilizing a Historical Control.

Abstract 654 Background:Phase 2 clinical trials of DF in the treatment of severe VOD/MOF have demonstrated a complete response (CR) in 36-46% of patients (pts) with encouraging overall survival and tolerability (Richardson Blood 2002; Richardson ASH 2006). Given the life-threatening nature of VOD/MOF, a trial randomizing pts to placebo or best supportive care was considered but rejected. A phase 3 trial, comparing DF in the treatment of VOD/MOF post-SCT to a contemporaneous historical control (HC) was therefore performed. The HC was created using a sequential review of medical charts starting 6 months prior to use of DF at each center. Methods:Eligible pts met Baltimore VOD criteria by D+21 (total bilirubin ≥ 2.0 mg/dL with ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) and either renal and/or pulmonary failure by D+28. Exclusion criteria: severe GvHD involving liver or gut; clinically significant bleeding; or need for >1 pressors to maintain BP. As this is a non-randomized study, the primary efficacy analysis compared CR by D+100, adjusted by quintiles of propensity score based on 4 stratification variables, at an overall two-sided 0.01 significance level (Koch et al,1989). CR was defined as bilirubin < 2 mg/dL + resolution of MOF; stratification variables were allogeneic/autologous SCT, adult/pediatric, 1 or 2+ SCTs, and ventilator/dialysis dependence. A secondary endpoint was mortality at D+100. DF was given at 6.25 mg/kg IV q6h; treatment duration was recommended for at least 21d. To create the HC, 35 centers sequentially reviewed up to 266 cases. To determine HC eligibility, the Medical Review Committee (MRC, composed of 2 independent expert hematologists) assessed all pts who met VOD criteria with MOF. The MRC were provided data for each pt (a redacted medical chart or pt narrative, depending on the privacy laws for each center) only up to the date on which the pt met inclusion criteria. The MRC remained blinded to outcome data at all times. One interim analysis was planned. Results:For the HC, 6821 medical charts were screened, identifying 123 pts with features consistent with VOD in a setting of renal and/or pulmonary dysfunction that were reviewed for eligibility by the MRC. The MRC selected 32 cases as having an unequivocal diagnosis of VOD whose MOF was secondary to VOD, who met all protocol entry criteria; for all eligible pts, a confounding diagnosis of GvHD was ruled out. In the DF-treated group, 102 pts were enrolled. Following the interim analysis (comparing 61 DF pts to 32 HC pts), the DMC recommended an increase in HC sample size to 51 pts; given the large number of medical charts already reviewed, this was not considered feasible. In the final analysis (comparing 102 DF pts to 32 HC pts), the 2 groups were balanced regarding stratification variables. Baseline demographics (DF vs HC pts): median age 21 vs 18 yrs (43% and 44% pediatric); 63% vs 53% male, 88% vs 84% allogeneic SCT; 13% vs 3% with prior SCT; and 38% vs 38% ventilator/dialysis dependent. Median time post-SCT to VOD diagnosis was 13 and 11 days. Acute leukemia was the underlying diagnosis in 44% and 47%. Median duration of DF therapy was 22 days (range 1-60 days), with a median daily dose of 19 mg/kg/d. For the primary efficacy analysis, D+100 CR rate equaled 24% vs 9% (99%CI difference in CR rate: -1–35%; 95%CI difference in CR rate: 3–30%); p=0.015. D+100 mortality rate equaled 62% vs 75% (95%CI difference in rate -32–3%); p=0.051 by stratified log-rank. Consistent with prior studies, DF in children resulted in higher CR compared with HC (CR 36% vs 7%; p=0.04). Use of DF was associated with improved outcome in less sick pts (D+100 CR for pts without ventilator dependence equaled 40% vs 9%; p=0.051 and for pts without dialysis dependence equaled 34% vs 9 %; p=0.027). For pts receiving autologous SCT (n=12 and 5 pts in DF and HC arms), DF was associated with markedly improved CR (75% vs 0%, p=0.005). Hemorrhagic adverse events (any grade) were similar between the two groups (65% vs 69%); 18% of DF pts experienced a drug-related toxicity that led to discontinuation. D+100 CR strongly correlated with D+100 survival in both DF and HC groups (p<0.0001, p=0.0016). Conclusions:DF improves CR by D+100 in pts with severe VOD/MOF post-SCT with a p value < 0.05. In addition, there was a trend towards improved D+100 survival in this critically ill population. DF-associated toxicities are consistent with prior studies, supporting the observation that DF is generally well tolerated. Disclosures:Richardson:Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Grupp:Gentium: Research Funding. Martin:Gentium: Research Funding. Corbacioglu:Gentium: Consultancy, Research Funding. Holler:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment. Soiffer:Gentium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Defibrotide (DF) for the Prevention of Hepatic Veno-Occlusive Disease (VOD) in Pediatric Stem Cell Transplantion: Results of a Prospective Phase II/III Randomized, Multicenter Study.

