Initial LDH Research Articles

No Differences in the Treatment Outcome in T-Cell Acute Lymphoblastic Leukemia/Lymphoma Regarding the Initial Bone Marrow Blasts Count: Results of the Russian Acute Lymphoblastic Leukemia (RALL) Study Group

IntroductionT-cell acute lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) originate from the common T-cell precursors and are formally differentiated by bone marrow blast count with less than 25% considered as T-LBL. ALL treatment protocols are successfully applied with quite similar long-term results in both entities. Dose intense chemotherapy is proposed to be the best option. RALL is conducting a prospective multicenter trial in the treatment of Ph-negative adult ALL patients based on the opposite approach - non-intensive but non-interruptive treatment (NCT01193933). T-LBL pts were included in the study.So we decided to define whether the difference in response rate and long-term results exists in T-ALL and T-LBL patients treated according to RALL-2009 protocol.Patients and MethodsThe therapy was unified for all Ph-negative ALL pts, but in T-cell ALL/LBL autologous hematopoietic stem cell transplantation (auto-HSCT) after non-myeloablative BEAM conditioning was scheduled as late intensification (+3-4 mo of CR) followed by prolonged 2 years maintenance. From Jan 2009, till Jul 2016, 30 centers enrolled 107 T-ALL/LBL pts. Median age was 28 years (15-54 y), 34 f / 73 m; early T-cell (TI/II) phenotype was verified in 56 (52.3%), mature (T-IV) - in 10 (9.4%), thymic (TIII, CD1a+) ALL - in 41 pts (38.3%). T-lymphoblastic lymphoma (T-LBL= <25% b/m blasts) was diagnosed in 22 pts (20,5%). We divided the analyzed population into 3 groups: < 5% b/m blasts, with 5-24%, ≥25%. Pts’ characteristics according to the b/m involvement are depicted in Table 1. Autologous HSCT was performed in 35, allogeneic-in 7 pts. The analysis was performed in July 2016.ResultsAs it’s shown in Table 1 the patients with T-LBL disregarding the % of blasts cells (<5% or 5-24%) have much less initial WBC and LDH levels, more frequent mediastinum involvement, less frequent CNS disease in comparison with T-ALL patients. There were no patients with pro-T-subtype (T1) T-LBL comparing with 42% of patients with pro-T-ALL. Mature T-subtype was slightly more frequent (4/22 vs 6/85) (p=0,1) in T-LBL. Total CR rate in 97 available for analysis patients was 87,6% (n=85), induction death was registered in 5,1% (n=5), resistance-in 7,2% (n=7). All induction deaths occurred in T-ALL patients, resistant cases were registered much more frequently (p=0,01) in T-LBL with less than 5% of blast cells than in T-ALL (3/10 vs 4/85). Only 35 of 85 (41,2%) CR pts underwent autologous HSCT due to logistics problems and refusals. Auto-HSCT was done at a median time of 6 mo from CR and pts proceeded to further maintenance. We compared 5-y disease-free survival (DFS) and probability of relapse (RP) in transplanted pts and those who survived in CR ≥ 6 months (land-mark) receiving only chemotherapy. This analysis was carried out in 2 cohorts of patients: T-LBL (<5%; 5-24%) and T-ALL (≥25%). Land-mark analysis demonstrated the essential benefit of auto-HSCT only for T-ALL patients: DFS from time of transplantation was 95% and from land-mark for chemotherapy group - 61% (p=0,005), RP-5% vs 30% (p=0,02). But in T-LBL pts there were no benefit of autologous HSCT over chemotherapy (DFS -100% vs 86%, RP-0% vs 14%, p=0,3). At 5 years overall survival (OS) for the whole T-ALL/T-LBL group constituted-66%, DFS-76%. There were no differences in OS (77% vs 66%, p=0,8) and in DFS (87% vs 74%, p=0,7) in T-LBL and T-ALL.ConclusionsOur data demonstrate that non-intensive, but non-interruptive treatment approach is effective as in T-ALL so in T-LBL. T-LBL patients had no induction mortality but more frequently were reported as having resistant disease on RALL-2009 protocol. Auto-HSCT after BEAM conditioning followed by maintenance provided substantial benefit only for patients with T-ALL, but not T-LBL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

No Major Differences in Outcomes Between the Initial and Relapse Episodes in Patients with Thrombotic Thrombocytopenic Purpura: The Experience from the Ohio State University Registry

Background:Thrombotic thrombocytopenic purpura (TTP) is characterized by consumptive thrombocytopenia and microangiopathic hemolytic anemia. At least a third of the patients with TTP will have one or more relapses throughout their life. There is very little data regarding the differences, if any, in clinical presentation and outcomes between the initial and subsequent TTP episodes. This information is relevant to understand if patients that present initially and those that present with a relapse can be seen as equal when being considered for clinical trials. Identifying the characteristics of patients that are prone to relapse will help guide the monitoring of patients after an acute episode of TTP to help to prevent relapse.Methods:Between March 2003 and June 2016 we collected clinical and laboratory data on all patients that presented to the Ohio State University with a diagnosis of acquired TTP (aTTP). The diagnostic criteria for aTTP included: thrombocytopenia, and a microangiopathic hemolytic anemia without an alternative explanation. The diagnosis was confirmed by the finding of severely deficient ADAMTS13 activity (<10%). Patients were consented to participate in our TTP registry and the information obtained included initial clinical presentation, platelets, LDH, kidney function, ADAMTS13 activity and inhibitor titer, number of plasma exchange (PEX) to achieve remission (defined as number of PEX needed to obtain a normal platelet count), and the outcome of the episode; clinical response (normal platelet count and LDH), exacerbation (recurrent TTP within 30 days of last PEX procedure), refractory (more than 30 PEX needed to obtain a clinical response), or death.Results:- All the patients enrolled were included in the study, except those with active cancer, leaving a total of 125 episodes from 57 patients.- 36 of the 57 patients had two or more TTP episodes (relapse rate 63.1%), with 21 of the 57 patients having 3 or more episodes. The time between episodes varied greatly, from 2 months to 8 years.- Of the 125 episodes, there were 42 initial and 83 relapses.- The initial group presented with central nervous system (CNS) symptoms more commonly than the relapse group. They also had significantly lower platelets and a higher LDH than the relapse group.- Regarding treatment, there was no significant difference in the number of PEX needed to achieve remission between the 2 groups. However, there was a significant number of patients in the initial group that needed more than 5 PEX to achieve remission, compared to the relapse group (p<0.0001)- There were no significant differences in the main clinical outcomes between the initial and relapse groups in rates of clinical response (p=0.267), exacerbation (p=0.483), refractory (p=0.075) or death (p=0.066)Conclusions:In their first episode of TTP, patients may present more ill than those patients having relapses (with more CNS symptoms, lower platelets and higher LDH), and may also require more PEX sessions to achieve remission. However, these findings do not change outcomes, and patients in their initial presentation and relapses can be seen as equal in terms of clinical response, exacerbation, refractory disease, and mortality rates. The high relapse rate seen in our registry may be due to the prolonged follow up (13 years) which is more than other series reported. Patients may have a relapse even after several years of being stable. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Therapeutic Efficacy of VICP+L-ASP/TKI on Adult Patients with B-ALL