Abstract 653 Background:Hepatic VOD is a life-threatening complication following SCT with a particularly high incidence in children. Development of VOD is one of the most common causes of early death after SCT. DF (Gentium SpA), a polydisperse oligonucleotide, demonstrates a protective effect on vascular endothelial cells in vitro. Small non-randomized trials to assess DF for the prophylaxis of VOD were promising without significant anticoagulant effects. Methods:Eligibility criteria included pts <18 years with myeloablative SCT and at least 1 of the following high risk criteria for VOD: conditioning with busulfan and melphalan, pre-existing liver disease, 2nd myeloablative transplant, allo-SCT for leukemia in 2nd relapse, macrophage activating syndromes, prior abdominal irradiation, prior gemtuzumab, osteopetrosis, and adrenoleukodystrophy. Pts were prospectively randomized to the control arm (no prophylactic DF) or to receive DF 25mg/kg/day IV from the start of conditioning until D+30 post SCT. All pts diagnosed with VOD received DF for treatment. Primary endpoint: incidence of hepatic VOD by D+30 using modified Seattle criteria (2 or more of the following: bilirubin > 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by abdominal ultrasound. A blinded independent review committee of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. Incidence and severity of graft versus host disease (GvHD) was assessed. As the true incidence of VOD in this population was unknown, the trial incorporated a planned adaptive interim analysis to be reviewed by an independent DSMB. Results:Based on the recommendations of the DSMB, 360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all randomized pts who signed informed consent (DF: 180; control: 176). Median age was 4.8 years; 24% infants, 52% children (ages 2-11 years) and 23% adolescents. 41% were female, 59% male. 68% were allo-, 31% auto-SCT. There were no significant differences between the two arms in disease types or risk factors. Ninety-three percent (93%) of the patients completed the primary endpoint at day +30. In the ITT analysis, 12% (22/180) of the pts of the DF arm and 20% (35/176) of the control group developed VOD by D+30 (P=0.054); in the PP analysis, the VOD incidence was 12% (20/164) vs 21% (35/169) (P=0.037). VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The composite score (assessing VOD morbidity and mortality) was significantly in favor of the DF arm (P=0.034). Significantly less acute GvHD by D+100 was reported in the DF pts (32% (57/180) vs 43% (75/176); P=0.023 by Wilcoxon test). Observation of VOD in either arm led to a higher mortality: mortality of pts with VOD equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Renal failure was observed in 1% (2/180 pts) of DF pts vs 6% (10/176) of the control (P=0.017); respiratory failure was observed in 7% vs 9% (NS); and encephalopathy in 1% vs 2% (NS). SAEs were experienced by 58% of the DF pts vs 59% of the control, including infections (24% vs 27%) and respiratory disorders (12% vs 9%); 9 hemorrhagic events were seen in the DF arm compared to 21 in the control. Conclusions:This Phase II/III randomized study demonstrates the efficacy and safety of DF in preventing VOD in pediatric pts at high risk of VOD. Use of prophylactic DF results in a 40% reduction in the incidence of VOD. Consistent with the role of DF in endothelial protection, both renal failure and acute GvHD were significantly lower in the DF arm. Safety of DF was confirmed by lack of significant toxicity (including hemorrhage). DF can be recommended for the prevention of VOD in this high risk population. Disclosures:Corbacioglu:Gentium S.p.A.: Consultancy, Research Funding. Massaro:Gentium S.p.A.: Consultancy. D'Agostino:Gentium S.p.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hoyle:Gentium S.p.A.: Employment. Iacobelli:Gentium: Employment.

Incidence of Veno-Occlusive Disease with IV in Busulfan Children Is Higher Than Expected: Preliminary Results of the VOD-DF Trial.

Abstract 3344Poster Board III-232 Background:Hepatic VOD is a life-threatening complication following SCT with a high incidence in children. Development of VOD is one of the most common causes of early death after SCT. Busulfan (BU), an alkylating agent with a very narrow therapeutic index is a commonly used conditioning agent in pediatric stem cell transplantation (SCT) with a strong correlation between AUC and both efficacy and toxicity. Oral BU (poBU) has significant age-related and interpatient pharmacokinetic differences and was linked with an increased risk for VOD. IV busulfan (ivBU) yielded promising results in some studies to be associated with low toxicity profile, especially with a reduced incidence of VOD. Methods:Patients <18 years with myeloablative SCT were included in a prospective multicenter phase II/III trial to evaluate the efficacy of Defibrotide (DF). Eligibility criteria included conditioning with BU (iv and po) and melphalan (MEL). Pts were prospectively randomized to the control arm or to receive DF. Primary endpoint was the incidence of hepatic VOD by D+30 using modified Seattle criteria (2 or more of the following: bilirubin > 2 mg/dL, hepatomegaly, ascites and/or unexplained weight gain > 5%). VOD was assessed by physical exam; hepatomegaly and ascites were confirmed by ultrasound. A blinded IRC of 3 expert hematologists confirmed the diagnosis of VOD. Although the study was not powered to assess mortality, a composite score was assessed as a secondary endpoint that incorporated VOD-associated toxicity (respiratory failure, renal failure, encephalopathy) and mortality. The additional analysis of the influence of BU on VOD was not planned and is therefore explorative. Results:360 pts were enrolled between January 2006 and January 2009 by 28 centers in the EU and Israel. An Intent-to-Treat (ITT) analysis was performed on all pts who signed informed consent (n=356). 251 (71%) pts from the ITT population were conditioned with BU (64% ivBU; 36% poBU). 202 (55%) were treated with BU and Melphalan (MEL) (60% ivBU; 40% poBU). In 49 (14%) BU was used without MEL (80% ivBU; 20% poBU). In children <2yrs 44 (12%) were conditioned with BU/MEL (59% ivBU; 41% poBU) and 26 (7%) were conditioned without MEL (85% ivBU; 15% poBU).The median age of patients with iv BU was 3.65 yrs and 5,13 yrs with poBU; 28% infants, 50% children (ages 2-11 yrs) and 22% adolescents (evenly distributed). 45% female, 55% male (evenly distributed). Allo-SCT was performed in 69% with ivBU and 46% with poBU (remaining with auto-SCT). The diagnoses were evenly distributed between poBU and ivBU. Except in AML 18% were conditioned with ivBU and 32% with poBU. Preexisting liver disease was present in 23% ivBU and 9% poBU pts, of which 46% (17/37) ivBU and 37% (3/8) poBU had elevated transaminases. Overall VOD was experienced by 23% of the infants, 14% of the children and 13% of the adolescents. The overall incidence of VOD in pts treated with BU was 18%. VOD was diagnosed in 24% ivBU vs 8% poBU pts. In pts treated with BU/MEL VOD was diagnosed in 16%. VOD in ivBU/MEL was 21% (26) vs 8% (6) in poBU/MEL. In BU without MEL VOD was diagnosed in 27% (13/49). 31% (12/39) in ivBU pts and 10% (1/10) in poBU pts. In infants treated with BU/MEL the incidence of VOD in the ivBU group was 23% (6/26) and 11% (2/18) in poBU. In BU without MEL in infants the incidences were 41% (9/22) ivBU versus none (0/4) in poBU. The diagnosis of VOD independent of severity was associated with a higher mortality and equaled 24.6% (14/57) compared to 7% in pts without VOD (21/299). Respiratory failure was observed in 10% (16/161) of ivBU vs 2% (2/90) of poBU pts (9% (11/122) vs 1% (1/80) iv vs po BU/MEL); renal failure in 5% (8/161) ivBu vs 1% (1/90) poBU (5% (6/122) vs none in iv vs po BU/MEL). The incidence of multi-organ-failure (MOF) by day +100 was 12% (19/161) in ivBU vs 3% (3/90) in poBU (p=0.022). Compared to all other pts the risk to develop VOD in infants treated with allo-SCT and ivBU is 2.4 times higher (p=0.003). Conclusions:Although the scope of this trial was not to assess the influence of BU on the incidence of VOD and there was an imbalanced distribution of liver diseases and a potential bias for other risk factors the incidence of VOD in ivBU was unexpectedly high especially in infants. Inasmuch this is due to a high interpatient variability of the AUC should be explored prospectively. Disclosures:Corbacioglu:Gentium S.p.A.: Consultancy, Research Funding.