To evaluate the therapeutic efficacy of VICP+L-ASP/TKI on adult patients with B-ALL and to explore the influence factors. Forty-one adult B-ALL patients treated with VICP+L-ASP/TKI from August 2008 to June 2014 were following-up. The complete remission(CR) rate, toxicity, overall survival(OS) and event free survival(EFS) after induction treatment were analyzed, the therapeutic outcome of patients between different risk stratification subgroups was compared, the influence of standardized consolidatory and maintaining treatment as well as allogeneic hematopoietic stem cell transplantation(allo-HSCT) on survival time was analyzed. The early death not occurred in 41 patients with B-ALL including 37 cases with CR; the CR rate of 1 course treatment was 90.2%. The follow-up time lasted to March 17, 2015, the median follow-up time was 25(9-79) months; the 1 year OS rate was 75.3%, the EFS rate was 58.3%. Analysis of risk factors showed that the initial WBC count over 30×109/L, LDH over 250 U/L and minimal residual disease(MRD) over 10-4 after treatment were poor prognostic factors. After remission, the standardized consolidatory treatment or allo-HSCT according to the "2012 China adult ALL diagnosis and treatment expert consensus" could improve long-term survival, 3 years OS rate was 73.8% and 61.5% respectively, 3 years EFS were 63.5% and 65.7% respectively. The main toxic and side effects were hematologic reactions, the hematologic adverse reaction of IV grade was observed in 97.6%(40/41) during induction treatment. Induction chemotherapy based on VICP+L-ASP/TKI and standardized consolidatory after remission according to the "2012 China adult acute lymphoblastic leukemia diagnosis and treatment expert consensus" can improve the therapeutic efficacy. The allo-HSCT should be actively performed for B-ALL paients with high risk(elevated initial WBC count and LDH level); at some time, the regularly monitoring MRD and adjusting therapeutic protocol according to monitoring result can promote the prognosis of adult B-ALL patients.

Outcome of t(4;14) in Multiple Myeloma – Princess Margaret Cancer Centre Experience Over the Last 10 Years

Translocation (4;14) is identified by FISH cytogenetics in approximately 15% of myeloma patients (pts). Pts with this translocation have a poor outcome characterized by initial response to induction chemotherapy but followed by rapid relapse and resistance to alkylating agents. Recent studies have suggested that novel agents such as bortezomib may improve both event-free survival and overall survival (OS). We reviewed the outcome of 74 consecutive myeloma pts with t(4;14) managed at Princess Margaret Cancer Centre between October 2002 and July 2012. Our goal was to evaluate the impact of specific pts' characteristics on OS and to assess outcome according to treatments received. Clinical characteristics at time of diagnosis for the 74 myeloma pts with t(4;14) are presented in [table 1][1]. The average age was 57 years (range 31-82 years) and 58% were male. Pts received a median of 2 lines of therapy (range 1-6). Of the 69 pts requiring treatment, 46% of pts received one year of bortezomib as part of the Canadian t(4;14) clinical trial, 32% of pts were treated with novel agents including bortezomib (given for an average of 4 months) and lenalidomide, 22% of pts received conventional treatment such as dexamethasone alone, thalidomide and/or melphalan. 20 pts underwent autologous stem cell transplantation (ASCT) as part of their first line treatment; 16 were single ASCT, 4 were tandem ASCT. The overall response rate to induction chemotherapy was 70%, with 60% complete response/very good partial response and 10% partial response. The median OS was 5 years and 3 year OS was 66%. Presence of p53 significantly decreased the 3 year OS (71% vs 29% for absence and presence of p53, respectively, log-rank p value=0.0017). Median follow-up was 2.43 years (range: 0.24-11.81 years). There was no significant difference in OS based on the type of first line treatment received. The 3 year OS was 69% for pts enrolled in the t(4;14) clinical trial, 65% for pts who received novel agents and 53% for pts who received conventional treatment (log-rank p value=0.33). In a multivariable analysis looking at pts' initial characteristics, p53 deletion, LDH, bone lesions and age at diagnosis were found to be significant predictors of overall survival while ISS staging and immunoglobulin isotype were not found to be significant for overall survival. In conclusion, in our retrospective single institution study, the median OS for pts with t(4;14) was 5 years. Older age, addition of p53 deletion, high LDH and presence of bone disease predicted a worse OS. Although the lack of significant difference in OS based on the type of first line treatment received may be due to the limited number of pts in our study, there was a trend towards improvement in OS for pts that received a bortezomib containing regimen versus those who received conventional agents. While the median OS for pts with t(4;14) in our study has increased compared to historical controls, new therapeutic options are still needed to further improve the outcome in this subset of pts3. 3 Keats JJ et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003 Feb 15;101(4):1520-9. View this table: Table 1 Clinical characteristics for the 74 myeloma pts with t(4;14) Disclosures: Reece: Celgene: Honoraria, Research Funding; Jansen: Honoraria, Research Funding; Onyx: Honoraria; Novartis: Honoraria; BMS: Research Funding; Merk: Honoraria, Research Funding; Millennium: Research Funding. [1]: #T1

Pleural fluid CRP, LDH, and pH as predictors of successful pleurodesis in malignant pleural effusions

BackgroundPleurodesis fails in 10–40% of patients with recurrent malignant pleural effusions (MPEs) and dyspnea. An accurate definition of the different characteristics of the patient would help to identify more precisely the population mostly benefiting from pleurodesis. AimWe aimed to assess the values of the initial pleural fluid LDH, CRP and pH characteristics on pleurodesis outcome for MPEs. MethodsBetween April 2013 and December 2014, 40 patients with MPE were subjected to pleurodesis with doxycycline and were divided into two groups, successful pleurodesis (group I) and failed pleurodesis (group II) according to their radiographic response at the end of the 4weeks follow-up period. Before pleurodesis, pleural tapping and the initial pleural fluid biochemical parameters (Total protein, glucose, PH, LDH and CRP levels) were measured. ResultsAfter 4weeks follow up, the success rate of pleurodesis was 62.5%. In successful pleurodesis, the initial total pleural fluid proteins, pleural fluid LDH and pleural fluid CRP were significantly lower than unsuccessful pleurodesis, with P-values <0.05, <0.001, <0.05 respectively while, pleural fluid glucose was statistically very highly significantly lower at the unsuccessful pleurodesis group (P<0.001). Both groups together revealed positive correlation between pleural fluid LDH at one side and (pleural fluid CRP and proteins) at the other side (P-value<0.01 and <0.05) respectively, while, there was a negative correlation between pleural fluid LDH and pleural fluid glucose (P-value<0.01). The complications of tube thoracotomy and pleurodesis in both successful and failed pleurodesis were higher in unsuccessful pleurodesis than in successful pleurodesis. ConclusionHigh CRP, high LDH and low PH in MPEs have a poorer outcome of pleurodesis. So, it may be advantageous when selecting patients for pleurodesis to include in their routine tests, the initial pleural fluid CRP, LDH and PH levels.

Expression of SLC25A38 in leukemic cells from children with acute lymphoblastic leukemia

This study was aimed to investigate the SLC25A38 expression in pediatric patients with acute lymphoblastic leukemia (ALL) and its clinical significance. A total of 23 newly diagnosed ALL pedictric patients were enrolled in test group, 10 pediatric patients with non-hematologic malignancies were selected as control group. The expression in protein and mRNA levels of SLC25A38 were detected by Western blot and real-time PCR respectively. The results showed that the SLC25A38 protein was positive in 8 of 23 pediatric ALL patients (34.78%), while no positive case was found in 10 controls. The relative expression level of SLC25A38 mRNA was 0.4673 ± 0.05344 in SLC25A38-protein positive group of ALL patients, while that was 1.296 ± 0.2517 in SLC25A38-protein negative group of ALL patients. The expression level of SLC25A38 mRNA in SLC25A38-protein positive group was significantly lower than that in negative group (P = 0.001) . No statistically significant difference was found in comparison of SLC25A38-protein negative group of ALL patients with the control group (P = 0.1097). The analysis of clinical data showed that there were significantly differences in sex, immunophenotype, initial peripheral white blood cell count and LDH between the SLC25A38-protein positive and SLC25A38-protein negative groups (P < 0.05). It is concluded that as a novel protein, SLC25A38 highly expressed in pediatric ALL patients, indicating that SLC25A38 may serve as a molecular marker and potential therapeutic target for acute lymphoblastic leukemia in children.

Outcome Of t(4;14) In Multiple Myeloma - Princess Margaret Cancer Centre Experience Over The Last 10 Years