5-Year Follow-up of Patients with Relapsed/Refractory CLL Treated with Standard Chemotherapy with or without Oblimersen in Randomized Phase III Trial: Prognostic Factors and Predictive Factors for Treatment Effect

Background: A randomized Phase 3 trial was performed to compare the efficacy and safety of fludarabine/cyclophosphamide (Flu/Cy) combined with oblimersen (OBL; Genasense®; G3139) or administered alone in patients (pts) with relapsed or refractory CLL. The primary objective was to compare the proportion of pts who achieved complete response (CR, including nodular partial response) between treatment arms.Methods: Pts (N = 241) were stratified according to response to prior fludarabine therapy (relapsed [sensitive] versus [v] refractory); number of prior regimens (1 to 2 v 3 or more), and duration of response to last therapy (> 6 months v ≤ 6 months) and randomly assigned (1:1) to treatment arms. Treatment included up to six 28-day cycles of OBL 3 mg/kg/d as a 7-day continuous IV infusion and Flu 25 mg/m2/d IV over 20 to 30 minutes followed by Cy 250 mg/m2/d IV over 30 to 60 minutes on days 5, 6, and 7, or the Flu/Cy regimen alone on days 1, 2, and 3. Response was determined according to National Cancer Institute-Sponsored Working Group guidelines (Cheson et al, J Clin Oncol, 1996), based on determinations of an independent hematopathologist and expert hematologist who were blinded to treatment. Univariate and multivariate analyses of protocol-specified prognostic factors for overall survival were performed. Five-year survival data were recently collected.Results: The primary endpoint was met; the CR rate was 17% in the OBL + Flu/Cy arm and 7% in the Flu/Cy arm (p = 0.025). Only 7 subjects were lost to 5-year follow-up. Univariate analyses confirmed the prognostic value of the trial stratification factors for survival. In addition, baseline beta-2 microglobulin (< 4 mg/L v ≥ 4 mg/L) and baseline serum LDH (< ULN v ≥ ULN) were highly prognostic (p< 0.0001). Multivariate analyses showed that the number of prior regimens, age (< 65 years v ≥ 65 years), baseline beta-2 microglobulin (< 4 mg/L v ≥ 4 mg/L), and baseline serum LDH (< ULN v ≥ ULN) were prognostic for survival. Among all prognostic factors examined in multivariate analyses, a significant interaction with treatment was detected only for fludarabine sensitivity. Maximum benefit with OBL was observed in fludarabine-sensitive pts (OBL + Flu/Cy arm, 51 pts; Flu/Cy arm, 50 pts), ie, those who had a partial response or better for ≥ 6 months after their last prior fludarabine-containing therapy and then relapsed. The median age of fludarabine-sensitive pts was 64.0 years in both arms; 80% and 70% of these pts were men in the OBL + Flu/Cy arm and the Flu/Cy arm, respectively. Disease-related findings, prognostic factors, and prior treatments among fludarabine-sensitive pts were similar in the 2 treatment arms. The proportion of fludarabine-sensitive pts with CR was significantly greater in the OBL + Flu/Cy arm (25%) than in the Flu/Cy arm (6%; p = 0.016). With 5-year follow-up, there was a statistically significant survival benefit in the OBL + Flu/Cy arm among fludarabine-sensitive pts (hazard ratio = 0.50; p = 0.004; see figure). [Display omitted] Conclusions: In the setting of relapsed/refractory CLL in a randomized Phase III trial, the number of prior regimens, age, beta-2 microglobulin, and serum LDH were prognostic for survival based on multivariate analyses. Fludarabine sensitivity was predictive of the treatment effect of the OBL + Flu/Cy regimen, and a 50% reduction in the risk of death was observed among fludarabine-sensitive pts treated with OBL in addition to a standard Flu/Cy regimen.