Translocation (4;14) is identified by FISH cytogenetics in approximately 15% of myeloma patients (pts). Pts with this translocation have a poor outcome characterized by initial response to induction chemotherapy but followed by rapid relapse and resistance to alkylating agents. Recent studies have suggested that novel agents such as bortezomib may improve both event-free survival and overall survival (OS). We reviewed the outcome of 74 consecutive myeloma pts with t(4;14) managed at Princess Margaret Cancer Centre between October 2002 and July 2012. Our goal was to evaluate the impact of specific pts' characteristics on OS and to assess outcome according to treatments received. Clinical characteristics at time of diagnosis for the 74 myeloma pts with t(4;14) are presented in table 1. The average age was 57 years (range 31-82 years) and 58% were male. Pts received a median of 2 lines of therapy (range 1-6). Of the 69 pts requiring treatment, 46% of pts received one year of bortezomib as part of the Canadian t(4;14) clinical trial, 32% of pts were treated with novel agents including bortezomib (given for an average of 4 months) and lenalidomide, 22% of pts received conventional treatment such as dexamethasone alone, thalidomide and/or melphalan. 20 pts underwent autologous stem cell transplantation (ASCT) as part of their first line treatment; 16 were single ASCT, 4 were tandem ASCT. The overall response rate to induction chemotherapy was 70%, with 60% complete response/very good partial response and 10% partial response. The median OS was 5 years and 3 year OS was 66%. Presence of p53 significantly decreased the 3 year OS (71% vs 29% for absence and presence of p53, respectively, log-rank p value=0.0017). Median follow-up was 2.43 years (range: 0.24-11.81 years). There was no significant difference in OS based on the type of first line treatment received. The 3 year OS was 69% for pts enrolled in the t(4;14) clinical trial, 65% for pts who received novel agents and 53% for pts who received conventional treatment (log-rank p value=0.33). In a multivariable analysis looking at pts' initial characteristics, p53 deletion, LDH, bone lesions and age at diagnosis were found to be significant predictors of overall survival while ISS staging and immunoglobulin isotype were not found to be significant for overall survival. In conclusion, in our retrospective single institution study, the median OS for pts with t(4;14) was 5 years. Older age, addition of p53 deletion, high LDH and presence of bone disease predicted a worse OS. Although the lack of significant difference in OS based on the type of first line treatment received may be due to the limited number of pts in our study, there was a trend towards improvement in OS for pts that received a bortezomib containing regimen versus those who received conventional agents. While the median OS for pts with t(4;14) in our study has increased compared to historical controls, new therapeutic options are still needed to further improve the outcome in this subset of pts3.3 Keats JJ et al. In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. Blood. 2003 Feb 15;101(4):1520-9.Table 1Clinical characteristics for the 74 myeloma pts with t(4;14)Clinical characteristicsAverageRange%Hemoglobin (g/L)10051-157Creatinine (μmol/L)13933-796Calcium (mmol/L)2.41.89-3.84B2-microglobulin (mg/L)4.51.58-20.25Albumin (g/L)3518-46ISS stage 145%ISS stage 236%ISS stage 319%Presence of bone lesions68%Mean % of nuclei positive for t(4;14)3%-71.5%25%Presence of del 13q/monosomy 13 by FISH77%Presence of del 17p by FISH10% Disclosures:Reece:Celgene: Honoraria, Research Funding; Jansen: Honoraria, Research Funding; Onyx: Honoraria; Novartis: Honoraria; BMS: Research Funding; Merk: Honoraria, Research Funding; Millennium: Research Funding.

A Modified Glasgow Prognostic Score (mGPS) Based On Systemic Inflammatory Response Is a Useful Indicator to Predict Response and Survival in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

AbstractAbstract 5089Systemic inflammatory responses as evidenced by CRP and albumin have reported as a useful indicator of prognosis in patients with advanced cancers. We retrospectively evaluated the relationship between the systemic inflammation score and survival in 213 patients with DLBCL receiving the first-line R-CHOP chemotherapy between October 2003 and December 2011 at Chonnam National University Hwasun Hospital. Patients were assorted into three groups based on initial serum CRP, albumin and LDH level at diagnosis, as named by ¡°modified Glasgow prognostic score (mGPS)¡±. Patients with elevated CRP (> 1. 0 mg/dL), hypoalbuminemia (< 3. 5 g/dL) and elevated LDH (> 1¢¥ upper normal value) were assigned a score of 2. Patients in whom one or two of these biochemical abnormalities was present were assigned of 1. Patients in whom neither of these abnormalities was present were assigned a score of 0. In Cox multivariate analysis, the independent poor prognostic factors for progression free survival (PFS) were mGPS 2 (HR 5. 415, 95% CI 2. 028–14. 454, P = 0. 001), ECOG PS ¡Ã 2 (HR 3. 504, 95% CI 1. 655–7. 419, P = 0. 001), and bulky lesion ¡Ã 10cm (HR 2. 030, 95% CI 1. 037–3. 972, P = 0. 039). In addition, the independent poor prognostic factors for overall survival (OS) were mGPS 2 (HR 5. 898, 95% CI 2. 028–14. 454, P = 0. 001) and ECOG PS ¡Ã 2 (HR 3. 525, 95% CI 1. 642–7. 567, P = 0. 001). The overall response rate, including complete response and partial response, for the R-CHOP chemotherapy was decreased according to the mGPS; 96. 7% at mGPS 0, 87% at mGPS 1, and 75% at mGPS 2 (P = 0. 009). This study suggest that the modified Glasgow prognostic score (mGPS) based on systemic inflammatory responses (CRP, albumin and LDH) was a useful prognostic indicator for OS and PFS and also a reliable method to predict the response for R-CHOP chemotherapy in patients with newly diagnosed DLBCL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Outcome and relapse risks of thrombotic thrombocytopaenic purpura: an Egyptian experience

BackgroundThrombotic thrombocytopaenic purpura (TTP) is a rare life-threatening disease. Plasma exchange has significantly decreased the mortality from this disease, which still tends to recur in a substantial proportion of patients....

Primary Central Nervous System Lymphoma (PCNSL) in Immunocompetent Patients: An Analysis of Prognostic Factors and Treatment Strategies

Abstract 4955 Background:The incidence of primary CNS lymphoma in immunocompetent patients is increasing for unknown reasons. Survival estimates from academic centers show an improvement in overall survival (OS) while community epidemiological data estimate minimal difference in OS in the last thirty years. Age greater than 60, poor performance status, elevated initial LDH, high CSF protein and involvement of deep regions of the brain have been associated with worse survival. Optimal dosing strategies and delivery of chemotherapy as well as the role of radiation therapy (RT) have yet to be clearly defined given the limitations of treatment related toxicity in patients achieving remissions. Purpose:To characterize the PCNSL patient population treated at a single institution by studying prognostic factors and assessing OS according to treatment strategies. Methods:45 cases of confirmed CNS Lymphoma diagnosed at Rush University Medical Center between January 2000 and November 2010 were studied. Demographic, clinical and treatment data were collected and reviewed. Hospital records and the Social Security Death Index were used to determine death dates. Survival data were compared based on treatment groups. Results:23 of the 45 cases met all inclusion criteria and had no evidence of previous systemic lymphoma or pre-morbid immunocompromised conditions (i.e. HIV). The age range at diagnosis was from 21 to 81 years old with a median age of 68. One patient had ocular involvement. Three patients had malignant cells in the CSF at diagnosis and 4 patients had multifocal tumors. Biopsies revealed one case of a cerebral T-cell lymphoma and 22 were diffuse large B-cell lymphoma (DLBCL). Elevated CSF protein above the mean (96.1 mg/dl) was associated with worse OS (p=0.02). Elevated LDH above the mean (227 U/L) was associated with worse OS (p= 0.039). Age, performance status and location of tumor within the brain (deep vs. superficial) did not correlate with survival patterns. Comparative survival analysis between treatment groups revealed no statistically significant difference (p=0.134). In addition to systemic chemotherapy, 15 patients received intrathecal chemotherapyTreatment StrategiesSingle-agent chemotherapy onlyPoly-chemotherapy onlyRT onlyPoly-chemotherapy +RTSingle-agent chemotherapy +RT# patients291101 Conclusions:The description of PCNSL in immunocompetent patients outside of the clinical-trial setting is necessary to inform prospective trial designs. This study supports the use of LDH and CSF protein in determining prognosis and treatment strategy. This analysis of conventional treatment is ongoing. Collaboration on gathering descriptive data for PCNSL in immunocompetent patients should be pursued. Disclosures:Gregory:Genentech:.