The First European Conference on Infections in Leukaemia – ECIL1: A current perspective

The First European Conference on Infections in Leukaemia – ECIL1 – was organised under the auspices of the Infectious Diseases Group of the European Organisation for Research and Treatment of Cancer (EORTC), the Infectious Diseases Working Party of the European Group for Blood and Bone Marrow Transplantation (EBMT), the Supportive Care Group of the European LeukaemiaNet (ELN) and the International Immunocompromised Host Society (ICHS). The objective of the meeting was to develop evidence-based guidelines for the management of bacterial and fungal infections in high-risk immunocompromised adult leukaemia patients and hematopoietic stem cell transplantation recipients. The conference was held on September 30th and October 1st, 2005 in Juan-les-Pins, France and brought together a panel of 59 expert haematologists, oncologists, microbiologists, infectious disease specialists and clinical trialists from across Europe, Israel and Australia. The ECIL1 Guidelines were formulated after lengthy discussion, debate and panel consensus on the findings from a relevant comprehensive literature search, results of a European current practice questionnaire and other international guidelines, specific to each of the six clinical areas examined. The final recommendations, published in the Supplements of this journal as a series of six manuscripts in 2007, were well received by the medical community. The ECIL1 organisers anticipated the need for regular review of these guidelines and the Second ECIL Conference was held in September 2007. Publication of the updated and expanded ECIL2 Guidelines is forthcoming. This paper provides a concise summary of the methodology and main recommendations of the ECIL1 Guidelines.

5,10‐methylenetetrahydrofolate reductase (MTHFR) polymorphisms and the risk of acute lymphoblastic leukemia (ALL) in Filipino children

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme in folate metabolism. Polymorphisms at the C677T and A1298C loci are associated with reduced activity; consequently more folate substrates are shunted toward thymidylate and DNA synthesis. Several studies have reported a reduced risk of developing ALL in children with MTHFR polymorphisms. The objective of this study was to determine the association between MTHFR polymorphisms and ALL in Filipino children. We conducted a case control study in children diagnosed with ALL at the Philippine General Hospital from 1/2001 through 12/2005. Bone marrow aspirate slides were reviewed by two expert hematologists to verify the morphologic diagnosis of ALL. DNA was isolated from the slides and MTHFR polymorphisms, C677T and A1298C, were determined using Taqman real-time PCR. Cord blood of healthy Filipino newborns served as control. There were a total of 191 ALL and 394 controls genotyped. The distribution of C677T polymorphisms was similar in the two groups (P = 1.0). However, for A1298C, there was significantly more AC and CC genotypes in the ALL compared to controls (P = 0.02; OR 1.57; CI: 1.08-2.28). The 1298C allele frequency for the control group was 36.8% and 677T allele frequency was 9.9%. A1298C polymorphisms is associated with an increased risk for ALL in Filipino children. This may be due to a difference in leukemia biology or to a high prevalence of folate deficiency in Filipinos. Our study reiterates the gene and environment interaction in leukemogenesis.

Pattern of Single Agent Rituximab Usage in Indolent Lymphoma and CLL beyond GELF and NCI Criteria.