Association of primary mediastinal B-cell lymphoma (PMBL) in children (C) and adolescents (A) with a significantly inferior prognosis: Final results of the FAB/LMB 96 trial

10001 Background: Single pediatric cooperative group studies have demonstrated an EFS ranging from 65 - 75% in C &amp; A with large cell lymphomas arising in the mediastinum (Lones/Cairo et al, J Clin Oncol, 2000; Burkhardt/Reiter et al, Br J Haematol, 2005; Seidman/Reiter et al, J Clin Oncol, 2003). Recently, Staudt and Shipp have independently demonstrated that following gene expression profiling by oligonucleotide microarray that PMBL resembles more like classical Hodgkin lymphoma than diffuse large B-cell lymphoma with enhanced NF-κB pathway gene expression (Rosenwald et al, J Exp Med, 2003; Abramson et al, Blood, 2005). It remains to be determined what the optimal therapy for C &amp; A with PMBL is and if poor outcome subgroups can be identified. Methods: We analyzed the results of C &amp; A with PMBL treated with group B therapy on FAB/LMB 96 (Patte/Cairo et al, Blood, 2007). Results: There were 528 patients with stage III/IV disease treated on group B therapy on FAB/LMB 96 resulting in a 2 yr EFS of 84% (CI95: 82–86%). Forty-two of these patients had PMBL; M/F: 26/16; 10 - 14 vs 15 -19 yrs: 28/14; and LDH &lt; 2 vs ≥ 2 upper normal: 20/22. Response to COP reduction: 1 CR (100%), 33 IR (20–99%) and 7 NR (&lt; 20%). There was no significant difference in EFS with respect to age, gender, COP response and initial LDH. 5 yr EFS and OS were 54% (CI95: 38–68%) and 73% (CI95: 56–84%), respectively. 5 yr EFS was significantly inferior compared to the remainder of the other patients with stage III disease treated on group B therapy (54%: CI95 38–68% vs 85%: CI95 81–88%) (p &lt; 0.001). Conclusions: PMBL in C &amp; A is associated with a significantly inferior EFS compared to other histological forms of stage III/IV mature B-NHL. Alternate treatment strategies including consideration of underlying biological differences need to be developed to improve EFS in C &amp; A with this poor-risk sub-group of mature B-NHL. No significant financial relationships to disclose.

Nucleation and growth of oriented layered hydroxides on polymer resin beads

Two types of layered metal hydroxides (layered Mg/Al double hydroxides and cobalt hydroxides) have been grown on the surface of cation-exchanged polymer resin beads. SEM images of the Mg/Al double hydroxide that nucleated on the surface of the Mg2+/Al3+-exchanged resin beads show it to have an initial LDH shell of ca. 150 nm and that this shell is constructed from a monolayer of LDH crystallites aligned edge-on. At longer reaction times LDH particles grow on top of this shell and lie flat on the surface. The overall thickness of the LDH coating is ca. 180 nm and it has been shown to have uniformly grown on the surface of the polymer bead. Layered α and β-type cobalt hydroxide can also be grown on the surface of Co2+-exchange resin beads.

Isolated rat ventricular myocytes retain protection afforded by in vivo hypoxic preconditioning or chronic hypoxia

Both hypoxic preconditioning (HP) and chronic hypoxia (CH) protect the heart against injury caused by acute oxygen deprivation. The aim of the study was to find out whether the protection was preserved in ventricular myocytes isolated after HP and CH of intact rats. Animals were exposed to normobaric hypoxia (10% O2) for 8, 24 h or 21 days followed by 24 h of normoxia. Myocytes were isolated from the left (LVM) and right (RVM) ventricles and the septum (SEPM), and subjected to 25 min of “anoxia” (metabolic inhibition) followed by 30 min of reoxygenation (A/R). Viability and LDH release were evaluated at the beginning of the experiment, after anoxia, and after reoxygenation. Neither HP nor CH affected the viability of the myocytes per se. Initial LDH (total and released) did not differ in LVM and SEPM from any hypoxic group; in contrast, CH doubled LDH in RVM. Both HP and CH increased the viability after A/R of LVM and SEPM more than twice compared to normoxic controls (HP: 80% and 83%, CH: 70% and 79%, controls: 33% and 39%, respectively). The RVM of the CH group exhibited a somewhat smaller protection (59% vs. 32% in the controls), possibly reflecting a negative influence of hypertrophy. Similar protective effects were observed when LDH release was measured just after anoxia. LDH release after A/R was significantly lower in HP groups compared to normoxic controls while protection afforded by CH was less pronounced (HP: 109%, 107% and 114%, CH: 117%, 125% and 125%, controls: 132%, 129% and 139% in LVM, SEPM and RVM, respectively). In conclusion, the protective effects of both HP and CH were retained in subsequently isolated cardiomyocytes subjected to an acute A/R protocol. Although the increase in viability was comparable, protection against irreversible A/R injury (LDH release) was somewhat greater in myocytes isolated from HP rats compared to CH animals.