The GELF criteria and NCI guidelines are accepted for treatment initiation for indolent lymphomas and CLL. However, the lower toxicity of single agent rituximab (SAR) compared with chemotherapy may affect treatment initiation. We sought to evaluate what criteria hematologists (n=12) in our institution used when treating indolent lymphoma and CLL with SAR.Methods: A complete data set of all patients(pts)receiving rituximab (R) at MSKCC from 05/02 through 05/07 was compiled. Pts were eligible for this study if they received SAR for indolent lymphoma or CLL without prior R for at least 6 months. A second treatment cycle given ≥6 months later after progression of disease (POD) was included. In contrast, in the absence of POD, subsequent courses of R maintenance to consolidate or maintain a prior response were excluded. Pts with previously transformed lymphoma were ≥five years from any aggressive lymphoma. The presence or absence of GELF criteria, FLIPI score, IPI score, Rai stage and NCI guidelines for the treatment of SLL/CLL was assessed.Results: SAR was given 285 times in 240 pts. 92 (32%) were treatment naive. Histologies included follicular lymphomas (FL) grades 1 and 2 (n=107), FL grade 3 or not otherwise specified (n=31), SLL/CLL (n=59), marginal zone (=54) and other indolent lymphomas (n=34). The pts ranged in age from 22 to 90, with a median age of 66. IPI scores: low risk in 159 (56%); FLIPI scores: low risk in 66 (58%). Additionally, among SLL/CLL patients, 42 out of 59 (71%) were classified as having Rai Low Risk disease. At treatment initiation 167/285 (59%) met no GELF criteria. Within histologic subsets the prevalence of GELF treatment indications did not differ substantially with respect to prior therapy, although NCI treatment guidelines were more prevalent among treatment naive patients with SLL/CLL than in relapsed pts.GELF and NCI Criteria by Histologic Subset and Prior Treatment PriorPrior RXNo GELFGELFNo NCI SLL/CLLIndicationNCI SLL/CLLIndicationFL (n=138)No (n=50)31 (62%)19 (38%)Yes (n=88)52 (59%)37 (41%)Non-FLL/SLL/CLL(n=88)No (n=43)29 (67%)14 (33%)Yes (n=45)28 (62%)17 (38%)SLL/CLL (n=59)No (n=30)8 (27%)22 (73%)12 (40%)18 (60%)Yes (n=29)11 (38%)18 (62%)15 (52%)14 (48%)For the subset of SLL/CLL pts, the presence of newer, adverse prognostic factors was determined including high ZAP-70, high CD38+, and unmutated VH gene. VH gene mutation status was not evaluated in any patient before immunotherapy. CD38 levels were checked in 28/59: 19 high positive, 2 low positive, and 7 negative. ZAP-70 was evaluated in 13/59 cases: 6 high positive, 3 low positive, and 4 negative. Physicians often stated more than one indication for therapy. The most common stated impetus for treatment was progression (63%). The justification for therapy involved symptoms in 6% of cases, threatened end-organ function in 16%, cytopenias in 10%, bulky disease in 5%, patient preference in 4%, histologic transformation in 1%, and other reasoning in 19%.Conclusions: At our institution, expert hematologists treating indolent lymphomas and CLL used criteria beyond GELF and NCI indications to justify therapy with SAR in more than half the patients receiving such therapy. This likely reflects the drug's low toxicity and, possibly, a desire to spare patients from future chemotherapy. This finding has significant implications for resource allocation. Future studies may demonstrate whether relatively early use of SAR results in diminished chemotherapy usage over a patient's lifetime.

Recommendations on haematological criteria for the diagnosis of epoetin‐induced pure red cell aplasia

Pure red cell aplasia (PRCA) is a rare condition characterised by an arrest in red blood cell production, which may be congenital or acquired. Recombinant human erythropoietin (epoetin) was introduced in 1989 for the treatment of anaemia of chronic kidney disease patients and has maintained an excellent therapeutic and safety record while treating hundreds of thousands of patients. A very rare, but serious adverse event associated with epoetin administration is a condition in which patients develop neutralising anti-erythropoietin antibodies and, consequently, PRCA. This condition is referred to as epoetin-induced PRCA (epo-PRCA). Since it is a rare condition, many haematologists and nephrologists around the world see the condition infrequently and may be uncertain about the diagnosis. For this reason, an ad hoc international working group of expert haematologists and nephrologists met together to derive new recommendations for the haematological diagnosis of epo-PRCA. These recommendations, which represent the consensus opinions of the working group, address haematological approaches to monitor and investigate suspected epo-PRCA and should help physicians differentiate between PRCA and other bone marrow diseases, as well as, between PRCA and epo-PRCA.