Randomized Comparison of Standard Induction with Daunorubicin (DNR) for 3 Days vs Idarubicin (IDA) for 3 or 4 Days in AML pts Aged 50 to 70 and of Maintenance with Interleukin 2. Final Analysis of the ALFA 9801 Study.

Background: For many years the ALFA Group has used high dose DNR, i.e 80 mg/m2/day for 3d as part of the induction regimen for untreated adult AML pts. As the equivalence of DNR and Ida is not known we conducted a phase III study to compare high dose DNR to Ida. We also tested the effect of IL2 for maintenance.Methods: Newly diagnosed AML, aged 50 to 70 years, were randomized to receive AraC 200 mg/m2/day IV x 7 d with either DNR: 80 mg/m2/d x 3 d (arm 1) or Ida: 12 mg/m2/d x 3 d (arm 2) or x 4 d (arm 3). Pts who failed could receive a salvage course with Mitoxantrone x 2 d and AraC1g/m2 12 hrs x 4d. Response was assessed after induction+/− salvage chemotherapy. CR pts received 2 consolidation courses according to the induction arm with DNR: 80 mg/m2 or Ida:12 mg/m2 for 1 day (first course) or 2 days (2nd course) and AraC:1g/m2/12 hrs x 4 days. Pts in CCR after the two consolidation courses were randomized to receive or not a maintenance immunotherapy with IL2: 5.106/m2 for 5 days monthly for12 months.Results: From 2001 to 2006, 468 pts were included (median age: 60 years). The 3 treatment arms were well matched for pretreatment characteristics. CR was achieved in 360/468 pts (77%): 109 (70%) pts arm 1, 129 (83%) arm 2, 122 (78%) arm 3 (p=0.02).70 pts, (45%) pts in the DNR arm reached CR after 1 course vs 97 (62%) and 90 (57%) in Ida arms (p= 0.006). Pts in Ida arms experienced more grade 3 or 4 mucositis (p=0.004) but no differences were observed between the 3 arms for duration of hospitalization, time to PMN or plts recovery, incidence of grade 3 or 4 infectious episodes and treatment related mortality. 3 year cumulative incidence of relapse was 69%, 63%, 62% resp in arms 1,2,3 (p=NS). 3 year EFS was 19%, 30%, 26% resp (p=0.06 for arm 1 vs arms 2 and 3). 3 year OS was 31%, 40% 41% resp in arms 1,2,3 (p=NS). Age (< or >60 years), sex, initial WBC counts, initial LDH (nl or >nl), DNR or Ida arms, need for a salvage course were not predictive for relapse, while 2yCIR was 43%, 64%, 77% among respectively fav, intermediate and unfav cytogenetic risk groups resp (p=0.0046). Of the 219 pts alive in CR after consolidations, 161 (73%) were randomized for maintenance. Only 22 of the 77 pts randomized for IL2 completed the 1 year treatment. 32 and 23 pts stopped IL2 resp because of relapse or intolerance. There were no differences in relapse or OS in both maintenance arms.Conclusion: Ida treatment even when compared to high doses of DNR yields higher CR rate and more CR after one course. This effect translated in slightly better EFS but not better CIR or OS. IL2 maintenance treatment at least as scheduled in this trial was difficult to apply and showed no impact on disease course.

RISK-adapted treatment of Burkitt’s lymphomas in childern

9034 Background and Purpose: Various treatment regimens have been implemented in an attempt to improveDFS of children with B cell lymphoma. We evaluates the treatment results of children with stage I, II III Burkitt’s lymphoma at 2 centers in Egypt. Patients and Methods: Patient recruitment in this open non-randomized study occurred from July 1998 to Dec 2002 . 97 patients with pathologically proven Burkitt’s lymphoma stage I to III were diagnosed . All patients were subjected to history, clinical examination, CSF, bone marrow and radiological evaluation. Patients with stage IV were excluded from. Patients with stage I and II received 4 cycles of (A→B→A→B), while patients with stage III received 8 cycles of (A→B→A→B→A→B→A→B). Intrathecals were given during the first 4 cycles. Cycle A was formed of cyclophosphamide, adriamycin, vincristine, cytosine arabinoside, plus intrathecal MTX and cytosine arabinoside. Cycle B was formed of ifosfamide, vepeside, methotrexate, vincristine and intrathecal cytosine arabinoside and mtx. Results: Patients was 97, their age ranged between 2 and 18, theirmean age was 8.6 and median was 8 years.The male to female ratio was 3.8:1. The primary site was the abdomen in 49 patients (50%), peripheral lymph node enlargement was encountered in 38 patients (39.1%). Jaw involvement occurred in 7 patients (7.2%). Two patients (2%) presented with Tonsilar mass and only one patient presented with mass at inner canthus (1%). Patients were staged according to St. Jude staging system. Patient distribution was as follows: Stage I, 18 (18.6%); stage II, 31 (32%); stage III, 48 (49.5%). In August 2003, 90 patients were in continuous complete remission with a follow up period ranged between 8 months and 53 months and a median 39 months. The projected 3 years DFS for the whole group was 93.8%±2.5%. Correlation between DFS and LDH was significant (P=0.01) while correlation with age, sex and stage was insignificant. Conclusions: Treatment result with the prescribed protocol is extremely good. The outcome of non advanced Burkitt’s lymphoma in rural areas of Egypt is comparable to all studies in developed countries. High dose methotrexate is not a must to improve survival of stage I-III Burkitt’s lymphoma. Initial serum LDH level is an important prognostic factor. Key words: Childhood, Burkitt’s lymph. No significant financial relationships to disclose.

Prognostic value of circulating KL‐6 in idiopathic pulmonary fibrosis

Circulating levels of KL-6, a high MW glycoprotein (MUC1 mucin), are elevated in a majority of patients with a number of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). However, KL-6 levels vary from patient to patient. The aim of the present study was to determine whether the serum KL-6 level at the time of diagnosis predicts prognosis in IPF. The relationship between clinical variables and prognosis in 27 patients with IPF were analysed retrospectively. The diagnosis was made by histological examination (n = 16) or on clinical findings including high-resolution CT scanning (n = 11). All patients were followed up for at least 3 years. Variables such as age, FVC%, PaO(2) at rest, initial LDH level, C-reactive protein and KL-6 were used for analysis. At the cut-off level determined by receiver operating characteristic curves, LDH and KL-6 showed a significant correlation with the patient's prognosis by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of prognosis. The patients were categorized by their serum KL-6 levels (as above or below the cut-off level of 1000 U/mL) and their survival estimated using the Kaplan-Meier method. The difference in median survival between the two groups was significant. The median survival of patients with low KL-6 was more than 36 months, whereas that of patients with high KL-6 was only 18 months. These results suggest that initial evaluation of serum KL-6 level can predict survival in patients with IPF.

Prognostic Model for Aggressive Non-Hodgkin Lymphoma.

There are two subgroups of the untreated lymphomas according to the outcome of the disease: indolent and aggressive. Unlike the indolent lymphoma, aggressive lymphomas are fatal in several weeks or months if untreated. However, the therapy available nowadays makes this group of patients with aggressive Non-Hodgkin's lymphoma curable. Autologous stem cell transplantation used as first-line therapy can improve overall survival in selected group of patients with aggressive Non-Hodgkin lymphoma. To make the right and optimal therapeutic approach we need to stratify those patients in subgroups of patients with "high" and "low" risk, which was achieved with this study. This study comprises 211 patients with histopathology diagnosis of aggressive Non-Hodgkin's lymphoma treated at the Department of Hematology in the period 1989–2002, which gave us the observation period of 6 to 183 months. There were 88 male patients, median age 53 years and 60 female, median age 52 years. Most of the patients were in the advanced clinical stage at the disease on the initial presentation of the disease, 24% of the patients in the third stage and 43% in the fourth stage. Bone marrow infiltration was found in 29%. Bcl-2 positively was confirmed in 26 cases by imunohistochemistry and there was proliferative index Ki-67 above 60% in 32 patients. Imunophenotipisation suggested that 80% of the cases are B-cell lymphoma. The patients were treated with antracicilin included regiments, most of them being CHOP regiment. After initial chemotherapy complete remission was achieved in 60%, partial response in 4% and there was no response in 32% with early deaths in 4%. At the end of the study 32% of the patients were alive and well, 32% were deceased and the reminder had unknown status. There was relapse of the disease in 50 patients with previous complete remission. According to the univariante analysis the following parameters had significantly influence the overall survival in the patients with aggressive Non-Hodgkin's lymphoma: initial anemia, initial LDH, the stage of the disease, ECOG score, bone marrow infiltration, number of sites of extranodal infiltration, lymphoma subgroup according to various classification systems, morphology of the lymphoma cell, imunophenotype profile, percent of Ki-67 positively, bcl-2 positively, time to complete remission. The multiply progression analysis produce mathematical model through which we can anticipate the expected survival in each patients individually based on the statistically most influential prognostic markers, those achieving stratification of the patients in risk groups. In our study 32% of the patients with "high" risk are alive and "low risk patients have 70% 5-years overall survival. With the use of this prognostic model for aggressive Non-Hodgkin's lymphoma we achieved risk based stratification of the patients even in the fourth stage of the disease with statistical significance. This prognostic model for aggressive Non-Hodgkin's lymphoma enables the clinical hematologist to create the optimal individual therapeutic approach for each patient with aggressive Non-Hodgkin's lymphoma. The patients with "high" risk are group of patients where beside the standard chemotherapy, use of aggressive chemotherapy and haematopoetic stem cell transplantation as well as the new therapeutic approaches would improve therapeutic results and overall survival.

Tumor Burden Related Immunodeficiency in Lymphoma Patients and Clinical Course.

The association of lymphoma with a plethora of secondary immune defects is well established. However, most investigations were performed many years ago and little is known about disease specific alterations of the immune system. From January 2003 to August 2004 50 patients with newly diagnosed malignant lymphoma were analyzed and compared with 50 healthy volunteers Corresponding in age and gender. Parameters of cellular and humoral immunity, including CBC, FACS analysis of lymphocyte subpopulations, cytokines (sIL2-R, IL-6, IL-10, TNF-a), serum complement components C3c, C4, CH50 and total concentrations of serum immunoglobulin IgG, IgM, IgA were measured. The median number of CD3+ and CD4+ lymphocyte subsets (p≤0.01) were significantly lower in lymphoma patients compared with matched healthy volunteers. The number of CD8+ T-cells was decreased in patients with bulky disease (p≤0.01). High-intermediate/high risk lymphoma (IPI 3-4 or aaIPI 2-3) had significantly higher CH50 (p=0,02), C3c (p≤0,01), sIL2-R (p≤0,01) and TNF-a levels (p=0,05) than patients with low/low-intermediate risk lymphoma. Infectious complications after chemotherapy (n=14) occurred frequently in patients with high initial LDH (p=0,04), low number of CD4+ (p=0,02) or CD8+ T-cells (p=0,04) and high levels of sIL2-R (p=0,02) or TNF-a (p=0,03). Relapse (n=6) was also observed in patients with decreased CD8+ T-cells (p=0,04) and in patients with high C4 levels (p=0,02). These results indicate that tumor burden in lymphoma patients significantly influenced the number of lymphocyte subsets, serum cytokine levels (sIL2R, TNF- a) and complement components (CH50, C3c). IPI-score and clinical course (infections and relapse) were related to the immunodeficiency. We conclude that measurement of peripheral blood lymphocyte subsets, cytokines and complement factors can be expected to improve existing methods of risk assignment in lymphoma.