Histologic verification of leukemia, myelodysplasia, and multiple myeloma diagnoses in patients in Ukraine, 1987-1998.

In preparation for a possible large epidemiological study of radiation-related leukemia in Chernobyl clean-up workers of Ukraine, histologic evaluation of 62 cases of leukemia and related disorders was conducted by a panel of expert hematologists and hematopathologists from the United States, France, and Ukraine. All cases were randomly selected from a surrogate population of men in the general population of 6 regions of Ukraine who were between the ages of 20 and 60 years in 1986 and were reported to have developed leukemia, myelodysplasia, or multiple myeloma between the years 1987 and 1998. The hematologists and hematopathologists on the panel were in agreement with one another and with the previously reported diagnoses and classifications of about 90% of the cases of acute and chronic leukemia in the study. These results suggest that strong reliance can be placed on the clinical diagnoses of acute and chronic forms of leukemia and multiple myeloma that have occurred in Ukrainian Chernobyl clean-up workers providing that the diagnoses are supported by records of the patients having had adequate histologic bone marrow studies. The number of cases in this study with the diagnosis of myelodysplasia, however, was too small to draw firm conclusions.

External Irradiation with Roentgen Rays and Radium in the Treatment of Human Leukemias, Lymphomas, and Allied Disorders of the Hemopoietic System

Roentgen therapy has its established place as a valuable palliative procedure in the treatment of human leukemias, lymphomas, and allied diseases. Its general and local effects in these disorders have been the subject of numerous reports by expert radiologists and hematologists. In the last decade radioactive isotopes and recently the nitrogen mustards have been added to the therapeutic arsenal against these diseases. The purpose of this presentation is to furnish an introduction to the papers2 on treatment with these new methods rather than to contribute anything new. As a basis for comparison with the results, complications, ad vantages, and limitations of the therapeutic use of these new compounds, we have reviewed 337 cases of blood dyscrasias treated by external irradiation in Billings Hospital (University of Chicago). Material The 337 cases represent the number of patients accepted for irradiation therapy from 1929 to 1945. The total number of patients with blood diseases seen in the clinics and in the hospital during that period could not be determined. The series consists of patients with leukemia, Hodgkin's disease, lymphosarcoma, and polycythemia rubra vera. The small number of patients with polycythemia rubra is included because in this group strides forward with the new agents have been made. In all cases of Hodgkin's disease and lymphosarcoma the diagnosis was verified by biopsy. In 33 per cent of leukemias confirmation was obtained by bone marrow aspiration or biopsy, lymphnode biopsy, or autopsy. Table I shows the number of cases in each group and some pertinent data. The distribution of the diagnoses is similar to that reported by Craver for the lymphoblastomas seen at Memorial Hospital, New York (3). The most frequently treated condition in both instances was Hodgkin's disease. We were able to keep track of the largest number of patients, relatively, in the leukemia group. Therapy The routine treatment in all four groups of disease was roentgen therapy given as local irradiation. Table II indicates the limited use of total body or wide-field spray irradiation, radium therapy, and chemical agents supporting or replacing roentgen irradiation. The chemicals were Fowler's solution in myelogenous leukemia, used systematically over long periods, radioactive phosphorus in polycythemia rubra, and nitrogen mustards in selected cases of all groups. Radical excision of a localized enlarged lymph node, which was the only sign of the disease, was performed in a single case of Hodgkin's disease. Supportive treatment with blood transfusions, iron, vitamins, adequate diet, plenty of rest, exposure to fresh air and sunshine, was used on a large scale and found to be of great importance in all groups. The roentgen ray quality used by us for the treatment of these conditions is h.v.l. 1.5 mm. Cu (200 kv., 1.0 mm. Cu plus 1.0 mm. Al filter).