Central Nervous System (CNS) Relapse in Adult Patients with Acute Lymphoblastic Leukemia (ALL): Frequency and Prognosis in 467 Patients without Cranial Irradiation for CNS Prophylaxis.

Background. Recurrence of ALL in CNS in adults is considered a poor prognostic feature but few studies have analyzed this issue. The objective of this study was to analyze the frequency, prognosis and predictive factors of CNS involvement and recurrence in adult patients with ALL treated with 4 PETHEMA protocols not including cranial irradiation for CNS prophylaxis.Methods. From June 1989 to December 2003, 467 adult patients (≥ 15-years-old) diagnosed with ALL were treated with one of the four consecutive protocols of PETHEMA group: ALL-89 (standard and high risk, n=108), ALL-93 (high risk, n=222), ALL-96 (standard risk, n=84), and ALL-97 (Burkitt's leukemia, n=53). CNS prophylaxis consisted of intrathecal (IT) injection of methotrexate (12 mg), cytarabine (30 mg) and hydrocortisone (20 mg), for 12–14 courses, together with high-dose systemic methotrexate and cytarabine during the early intensification phase. Cranial or craniospinal irradiation was not used in any case.Results. The median (SD) age was 33 (16) years and 272 (58%) were males. ALL type according to the FAB classification was: L1 28%, L2 61%, L3 11%. Immunological subtypes were: early-pre-B 15%, common 45%, pre-B 5%, mature B 11% and T 24%. CNS involvement at diagnosis was observed in 18 (3.9%) patients. Predictive factors for CNS involvement at diagnosis were: L3/mature B ALL (p<0.0001) and testicular involvement (p=0.006). Overall, complete remission (CR) was achieved in 381 (81%) of the patients, of whom 159 (42%) relapsed: 137 (36%) in bone marrow (BM) and 22 (5.8%) in CNS (14 isolated and 8 combined CNS and BM). The median (range) CR duration prior to CNS recurrence was 1.06 yr (95%CI0.11–2.01) for isolated CNS relapse, 0.6 yr (95%CI o.30–0.89) for combined relapse and 0.93 (95%CI 0.78–1.07) for BM relapse (p=0.76). No correlation was found between initial CNS involvement and CNS relapse. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse (p<0.001). Treatment of CNS relapse consisted of systemic and IT therapy in the 22 cases (cranial irradiation was added to one) and CR was attained in 7 (32%) out of 22 of these patients. Stem cell transplantation was performed in 4 patients and 3 patients developed a second CNS recurrence. The median overall survival (OS) after recurrence was 0.7 yr for isolated CNS relapse, 0.13 yr for combined relapse and 0.41 yr for BM relapse (p=0.11).Conclusions. The frequency of CNS relapse in adult ALL patients receiving IT and systemic therapy for CNS prophylaxis is similar to that observed in protocols including cranial irradiation. An initial LDH value > 1,000 U/L was the only factor associated with higher risk of CNS relapse. Adult patients with CNS recurrence have a poor prognosis, although it is not different from that observed in BM relapses.

HYPOTHERMIC MACHINE PERFUSION OF RAT LIVERS PRESERVES ENDOTHELIAL CELL FUNCTION

P26 Aims: The present study was conducted to investigate the effects of starch content of the preservation solution during hypothermic machine perfusion (HMP) on hepatic microcirculation and heptocellular function in an isolated perfused rat liver model. Methods: Livers isolated from male Sprague-Dawley rats (200-250g) were perfused with the University of Wisconsin (UW)-lactobinate solution (HMP group, n=6), modified UW solution (starch omitted) (HMP w/o starch group, n=6) at 0.4 ml/min/gliver or statically stored in the UW solution (SCS group, n=5) at 4°C for 24 hr. Following preservation, livers from HMP, HMP w/o starch, SCS and control group (without preservation, n=7) were perfused with Krebs-Henseleit Buffer solution at 37°C for 30 min. Samples were taken every 10 min during 30 min warm perfusion to assess hepatocellular damage and function (LDH and bile production). Endothelial cell function and permeability were determined by hyaluronic acid (HA) uptake and multiple indicator dilution (MID) method, respectively. Results: After 24hrs hypothermic preservation, HMP livers showed significant lower initial LDH level (110.1 ± 9.8 U/L) than HMP w/o starch (271.9± 46.7 U/L) and SCS groups (725.1 ± 138.3 U/L) (P < 0.05). After 30min rewarming, HMP displayed significantly lower LDH level (220.1 ± 55.1 U/L in HMP vs. 1371.3±215.9 U/L in HMP w/o starch, 884 ± 71.9 U/L in SCS, P < 0.05), higher bile production (0.82 ± 0.14 in HMP vs. 0.56 ± 0.05 in HMP w/o starch, 0.32 ± 0.08 in SCS unit: μl/min/g liver dry wt, P < 0.05). Endothelial cell function was also improved as indicated by HA uptake (18.6±2.3% in HMP vs. 8.9±2.4% in HMP w/o starch, 13.9±3.6% in SCS) and shorter transient time for albumin were observed in MID experiments (23 s in HMP vs. 49 s in HMP w/o starch, 43 s in SCS, P < 0.05) after 30 min rewarming. Liver wet and dry ratio and histological findings also confirmed ameliorated edema in the tissue of the HMP liver compared with the HMP w/o starch and SCS livers. Conclusions: These results suggest that the HMP with the UW solution improved endothelial cell function compared with SCS and HMP w/o starch following 24hr preservation resulting in less hepatocellular damage. These results also suggest that oncotic support appears to be an important component in preserving hepatic microcirculation.